Painful spinal metastases have been treated with conventional radiotherapy for decades, but one-third of the patients have insufficient pain relief after treatment and one-fifth need retreatment. Stereotactic radiotherapy is a method to increase the dose in the spinal metastases with a potentially longer lasting palliative effect without increasing the side effects of the treatment and thereby is expected to improve the quality of life significantly.This study is a multicenter prospective randomized clinical trial comparing conventional radiotherapy (1 x 8Gy) with stereotactic radiotherapy (1 x 20Gy) for pain reduction and quality of life in patients with painful spinal metastases. A total of 386 patients will be randomized between the two treatment groups. Besides pain measured by the Dutch Brief Pain Inventory, quality of life and cost-effectiveness also will be measured. The primary outcome is pain reduction at 6 weeks after treatment. Secondary outcomes will be the time to pain response, duration of pain relief, health-related quality of life and toxicity, as well as cost-effectiveness.This study investigates whether stereotactic radiotherapy with dose escalation for symptomatic spinal metastases can lead to improved pain reduction as compared to conventional radiotherapy without an increase of treatment-related side effects. These results will contribute to the optimization and individualization of the treatment for the patient.NCT02407795 .ClinicalTrials.gov identifier  Many patients diagnosed with cancer have already metastasized disease or will metastasize in time. When there are no curative options, treatment will be focused on maintaining optimal quality of life. Up to 70 % of all bony metastases are located in the spinal column. Spinal vertebral metastases can give serious pain complaints, which are likely to progress in time and thereby decrease the quality of life . BesidesConventional radiotherapy has been used for decades for palliation of pain caused by bone metastases. Patients are treated in a single or multiple fractions. Generally, a reduction in pain will occur in two-thirds of patients within 4 to 6 weeks after irradiation. Retreatment is necessary in up to 24 % of all patients . BecauseStereotactic body radiotherapy (SBRT) allows dose escalation to the spinal vertebra or paraspinal tumor with steep dose gradients that limit exposure to the spinal cord and other organs at risk. As the dose to the non-involved organs at risk is strongly reduced, fewer side effects will be expected compared to conventional radiotherapy. Due to the biologically higher dose that can be given to the target volume compared to conventional radiotherapy, better results are anticipated, especially when more radio-resistant tumors like renal carcinoma or melanoma are treated. Another question to be answered is whether we can identify a subgroup of patients that will benefit more from high dose stereotactic irradiation as compared to the conventionally used single fraction of 8Gy radiotherapy.No data are available from randomized clinical trials comparing the standard 8Gy to SBRT high dose, nor are there dedicated phase I dose escalation studies. The total dose and the fractionation schemes have been mainly dependent on the physician . The firThe aim of this study is to investigate whether stereotactic radiotherapy for symptomatic spinal metastases can lead to improved pain reduction as compared to conventional radiotherapy, without an increase of treatment related side effects and thereby result in a better quality of life. The primary objective is pain reduction, but we also focus on the duration of pain relief as an important secondary endpoint besides quality of life and cost-effectiveness. To answer these questions, an intensive scheme of time points for questionnaires and pain scores will be used. These results will contribute to the optimization and individualization of the treatment for the patient.This is a multicenter, prospective randomized clinical trial to investigate pain reduction after radiotherapy. Two different radiation doses will be evaluated: 1 x 20Gy by SBRT and 1 x 8Gy conventional radiotherapy.The primary objective is to investigate whether stereotactic radiotherapy for symptomatic spinal metastases can lead to improved pain reduction as compared to conventional radiotherapy without an increase of treatment-related side effects. The primary endpoint will be pain reduction after treatment. Secondary endpoints are time to pain response, duration of pain relief, quality of life, and toxicity. In addition, cost-effectiveness will be studied.Patients must be able to undergo radiotherapy and fulfill the eligibility criteria. The diagnosis of a solid tumor must be pathologically confirmed to make the patient eligible for the study. The extent of the metastases in the spine should be visualized on an MRI, no longer than two weeks before randomization or no longer than 6 weeks before the start of treatment. To determine the clinically relevant category of stability, the Spinal Instability Neoplastic Score (SINS) will be obtained and documented prior to treatment. Earlier studies showed that the sensitivity of SINS for potentially unstable or unstable lesions was 95.7 %, with a specificity of 79.5 % , 15. WriThe study is designed to be carried out in multiple centers in the Netherlands. Patient randomization will only be allowed from authorized investigators, their authorized staff members, or data manager. A patient can be randomized only after verification of eligibility. In case a patient is eligible and a written informed consent is obtained, the randomization form must be faxed or digitally sent to the Data Center. Randomization will be performed using a password-protected database (OpenClinica). Patients will be stratified on primary tumor type , Karnofsky performance status (60 to 70 versus 80 to 100) and number of spinal metastases .Histologically proven solid tumor with radiological diagnosis of spinal metastasesPain score minimum 2 on an 11-point scale (0 = no pain to 10 = worst imaginable pain)Maximum of two consecutive or noncontiguous spinal segments involved by tumor at current level of interestGross tumor optimally > 3 mm from the spinal cord on MRIKarnofsky performance status ≥ 60WHO 0-1-2Life expectancy > 6 weeksAge ≥ 18 yearsNonpregnant, nonlactating female patients. Sexually active patients of childbearing potential must implement effective contraceptive practices during the studyWritten informed consentInclusion criteria are as follows:History of previous radiotherapy to the spine at the current level of interest or overlapping locationChemotherapy or targeted systemic therapy within 14 days of radiotherapySpinal instability or neurological deficit resulting from bony compression of neural structuresPathologic fracture or impending fracture needing surgical fixationPrior surgery to the spine at the current level of interest or overlapping locationGross tumor < 3 mm from the spinal cord on MRIMore than 25 % spinal canal compromisePatients with a pacemaker such that MRI cannot be performed or the treatment cannot be delivered safelyPatients not able to undergo MRIEarlier nuclear medicine treatment for example strontium 89 treatmentPregnancyAltered mental status that would prohibit the understanding and giving of informed consentExclusion criteria are as follows:Days 0 to 14: their daily average, worst and present pain, intake of medication (dosage), and effect of medication (BPI)Days 0, 7, and 14: effect of their pain on quality of life items Weeks 4 and 6 and months 2, 3, 4, 6, 9, 12, and thereafter, every 6 months with a maximum of 5 years or until death, both the BPI and QOL questionnaires. Concomitant use of analgesics should be noted.Time to response is calculated from the date of randomization. Pain is self-reported by the patient and will be measured by an adjusted version for daily use of the Dutch Brief Pain Inventory (BPI). The BPI assesses pain on a 0–10 scale, where 0 is no pain and 10 is worst imaginable pain. It also has a questionnaire that consists of questions on severity of pain, impact of pain on daily function, location of pain, pain medications, and amount of pain relief in the past 24 hours or the past week. It is a short questionnaire that requires 5 minutes to complete. The BPI has been validated in more than 25 different languages. Response to treatment is calculated taking into account changes in the administration of opioids. Quality of life will be assessed using the EORTC QLQ-C15-PAL and the EORTC QLQ-BM22 –18. ThesPost-treatment diagnostics should be performed according to the institutions routine guidelines. Recurrence of disease should preferably be confirmed using MRI. Tumor growth less than 25 % is classified as stable disease. Data needed for re-irradiation and the occurrence of spinal cord compression and/or fractures, along with data on systemic treatment are collected at 3-month intervals at the institutes.The pain score will be divided into four response categories for analyses. Complete response (CR) is defined as a pain score of 0 at the treated site, with no concomitant increase in analgesic intake. Partial response (PR) is defined as a pain reduction of 2 or more at the treated side on a scale of 0 to 10 without analgesic increase, or an analgesic reduction of 25 % or more from baseline without an increase in pain. Pain progression (PP) is defined as an increase in pain score of 2 or more above baseline at the treated site with stable analgesic intake or an increase of 25 % or more in analgesic intake compared with baseline with the pain score stable or 1 point above baseline. Stable pain (SP) is defined as any response that is not captured by the complete response, partial response, or pain progression definitions. Responders are defined as CR + PR; nonresponders are defined as PP + SP.For conventional radiotherapy, a single dose of 8Gy will be given using a linear accelerator with at least 6 MV photons. Preferably patients are treated using the ICRU guidelines, but there are no restrictions formulated with respect to the radiation technique. Patients should be treated according to the standard treatment protocol per institution.For stereotactic treatment 1 x 20Gy), patients will be prepared with a dedicated CT simulator in treatment position with an immobilization device as used per institution. Standard position is supine, no prone position is allowed. Scans should be matched with the pretreatment (diagnostic) MRI images as they provide better delineation of the tumor and the spinal cord than the simulator CT scan. Target volumes are defined according to the ICRU Reports 50 and 62 and according to the International Spine Radiosurgery Consortium Consensus Guidelines for Target Volume Definition in Spinal Stereotactic Radiosurgery Gy, patie. CircumfThe primary outcome of interest in this study is a reduction of pain of 2 points at 6 weeks since baseline. The literature shows that in patients with conventional radiotherapy the percentage of patients with pain reduction ranges from 66 % to 72 %. We assume that the percentage of patients with pain reduction is 70 % in the group with conventional radiotherapy compared to 85 % in the group with stereotactic radiotherapy. Therefore, 135 patients are needed in each group to obtain a power of 80 % . We adjust for a drop-out rate of 30 % and will include a total of 386 patients. The primary analysis will be the comparison between the two treatment arms of the proportion of patients with pain reduction, defined as a decrease in pain score of at least 2 points from initial pain score, at 6 weeks. Time to pain progression, radiation-induced fracture and/or death will be calculated from date of randomization to the documentation. For the calculation of response, no fixed time interval from the date of randomization will be applied. Response of treatment will be calculated if at least two successive follow-up pain scores are available.The protocol has been written and will be conducted according to the ICH Harmonized Tripartite Guideline for Good Clinical Practice. The study protocol was approved by the Central Dutch Medical Ethical Committee of the Radboud University Medical Center Nijmegen (2014). The regulations regarding medical confidentiality and data protection are fulfilled.The aim of this trial is to test the hypothesis that stereotactic radiotherapy gives a better and longer lasting reduction of pain, better local control, and therefore a better quality of life without an increase of treatment-related side effects compared to conventional radiotherapy for symptomatic spinal metastases. Recent trials and reports using SBRT show excellent local control and a fast pain reduction in 1 to 2 weeks when treating painful spinal metastases , 22–26. Quality of life is an important issue in cancer patients at all stages of disease. Quality of life is affected by many factors such as the disease itself, but also psychological and social factors. In patients with pain, the quality of life can be impaired due to the pain or the disease itself but also by the multiple treatments to which patients are exposed. The minimization of hospital visits is important. Furthermore, the analgesics can give side effects that may have a negative impact on the quality of life. Radiotherapy can reduce pain resulting from bone metastases and reduce analgesic use and it side effect, thereby improving the quality of life . KnowledThe question to be answered is whether we can identify a subgroup of patients that will benefit from a high dose stereotactic irradiation and consequently have a better quality of life as compared to the frequently used single fraction of low-dose conventional radiotherapy. This in order to optimize and to individualize the treatment options for the patient.This trial began in May 2015 and is currently recruiting.


Intra-articular (IA) injection of hyaluronic acid (HA) into the hip joint appears to be safe and well tolerated but only a small number of randomized clinical trials in humans has been published. The objective of this prospective study was to evaluate the efficacy and safety of a single IA injection of high-molecular-weight (2800 kDa) HA (Coxarthrum) for hip osteoarthritis.All patients received a single IA administration of 2.5 % sodium hyaluronate (75 mg/3 mL) of high molecular weight. Fluoroscopy requires an iodized contrast medium  which highlights the capsule before administering HA. Patients were evaluated before IA injection (T0), after 3 months, after 6 months and after 1 year from injection. Results were evaluated by the Brief Pain Inventory (BPI II), Harris Hip Score and a visual analog scale of pain (pain VAS). All treated patients were considered for statistical analysis.p < 0.001). Changes in pain score compared to the previous visit were statistically significant for the worst pain in the second quarter post-intervention (p = 0.037) and for mean pain in the second semester post-intervention (p = 0.043) The evolution of the Harris Hip Score was statistically highly significant (p < 0.001) between T0 and the following visits ; after a significant change between T0 and T0 + 3 months, the score remained stable. The evolution of the pain VAS showed a statistically highly significant improvement (p < 0.001) between T0 and T0 + 3 months; thereafter it remained stable from the first quarter post-intervention. No serious adverse event was noted; 12 cases (0.5 %) of pain associated with transient synovitis are noteworthy.Two hundred seven patients were included at T0. The mean age was 67 years (range 46–81). Regarding BPI severity score, changes in pain between T0 and the three following visits were statistically highly significant (This study shows that a single IA injection of Coxarthrum is effective from the third month and that the results are stable or continue to improve up to 1 year.IV. Osteoarthritis has a very high prevalence globally. It is a source of pain and deterioration of joint function, with important socioeconomic consequences. The related pain is poorly evaluated by doctors, who underestimate its intensity when the pain is reported by the patient as being high, and overestimate it when it is reported as being weak . The incN-acetylglucosamine; it is a constituent of synovial fluid in normal and osteoarthritic joints and is synthesized by chondrocytes and synoviocytes [Optimal management of osteoarthritis requires a combination of non-pharmacological and pharmacological modalities. Among the latter are injections of intra-articular (IA) hyaluronic acid (HA), first isolated in 1934 by Karl Meyer in the vitreous humor; the first human clinical use of IA HA in the treatment of knee arthritis was made in 1975, and the first trials date back to 1980 [viocytes . HA has HA may be useful in patients with knee or hip osteoarthritis. The symptomatic benefit is delayed in comparison with that of intra-articular injections of corticosteroids, but it is prolonged. The IA injections of HA are widely used and recommended in existing guidelines as a useful therapeutic modality to treat patients with knee osteoarthritis; there is less experimental evidence of efficacy for hip arthritis than for knee arthritis .IA injection of HA into the hip joint appears to be safe and well tolerated  but onlyData from a meta-analysis in knee arthritis suggested that the heterogeneity between trials might be due to the higher MW products having greater efficacy. Indeed, HA preparations may broadly be classified according to their MW and formulation type: solutions of low MW 500–1200 kDa), solutions of high MW (6000 kDa), cross-linked HA and solutions of non-animal stabilized HA (NASHA) –12.00 kDa, sAs a consequence, the objective of this prospective study was to evaluate the efficacy and safety of IA injection of a single dose of high MW (2800 kDa) HA (75 mg/3 mL)  for hip osteoarthritis.The study protocol was approved according to the modalities planned by Ethical Committee. We conducted a single-center, prospective, unblinded study. After baseline (T0), patients were to be reviewed at 3, 6 and 12 months. Inclusion criteria were age more than 40 years, mono- or bilateral hip arthritis with X-ray proof of at least partially preserved joint space (Kellgren–Lawrence stage 2–3 ), good o® software (version 9.2). At each study time , mean, standard deviation and median endpoints were calculated. For the same endpoint, comparisons were made at different study times using Student’s t test for paired samples. Results were considered statistically significant for values of p < 0.05.All treated patients were considered for statistical analysis, which was performed in SAS2) was 22.8 (range 18.8–29.9). Radiological evaluation of osteoarthritis showed a Kellgren–Lawrence stage 2 in 83 (40.1 %) patients and a Kellgren–Lawrence stage 3 in 124 (59.9 %) patients. The number of included patients who completed the questionnaires in the various planned visits gradually decreased over time; however, data from three-quarters of patients were still available after 6 months, and data from over half the patients after 1 year. The data of pain VAS were less available than those of the BPI II questionnaires and the Harris Hip Score (Table Two hundred seven patients were included at T0. One hundred twenty-six were women 61 %) and eighty-one were men (49 %). The mean age was 67 years (range 46–81). Mean body mass index (kg/m % and eip < 0.001). Changes in pain score compared to the previous visit were statistically significant for the worst pain in the second quarter post-intervention (p = 0.037) and for mean pain in the second semester post-intervention (p = 0.043)  Table . Changesp < 0.001) for the three items describing disturbances of social life . The evolution of the BPI interference score measured against the previous visit was also highly significant (p < 0.001) from the second quarter post-intervention for sleep and for the second semester post-intervention for mood. It was significant (p < 0.05) concerning professional activities for the second semester post-intervention . The evolution of the BPI interference overall score measured against the previous visit was statistically significant in the second quarter post-intervention (p < 0.01) and statistically highly significant during the second semester post-intervention (p < 0.001)  Table .Table 4Ep < 0.001) between T0 and the following visits ; after a significant change between T0 and T0 + 3 months, the score remained stable  between T0 and T0 + 3 months; thereafter it remained stable from the first quarter post-intervention.As for the evolution of the Harris Hip Score, the evolution of the pain VAS showed a statistically highly significant improvement  of pain associated with transient synovitis (during 24 h) are noteworthy.To evaluate the efficacy and safety of a single IA of HA (75 mg/3 mL) of high MW (2800 kDa) (Coxarthrum) for hip osteoarthritis pain management, we included in our study two hundred seven patients. In this unblinded prospective study, changes in all outcome measures were significantly in favor of a single IA injection, whether it was the BPI severity score, the BPI interference score, the Harris Hip Score or the pain VAS. This trend was very clear from T0 + 3 months; then the results remained stable or continued to improve on all these criteria.Only a small number of scientific papers containing statistically significant results about hip IA injection of HA are available in the literature despite the hip being the second most common site of arthritis.Conrozier and colleagues  retrospep < 0.001). No significant differences were observed between the results obtained in the two study groups treated with the different HA molecules [A prospective double-blind study compared the effect of high MW and low MW HA, together with a placebo. In this study 59 patients were evaluated at time intervals of 1, 3 and 6 months after the first infiltration. Similarly to our study, improvement of scores was noted at 1 month and remained significant up to 6 months in both groups compared to the placebo group (olecules .p < 0.007).Berg and Olsson  studied Colen and colleagues  evaluateTo overcome the problem of selectivity and operator-dependent approach to hip viscosupplementation, a clear identification of whether or not the patient is suitable for HA infiltration treatment in the hip is mandatory. Although studies of variability in the efficacy of HA infiltration therapy in the hip compared to the gravity of the hip arthritis have not yet been carried out, it can reasonably be assumed, as reported by knee viscosupplementation studies, that the possibilities of efficacy and duration of the beneficial effects of the treatment are inversely proportional to the gravity of the disease . For thiRecently, to clarify some aspects of viscosupplementation treatment, a review of the literature confirmed that IA HA is an effective treatment for mild to moderate osteoarthritis but it is not an alternative to surgery in advanced cartilage degeneration .Fluoroscopic guidance is one of the possible radiological guidances when performing IA hip injection. Due to the narrow IA space, performing a “blind” hip IA injection is not recommended . UltrasoIn our experience, we observed 12 cases of pain associated with transient synovitis after IA injection. As reported in the literature –24, tranFurther studies are needed on unresolved hip viscosupplementation issues including cost–effectiveness of therapy, relation between molecular weight and effectiveness, and how to best incorporate viscosupplementation into an arthritis therapy algorithm. Our experience proved the efficacy of IA HA injection for hip arthritis treatment.A single dose of HA (75 mg/3 mL) of high MW (2800 kDa) is proving to be safe and effective for pain control in patients with hip arthritis (Kellgren–Lawrence stages 2 and 3) before indications for hip arthroplasty. Viscosupplementation is effective from the third month and the results are stable or continue to improve up to 1 year.


Herpes zoster (HZ) is a painful condition that can have a substantial negative impact on patients’ lives. However, UK-specific data on the debilitating impact of HZ, in terms of patients’ experience of pain and impairments in Health-Related Quality of Life (HRQoL) are limited. The Zoster Quality of Life (ZQOL) study, a large-scale UK cross-sectional study, was conducted to quantify the burden of HZ in UK patients.A total of 229 HZ patients aged 50 years or over were recruited from primary and secondary/tertiary care centres throughout the UK. Patients completed a battery of validated questionnaires, including the Zoster Brief Pain Inventory (ZBPI), the Medical Outcomes Study Short-Form 36 (SF-36) and the EuroQol-5 Dimensions (EQ-5D) on initial presentation to the doctor and again 7–14 days later. At follow-up patients also completed the Treatment Satisfaction with Medication (TSQM) questionnaire. Where available, mean questionnaire scores in the HZ population were compared to scores for age-matched norms to investigate the burden associated with HZ.Pain was prominent among patients, with 57.9% at the initial study visit reporting pain in the preceding 24 hours at levels typically considered to have a significant impact on HRQoL (i.e. ZBPI worst pain ≥ 5). This was reflected in SF-36 and EQ-5D scores that were significantly lower for patients when compared to age-matched norms (p < 0.05) - except for the SF-36 domain of physical functioning. HRQoL was inversely associated with levels of reported pain, with those patients in the greatest amount of pain reporting the greatest HRQoL impact. However, there was no association between pain severity and participant age. The majority of patients (69.4%) received antivirals within 72 hours of rash appearing and 69.9% of patients were also taking analgesics for the management of HZ pain. TSQM scores indicated that patients were least satisfied with the effectiveness of their prescribed treatment.The acute presentation of HZ is a painful experience that can have a significant impact on the physical and mental wellbeing of sufferers. Findings highlight significant unmet need among patients, particularly in terms of the effectiveness of therapies for the management of HZ. Herpes Zoster (HZ), often referred to as ‘shingles’, is a viral condition resulting from reactivation of latent varicella-zoster virus (VZV) which is responsible for childhood ‘chickenpox’ (primary infection). Approximately one in four persons will develop HZ during their lifetime, leading to an estimated 200,000 episodes in the UK annually . IncidenHZ manifests in three phases: prodromal, acute and chronic (i.e. long-term complications that may result from HZ). For many patients, each of the phases is characterised by pain. Diagnosis and treatment occur in the acute phase upon the presentation of a unilateral dermatomal rash, which may occur anywhere on the body but most commonly presents on the trunk. The rash may also be present around the nose and eyes ). The dermatological rash and pain associated with HZ typically resolves within one month of presentation . HoweverPast cross-sectional, epidemiological studies have demonstrated that the pain, and resulting discomfort, associated with HZ and PHN have a substantial and negative impact on patients’ Health-related Quality of Life (HRQoL) and patients’ ability to engage in activities of daily living -11. In aTo date, however, only limited real-world evaluation of the burden of HZ and PHN specific to UK patients has been conducted, and what research has been conducted is limited by relatively small sample sizes and a lack of geographic representation . HoweverTo address this need, the Zoster Quality of Life (ZQOL) study, the first UK-wide real-world study designed to assess the clinical characterisation, patient-reported burden and wider societal burden associated with HZ and PHN was conducted. HZ-specific information derived from the ZQOL study is outlined herein (ZQOL study findings for PHN patients are reported in a separate manuscript) . SpecifiThe ZQOL study adopted a cross-sectional observational design involving data collection from HZ/PHN patients and their treating doctors Figure . No mediA total of 230 HZ patients were targeted for recruitment to the ZQOL to ensure sufficient power for pre-specified primary statistical analyses . This sample size was verified via 100,000 Monte Carlo simulations, using the Hochberg (1988) Step-up Procedure to control for family-wise error rate in multiple comparisons . As a reConsecutive patients presenting with HZ at the site as part of routine clinical practice were considered for participation in the study. Patient eligibility for participation in the study was ascertained by doctor completion of a study-specific case report form. To be eligible for participation in the ZQOL study patients were required to present to the doctor with a visible HZ rash . Furthermore, in accordance with data suggesting that the incidence and severity of HZ increases significantly in adults over the age of 50 , only paTo promote the ecological validity of the study , extensive exclusion criteria were not employed. However, to protect the integrity of study findings, HZ patients with health impairments that may make it difficult for them to complete the required battery of PRO instruments  were excluded from participation. Similarly, patients whose medical background may make it difficult to interpret study results  were also excluded. Of note, PRO instruments were only provided in English and non-English speakers were excluded from participation in the study.Prior to recruitment of study patients, all site staff received formal training in study procedures, including procedures for administering Patient-Reported Outcome (PRO) questionnaires to patients to ensure standardisation and minimisation of missing data . In addition, as a pre-requisite of site participation, all site staff were required to demonstrate evidence of completion of good clinical practice training.At the initial site visit, once informed consent had been obtained and participant eligibility for participation confirmed, patients were asked by study staff to complete a combination of validated and specially designed PRO questionnaires. All questionnaires were bound in a study booklet to ensure standardisation of presentation and order of completion among all patients. Participants were informed prior to obtaining consent that completion of the PRO questionnaires should take no more than 30 minutes.There is no consensus in the research literature as to the stage of the acute HZ episode at which pain and HRQoL impact are at their highest ,23. TherData were collected using the following PRO questionnaires:Patient socio-demographic questionnaire: Used to collect patient socio-demographic data  and data concerning patients’ experiences of HZ (e.g. symptoms during the acute phase of disease presentation). In addition this questionnaire also included questions concerning the impact of shingles on patients’ daily lives . Details of medical care (e.g. number of doctor consultations) and treatment (e.g. use of non-prescription drugs) for shingles were also collected. Completed at initial visit only.•Zoster Brief Pain Inventory (ZBPI)[: The ZBPI is designed specifically to evaluate pain intensity due to HZ  and the extent that this may interfere with respondent’s activities of daily living. The instrument comprises 15 items taken from the Brief Pain Inventory-Short Form, a well-validated PRO measure applied in a broad spectrum of medical conditions [•ry (ZBPI): The ZBPnditions  and inclnditions  and the nditions ,8. ComplMOS 36-item Short-Form Health Survey (SF-36) Acute Form[: The SF-36 is a standardised generic questionnaire that consists of 36 items evaluating HRQoL. The psychometric validity of the SF-36 is well-established. In particular, the SF-36 has demonstrated validity for use in HZ and PHN populations [Scores for the eight scale dimensions and two summary scores were calculated using norm-based scoring (NBS) algorithms which employ a linear T-score transformation with mean = 50 and standard deviation = 10 – making it possible to meaningfully compare scores across domains/summary scores [•cute Form: The SF-ulations ,11. Itemy scores . CompletThe EuroQoL 5 Dimensions questionnaire (EQ-5D)[: The EQ-5D is a standardised generic questionnaire comprising 5 items that are used to provide a simple descriptive profile and a single index value for health status (ranging from 0-1): EQ-5D Health State Index (HSI). In addition, the EQ-5D also includes a patient-completed visual analogue scale, which records the respondent’s self-rated health (SRH) on a vertical scale where the endpoints are labelled from 0  to 100 . Completed at initial visit and follow-up.•e (EQ-5D): The EQ-Treatment Satisfaction Questionnaire for Medication (TSQM) Version II[: The TSQM Version II is an 11-item questionnaire designed to assess patients’ satisfaction with various aspects of their medication, including side effects (3 items + 1 yes/no stem), effectiveness (2 items), convenience (3 items) and overall treatment satisfaction (2 items). Items are assessed using 5-point and 7-point Likert scales ranging from ‘Extremely dissatisfied’ to ‘Extremely satisfied’, but scores on all domains are transformed to a 0-100 scale whereby higher scores indicate greater levels of patient satisfaction. Completed at follow-up only.•ersion II: The TSQTo complement and facilitate interpretation of PRO data, data concerning patient’s clinical and treatment history were collected as part of the doctor-completed case report form.The ZQOL study was designed and conducted in accordance with the principles set forth in the Declaration of Helsinki . In accoAll planned statistical analyses were specified a priori in a formally developed Statistical Analysis Plan (SAP). All study data were subject to extensive quality control checks prior to the conduct of analyses. Where doctor-reported information was not clear, follow-ups with doctors were made to resolve queries. In accordance with developer instructions, if missing data for a SF-36 domain were < 50% then data were imputed using the mean of participants’ responses to the completed items . MissingTo quantify the burden associated with HZ, mean SF-36 and EQ-5D scores from ZQOL study samples were compared to published age-matched normative values for the respective questionnaires ,33. The In addition, a number of sub-analyses were conducted upon patient scores on the composite domains of the ZBPI (pain severity and pain interference), SF-36 (PCS and MCS) and EQ-5D (HSI and SRH) to test a number of pre-specified hypotheses, including:Age: Prior research has indicated HZ disease severity increases with age . The assGender: In light of previous evidence suggesting differential reports of pain severity, pain interference and HRQoL impact by gender across a range of medical conditions (including HZ) ,39, meanAntiviral use: There is evidence to suggest that use of antivirals within 72 hours of rash onset can reduce the severity and duration of the HZ episode -42. To a.Pain severity (ZBPI ‘Worst pain’): It was expected that pain interference and HRQoL impact would be greatest among patients reporting the greatest levels of pain. Pain interference and HRQoL were therefore to be compared amongst groups of patients stratified according to empirically confirmed categorisations of scores on the ‘Worst pain’ item of the ZBPI: none (0); mild (1–4); moderate (5–6); severe (7–10) . ZBPI raIn order to explore potential predictors of pain and HRQOL (as assessed by composite scores for the aforementioned PRO questionnaires), a series of ordinary least squares (OLS) regression analyses were conducted. Independent predictor variables included: socio-demographic variables ; time elapsed since first appearance of rash; diagnosis of HZO; antiviral prescription within 72 hrs of rash presentation; level of analgesics used (level 1 vs. level 2 vs. level 3); hospitalisations (binary – Yes/No); Co-morbidities; and ZBPI ‘Worst pain’ item scores.A total of 229 HZ patients 214 HZ, 15 HZO) were recruited to the ZQOL study between April 2010 and May 2011 (Table  HZO wereFor 79.9% (n = 183) of HZ patients, this was their first episode of the disease. Among patients who had experienced HZ before, the majority had experienced just one prior episode. That 20.1% (n = 46) of patients were experiencing a recurrent episode of HZ  suggests that HZ is not a once in a lifetime event and supports recent evidence indicating that recurrent episodes of HZ are more common than previously reported .Almost all patients 97.4%; 223) were described by their physicians as presenting with classic HZ . The majority of HZ rashes were described by doctors as being erythematous  or simple vesicles  in appearance, of a small size  and a medium density . Among ZQOL study patients, the HZ rash most commonly affected more than one site of the body  and most frequently presented on the chest/rib cage , abdomen/flanks , and head and neck   of HZ patients reported experiencing pain due to their HZ rash. Reports from patients indicated that this pain was persistent in nature, being present ‘Most of the time’  or ‘All the time’ . The experience of pain following HZ rash onset was qualitatively similar to that experienced prior to rash onset with ‘tender’ , ‘sensitive’ , ‘itching’ , ‘burning’  and ‘aching’  emerging as the terms most frequently selected by patients to describe their pain.In addition to pain, findings from the ZQOL study reveal that HZ patients also experience a range of other symptoms during the acute phase of HZ. In particular, symptoms of fatigue , stomach upsets , change in bowel movements  and muscle weakness  were commonly experienced by study patients. This is in contrast to prior research which suggests that such symptoms occur in <20% of patients .ZBPI scores from ZQOL study patients indicated that pain severity and pain interference, as assessed by ZBPI composite scores and individual ZBPI items, were highest on initial presentation to the recruiting doctor with a visible HZ rash than compared to 7–14 days later at follow-up Figure . During Comparison of patient ratings of pain as defined according to empirically established cut-offs for the ZBPI worst pain item   and doctIn contrast to prior research suggesting a link between HZ pain severity/interference and age , calcular2 = 0.065), patient BMI (r2 = 0.043), the length of time since the patient’s HZ rash first appeared (r2 = 0.030) and presence of a respiratory disorder (r2 = 0.023) were able to explain 14.2% of the variance in ZBPI pain severity composite scores. Similar regression analyses revealed that patient ratings of ‘worst pain’ (r2 = 0.268), use of level 2/3 analgesics (r2 = 0.024) and presence of a respiratory disorder (r2 = 0.016) accounted for 36.0% of the variation in pain interference scores.Prediction of ZBPI composite scores via ordinary least squares regression analyses revealed that patient use of level 2/3 analgesics  compared to values derived from an age-matched normative population Figure . DeficitCalculation of spearman rho correlation coefficients revealed no significant association between patients’ age and PCS and MCS scores. Significant differences were also not observed between subgroups of HZ patients defined according to antiviral use. Differences in PCS and MCS scores were observed between male and female HZ patients, with females scoring lower on both domains. However, differences were only statistically significant for MCS scores. A significant linear relationship between PCS and MCS scores was observed for patients classified according to empirically confirmed cut-offs for pain severity Table .r2 = 0.061), patient ratings of ‘worst pain’ (r2 = 0.048), use of level 2/3 analgesics (r2 = 0.043), patient BMI scores (r2 = 0.035) and the presence of a respiratory disorder (r2 = 0.021) collectively explained 27.2% of the variance in PCS scores. Similar regression analyses revealed that patient ratings of ‘worst pain’ (r2 = 0.039), patient’s gender (r2 = 0.033), prescription of antiviral medication within 72 hours of the onset of the HZ rash (r2 = 0.029) and presence of a psychological/psychiatric disorder (r2 = 0.023) accounted for 12.1% of the variance in MCS scores.Ordinary least squares regression analyses revealed the presence of rheumatoid/neurological disorders  at both the initial visit and at follow-up Figure .Calculation of spearman rho correlation coefficients revealed no significant association between patients’ age and SRH and HSI scores. Significant differences were also not observed between subgroups of HZ patients defined according to antiviral use. Differences in SRH and HSI scores were observed between male and female HZ patients, with females scoring lower on both domains. Differences, however, were only statistically significant for SRH scores. A significant linear relationship between SRH and HSI scores was observed for patients classified according to empirically confirmed cut-offs for pain severity Table .r2 = 0.049), psychological/psychiatric (r2 = 0.034), or ‘uncategorised’ disorders (r2 = 0.016), the ‘Worst pain’ experienced (r2 = 0.085) and patient use of level 2/3 analgesics (r2 = 0.021) explained 22.0% of the variance in SRH scores. The presence of a psychological/psychiatric (r2 = 0.025), rheumatoid/neurological (r2 = 0.043), the ‘Worst pain’ experienced (r2 = 0.041) and patient use of level 2/3 analgesics (r2 = 0.073) explained 20.7% of the variance in HSI scores.Ordinary least squares regression analyses indicated that the presence of rheumatoid/neurological  reported that their work had been affected by their HZ with 32 of these patients having to take time off work as a result of their HZ. Among those patients who reported that their work had been affected by their HZ, the average number of days off work was 5.4 days (range = 0–28). Reports from the entire HZ patient sample indicate that the mean number of days that they were unable to take part in their usual activities was 3.9 days (range = 0–21).Clinician reports indicated that HZ patients were taking an average of four medications to treat their HZ . Antiviral therapies (predominately acyclovir) were the most common treatment prescribed by doctors for the management of HZ  with the majority of patients  prescribed antivirals within 72 hours of the onset of their rash, the timeframe in which they have demonstrated efficacy -42. PresHZ patients were classified according to antiviral and analgesic medication use. Across all groups, TSQM scores indicated that patients were least satisfied with the perceived effectiveness of treatment and most satisfied with the side effects experienced. No significant or clinically meaningful differences were observed between patients receiving different treatment for the management of their HZ Figure .The value of real-world data summarising patients’ experiences of living with a health condition in informing decisions regarding the management of that condition and access to new medicines in national markets are becoming increasingly recognised. As stipulated in the UK Government’s Health and Social Care Act, the proposed commissioning outcomes framework  will place a strong emphasis on promoting decision-making that is driven by the patient experience; as likely measured by PRO questionnaires . ConductResults from the ZQOL study indicated that more than half of study participants with HZ 57.9%) reported pain at levels typically considered indicative of significant HRQOL burden . There i7.9% repoConsistent findings across the PRO measures employed in the ZQOL study were observed. For example, that a high proportion of patients experienced problems conducting usual activities (as measured by the EQ-5D) is consistent with significant and clinically meaningful deficits observed for SF-36 domains of Role-Physical and Social Functioning and ZBPI ratings of interference on general activities. Similarly, reports of high levels of interference in sleep (as measured by the ZBPI) are consistent with statistically and clinically meaningful deficits observed for the SF-36 Vitality domain. Furthermore, that problems with Self-Care were least frequently reported by participants completing the EQ-5D is also consistent with SF-36 scores for Physical Functioning where statistically significant deficits compared to norms were not observed. Statistically and clinically meaningful deficits observed for the SF-36 domains of Role-Emotional and Mental Health, however, indicate that the mental impact of HZ is likely to extend beyond anxiety and mood .Investigation of the burden of HZ in this manner is important for understanding the value of therapies in a given disease area and for facilitating decisions regarding reimbursement. This is particularly true for countries (including the UK), where health authorities may have to determine allocation of finite resources across different diseases. The introduction of Value-Based Pricing (VBP) of medicines into the NHS in 2014, for example, will mean increased emphasis being placed on the generation of robust real-world evidence to support pricing and reimbursement decisions .Limitations on available resources often mean that there is pressure on health providers to target resources to those patients with the greatest health needs. Consistent with hypotheses of a linear relationship between pain severity, pain interference and HRQoL impact, patient-reported levels of pain severity were found to the most consistent and most significant predictor of HRQoL burden. Specifically, the greatest levels of burden were observed in those patients experiencing the most severe levels of pain ,7,9,10. Prior research findings from retrospective reviews of medical records and databases indicate that care of HZ patients is associated with significant direct and indirect costs ,14-16,50Existing guidelines for healthcare professionals recommend that all HZ patients ≥50 years be prescribed antivirals for the management of their condition . ConsistFindings from the ZQOL study have implications in terms of provision of frontline services for HZ and patients and wider implications in terms of the national availability of means to prevent and manage HZ.As life expectancy throughout the developed world continues to rise, effective management of HZ becomes increasingly important in order to minimise the individual patient and societal burden associated with these conditions. Findings from the ZQOL study support the notion that, in order to address the unmet needs prevalent among HZ patients and to reduce the economic burden associated with HZ, there is a need to move away from therapies designed to manage the symptoms of HZ. Rather, more targeted therapies designed to reduce the burden of HZ by preventing VZV reactivation and attenuating pain severity during the HZ rash and persistence of pain following the resolution of the HZ rash are needed. This is in line with worldwide health authority initiatives, which have stressed the prioritisation of preventative measures, so as to reduce the burden on healthcare conditions on individuals, healthcare systems and society as a whole . FurtherRecent years, have seen documented evidence of the efficacy of a VZV vaccine in the prevention of HZ and PHN episodes and attenuation of the severity of HZ and PHN episodes and associated impact . The VZVFrom the perspective of frontline service provision, findings from the ZQOL study indicate the need for better observation and monitoring of patients treated in primary care to ensure adequate management of HZ. The disconnect evident between patient and doctor assessments of disease severity, especially in terms of severity of pain experienced, indicates the need for doctors to ensure open communication with patients in terms of their current experiences of HZ and PHN. In addition, there appears to be dissatisfaction among HZ patients, especially with regard to the perceived efficacy of treatments, which is presumably driven by experience of inadequate relief of symptoms. Thus, doctor communication of the value of prescribed therapies and setting realistic patient expectations of treatment outcomes may also help to improve adjustment in patients with HZ. Use of standardised PRO questionnaires as utilised in the ZQOL study (e.g. ZBPI and SF-36) may be of value to doctors in clinical practice, both in terms of obtaining symptom and HRQoL reports directly from the patient themselves and also providing patients with a perceived degree of input into their own treatment decisions.The UK is a multi-cultural society, with findings from the 2011 UK census indicating that 7.7million (14.0%) of the population in England and Wales belonged to non-white ethnic groups. However, it should be noted that despite recruitment of HZ patients from regional sites throughout the UK, the proportion of non-Caucasian patients in the ZQOL study (0.4%) is lower than UK population estimates and less than reported in prior studies in this area ,8,10. ThWhilst cross-sectional data generated from the ZQOL study and other studies provides insight into the collective burden experienced by patients with HZ, the lack of long-term follow-up and repeated data collection over time mean that there is limited understanding of the impact of long-term complications of HZ. In particular, research to help further understand factors that may explain the development of PHN in only a subset of HZ patients (and identify those most at risk of developing PHN) and to also understand the impact, at an individual level, that the progression of HZ to PHN has on patients (particularly in terms of pain and HRQoL impact) would be of value.Research evaluating the burden of the HZ and PHN has, to date, focussed almost exclusively on patient-centred outcomes and costs incurred by healthcare systems and society. However, as a disease most prevalent among those aged 50 years or over, many of whom (based on ZQOL study data) are expected to be living with someone else, it is likely that a significant proportion of patients will receive regular assistance from informal caregivers. The impact on these caregivers providing care to a patient both during the acute presentation and HZ and during any long-term complications (e.g. PHN), however, remains largely unexplored.Finally, while information collected using formal PRO questionnaires provides a valid means of ‘quantifying’ the burden of HZ, qualitative research exploring the ‘lived experience’ of HZ from a patient’s perspective would be beneficial for further understanding the burden and unmet needs among HZ patients. To the authors’ knowledge, however, no qualitative accounts of the experiences of HZ and PHN within the scientific literature have been published to date.As the largest and first UK-wide cross-sectional study conducted in HZ patients, the ZQOL study provides much needed information regarding the characterisation and management of HZ and the resulting burden associated with the condition from a patient and wider societal perspective. The data from this study offer further support to the characterisation of HZ as a painful condition that can have a significant impact on patients’ lives and result in significant costs for healthcare providers. Data from this study also highlight the current unmet need and inadequacy of current treatments in HZ patients, reinforcing the need for effective preventative strategies (such as vaccination) and early intervention.EQ-5D: EuroQol-5 dimensions; HSI: Health state index; HRQoL: Health-related quality of life; HZ: Herpes zoster; HZO: Herpes zoster ophthalmicus; MSC: Mental component summary; NHS: National health service; OLS: Ordinary least squares; PCS: Physical component summary; PHN: Post-herpetic neuralgia; PRO: Patient-reported outcome; QIPP: Quality, innovation, productivity and prevention; SAP: Statistical Analysis Plan; SF-36: Study short-form 36; SRH: Self-rated health status; TSQM: Treatment satisfaction with medication; VZV: Varicella-zoster virus; ZBPI: Zoster brief pain inventory; ZQOL: Zoster quality of life.AG and LA are employees of Adelphi Values, a health outcomes agency commissioned by Sanofi Pasteur MSD, to conduct, analyse and communicate findings from this research on their behalf. SC and AM are employees of Sanofi Pasteur MSD, a provider of a herpes zoster vaccine approved in the European Union. RJ has received consultancy and lecture fees from Sanofi Pasteur MSD, Merck and Merck Frosst. MS has no competing interests to declare.AG and LA led the design and conduct of the study, analysis and interpretation of study findings and drafting of the manuscript. SC facilitated the conduct of the study, analysis and interpretation of study findings and drafting of the manuscript. AM, RJ & MS contributed to study design, interpretation of study findings and review of the manuscript from a clinical perspective. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2334/14/402/prepub


Objective. Currently, an overview of the management of knee pain in general practitioner's offices is not available. The main concern of this study was to evaluate the consultation prevalence of knee pain, accompanying symptoms, the frequency of diagnostic and therapeutic procedures, and results of encounters of patients suffering from knee pain. Methods. For the SESAM 2 study cross-sectional data was collected from randomly selected patients during one year and compared with publicly available data from the Dutch Transition Project. Results. Overall, 127 out of 8,877 (1.4%) patients of the SESAM 2 study and 6,754 out of 149,238 (4.5%) patients of the Dutch Transition Project consulted for knee pain. Drug prescription, follow-up consultation, giving doctor's advice, and referral to a specialist or physiotherapist were the most frequent procedures. Osteoarthritis of the knee and other musculoskeletal diseases were the most frequent results of encounter. Overweight, age, gender, and other musculoskeletal diseases were found to be significantly associated with knee pain. Conclusion. Knee pain in general practice settings is mainly associated with chronic problems. Dangerous outcomes (as suspected fracture or thrombosis) are rare. Further research is needed in order to reduce the influence knee pain has on daily living. Knee pain is a common complaint and is therefore a typical reason for consulting the general practitioner. Knee pain occurs increasingly with advanced age  and amonCurrently, an overview of the management of knee pain in general practitioner's offices is not available. The main concern of this investigation was to evaluate the consultation prevalence of knee pain, the frequency of diagnostic and therapeutic procedures, accompanying symptoms, and results of encounters of patients suffering from knee pain. Therefore, data from the German SESAM 2 study and the Dutch Transition Project  were anaAll general practitioners in Saxony were contacted by the Saxon Society of General Medicine (SGAM). They received no incentive for their participation. The study was designed to document reasons for encounter, diagnostic and therapeutic procedures and the result of the encounter (chosen diagnosis).Of the 2,510 general practitioners that were contacted, 270 agreed to participate and 209 cooperated for the entire study period of one year. Cross-sectional information was collected from October 1, 1999 until September 30, 2000. Case recording was carried out on one day a week , chosen at random. Data was collected for one of ten patients previously known to the practitioner. Multiple recording of the same patient was avoided. House calls were not considered. A total of 8,877 patients were included. A standardized data collection form was used [http://www.transitieproject.nl/ and can be analysed using the software that is contained within the database. The performance of the SESAM 2 study was in accordance which the guidelines of the Institutional Review Board/Ethics Committee. As stated by the Ethics Committee no special approval was demanded.As described elsewhere, the SESAM 2 study provides independent and unbiased cross-sectional data from a daily primary care setting , 11. Sinχ2 test. Differences were stated as statistically significant for P < 0.05.Statistical analysis of the SESAM 2 data was performed using Statistical Packages for Social Sciences . As indicated, data was compared using Fisher's exact test and Within the SESAM 2 study 209 general practitioners participated and 8,877 patients were reported by them. Of those 5,050 (56.9%) were females, 3,824 (43.1%) were males, and 3 patients were not specified. During the study period 127 patients consulted their general practitioner because of knee pain. This means a consultation prevalence (cp) of 1.4%. Of the 127 patients 64 (50.4%) were females.The Dutch Transition Project contains data from 149,238 as active listed patients. Of those 84,285 (56.5%) were females. A total of 6,754 (4.5%) patients, thereby 3,630 (53.8%) females, consulted their general practitioner because of knee pain. There were 5,430 patients consulting for newly occurred and 2,234 for previously known knee pain during the study period. The distribution of the patients consulting for knee pain among different age groups is given in P < 0.01 for each age group). This was also the case for previously known knee pain at the age range from 25 to 44 years. In contrast, at the ages of 65 to 74 years, women were statistically significantly more affected by new and previously known knee pain (P < 0.01 for each) and suffered more frequently from knee pain at an age over 75 (P < 0.01) than men.The Dutch Transition Project revealed that at the age range of 15 to 44 men suffer more frequently from new knee pain (The diagnostic and therapeutic procedures that were performed in patients that consulted for knee pain are summarized in We compared the frequencies of results of encounter of patients consulting for knee pain to those of those without knee pain. As indicated in n = 127) and within the group of consultations for newly occurred knee pain from the Dutch Transition Project , six patients had a suspected thrombosis and two a suspected fracture of the tibia or fibula.Our study confirmed that knee pain is a regularly occurring reason for encounter in general practice. Women at an older age suffered from knee pain significantly more often than men. The most common reason for knee pain at advanced age was osteoarthritis of the knee.Since SESAM 2 there has not been any new relevant published data from cross-sectional studies regarding knee pain in general practice. The SESAM 2 study showed that with a consultation prevalence of 1.4% patients with knee pain represent a respectable group in general practice; however, this lays markedly below the overall prevalence in the general population: it is assumed that more than 25% of our society suffers from constant knee pain. The group of patients with knee pain who consult their general practitioner is quantified with 25% . Among oThe recent data suggest that men younger than 65 years do suffer more often from knee pain than age matched women. This might be a result of sports related injuries and chronic articular changes . Women sKnee pain is occasionally accompanied by other symptoms, which particularly affect the musculoskeletal system  in the form of pain, stiffness, and swelling. Furthermore, unspecific symptoms such as fever, fatigue, and weakness rarely appear.In a general practice setting the anamnesis , 19 and In a general practitioner setting knee pain is most commonly caused by disorders of the knee and the lumbar spine. Seldom occurring reasons of knee pain, such as psychological and neurological diseases, play a role . DangeroThe most common therapeutic procedures were the prescription of drugs followed by physical therapy and doctor's advice. Most of the therapeutic procedures were applied much less frequently in the Dutch Transition Project than they were assessed during the SESAM 2 study. This can be caused by the fact that the documented procedures in the SESAM 2 study must not necessarily be related to knee pain . Another possible cause might be found in the study design. During the SESAM 2 study only individual cases were ascertained and the patient as well as doctor was aware of the special situation. This might have led to behavioural changes of the doctor towards a social desirable behaviour. Within the Dutch Transition Project all patients were ascertained regardless of the individual. Encoding “doctor's advice” as a precise procedure is not possible using the ICD-10 as it was used during the SESAM 2 study but explicitly with the ICPC-2 used during the Dutch Transition Project. This circumstance might have led to neglecting documentation of this procedure during the SESAM 2 study and be jointly responsible for the remarkably big difference in frequency comparing the two studies.Porcheret et al.  developeIn summary, we conclude from our findings that knee pain in general practice settings is mainly associated with chronic problems. Dangerous outcomes (as suspected fracture or thrombosis) are rare. Further research is needed in order to reduce the influence knee pain has on daily living.


The purpose of this article is to investigate the efficacy and safety of frovatriptan plus dexketoprofen 25 or 37.5 mg  compared to that of frovatriptan 2.5 mg (Frova) in menstrually related migraine (MRM).The aim of this article is to analyze a subgroup of 76 women who treated an MRM attack in this multicenter, randomized, double-blind, parallel-group study.The primary end-point was the proportion of patients who were pain free (PF) at two hours. Secondary end-points included pain-relief (PR) at two hours and 48 hours sustained pain free (SPF).p < 0.05). PR at two hours was Frova 52%, FroDex25 81% and FroDex37.5 88%, while 48 hours SPF was 18% under Frova, 30% under FroDex25 and 44% under FroDex37.5.PF rates at two hours were 29% under Frova, 48% under FroDex25 and 64% under FroDex37.5 (Combining frovatriptan+dexketoprofen produced higher PF rates at two hours compared to Frova while maintaining efficacy at 48 hours. Tolerability profiles were comparable. The International Headache Society (IHS) defines menstrually related migraine (MRM) as attacks, in a menstruating woman, fulfilling the criteria for migraine without aura occurring on days –2 to +3 of menstruation in at least two of three menstrual cycles and additionally at other times of the cycle .These migraine attacks represent a challenge both for the patient and the headache specialist as they have been shown to be more impairing and longer lasting than non-MRM attacks .The first step of the acute treatment of MRM includes triptans followed by nonsteroidal anti-inflammatory drugs (NSAIDs) . If the Recently the combination of frovatriptan plus dexketoprofen (FroDex) at two different doses proved to be better than frovatriptan (Frova) alone in 314 patients with migraine with or without aura . The ratThe aim of this subgroup analysis was to compare the efficacy and tolerability of frovatriptan plus dexketoprofen in two different dosages with that of frovatriptan alone in women suffering from MRM.Details regarding the study population have already been described in the main study .Women with a history of MRM who treated a menstrual attack were selected for this analysis. MRM was defined, according to IHS criteria, as migraine without aura attacks in a menstruating woman, occurring on day 1 ± 2 (namely days −2 to +3) of menstruation in at least two out of three menstrual cycles and additionally at other times of the cycle  and had treated one episode of menstrual migraine during the study.The present subanalysis was predefined in the statistical analysis plan and original protocol of the main study .rate of headache relief at two hours, defined as the percentage of patients with a decrease in headache from severe or moderate to mild or none within two hours ;sustained pain-free rates, defined as the percentage of patients pain free within two hours with no use of rescue medication or recurrence within 48 hours ;patients’ preference for treatments.The primary end-point was the proportion of patients pain free at two hours, defined as patients free of pain at two hours before any rescue medication . SecondaThe primary variable was assessed by the Fisher Freeman Halton chi-square exact test using a 3 × 2 contingency table for tests of association and a 2 × 2 contingency table for comparisons between treatments.The secondary end-points were assessed in the same way as the primary variable. The level of statistical significance was set at 0.05 for all analyses.A total of 248 women were enrolled in the main study, of whom 76 suffering from MRM were included in this analysis .Figure p < 0.05). The proportion of pain-free patients at two hours was 29% (nine of 28) under Frova, 48% (11/23) under FroDex25 and 64% (16/25) under FroDex37.5 (p < 0.05)  .Figure The proportions of pain relief patients felt at two hours were 52% (13/28) for Frova, 81% (17/23) for FroDex 25 and 88% (22/25) for FroDex 37.5.The proportions of patients who were sustained pain free at 48 hours were 18% (five of 28) under Frova, 30% (seven of 23) under FroDex25 and 44% under FroDex37.5 (11/25).The treatment was judged excellent or good by 47% (13/28) in the Frova group, 61% (14/23) in the FroDex25 group and 80% (20/25) in the FroDex37.5 group.Overall, 14 treatment-emergent adverse events (three drug related) were reported in the MRM population: two with Frova (0 drug related), eight with FroDex25 (two drug related) and four with FroDex37.5 (one drug related). No events caused withdrawal from the study.This subanalysis of a direct comparative pilot study showed that the combination of frovatriptan + dexketoprofen 25 mg or 37.5 mg was effective in the treatment of MRM, while maintaining a good tolerability profile.Our most relevant finding was that the primary end-point, pain-free rate at two hours, was significantly higher with combination therapy than with Frova (29%) reaching 48% in the FroDex25 group and 64% in the FroDex 37.5 group. Interestingly the results obtained with the combination therapy are in line with those obtained with sumatriptan+naproxen sodium (pain free at two hours: 42%–52% with combination therapy vs 22%–23% with placebo) (As far the secondary end-points are concerned, the results of pain relief obtained at two hours were similar, showing a faster onset of action of the combination therapy. A sustained pain-free status is today considered the ideal migraine treatment response and the hardest end-point achievable in clinical studies. Sustained pain-free definition was calculated according to IHS guidelines; to our knowledge these are the first data published using this definition . The 48 Interestingly, preference expressed by patients for the combination therapy showed a similar trend to the efficacy end-points results; we must underline that treatment was given in a double-blind fashion. All the study treatments were safe and well tolerated and the rate of treatment-related adverse events was low.Notably, the baseline characteristics of the MRM population showed that these women had a higher MIDAS score and a higher proportion of associated symptoms than did the general female population of the main study, confirming that MRM attacks are more disabling and difficult to treat .The results of this study should be interpreted in the context of its limitations. First, this is a subanalysis of a direct comparative pilot study and even if the statistical analysis plan and original protocol of the main study were predefined, this could be a limitation. Moreover, an a priori sample size was not calculated and post-hoc power was below 80%. This underpowered analysis was carried out with the clear purpose to create hypotheses that could be tested in a much larger trial.A second limitation is that the tablets of frovatriptan, dexketoprofen and placebo were over-encapsulated separately. The third limitation is that our study did not include a dexketoprofen arm, but we must underline that the purpose of developing a combination therapy is to maximize both the pain-free rate at two hours and the sustained pain-free rate at 48 hours; dexketoprofen is well known to have a short half-life and its sustained effect is probably not relevant. Finally, our study did not include a placebo arm and for the secondary end-points lacked a correction for multiple statistical testing.In this sub-population analysis, we have shown that the association of FroDex may be better than Frova alone in the treatment of MRM and may be an additional option in this difficult-to-treat type of migraine.In the near future we expect that more and more combinations of a triptan and an NSAID will be approved. The therapeutic synergism between these two antimigraine drug classes will help achieving a more prompt and consistent pain relief and will reduce the disability associated with the acute migraine attack. Taking into account the important role of PGs in the genesis of menstrual migraine, it is reasonable to assume that this type of migraine will particularly benefit from a combination of a triptan and an NSAID. Further large, ad-hoc clinical trials are needed confirm these results.A subgroup analysis on the combined use of frovatriptan plus dexketoprofen in menstrually related migraine was conducted.We sought to confirm the sound suggestion that combination therapy produces higher pain-free rates than frovatriptan monotherapy.Our results suggest that, in general terms, combination therapy has better results than monotherapy in most of the typical end-points for the treatment of migraine.


Whether low socioeconomic status (SES) is associated with worse rheumatoid arthritis (RA) outcomes in countries with general tax-financed healthcare systems (such as Sweden) remains to be elucidated. Our aim was to investigate the influence of educational background (achieving university/college degree (high) or not (low)) on the outcomes of early RA, in terms of disease activity (DAS28), pain (VAS-pain), and functional impairment (HAQ).We evaluated DMARD-naïve RA patients recruited in the Epidemiological Investigation of RA (EIRA) study with outcomes followed in the Swedish Rheumatology Quality (SRQ) register (N = 3021). Outcomes were categorized in three ways: 1) scores equal to/above median vs. below median; 2) DAS28-based low disease activity, good response, remission; 3) scores decreased over the median vs. less than median. Associations between educational background and outcomes were calculated by modified Poisson regressions, at diagnosis and at each of the three standard  follow-up visits.Patients with different educational background had similar symptom durations (195 days) and anti-rheumatic therapies at baseline, and comparable treatment patterns during follow-up. Patients with a high education level had significantly less pain and less functional disability at baseline and throughout the whole follow-up period (VAS-pain: baseline: 49 (28-67) vs. 53 (33-71), p <0.0001; 1-year visit: RR = 0.81 (95 % CI 0.73-0.90). HAQ: baseline: 0.88 (0.50-1.38) vs. 1.00 (0.63-1.50), p = 0.001; 1-year visit: 0.84 (0.77-0.92)). They also had greater chances to achieve pain remission (VAS-pain ≤20) after one year (1.17 (1.07-1.28)). Adjustments for smoking and BMI altered the results only marginally. Educational background did not influence DAS28-based outcomes.In Sweden, with tax-financed, generally accessible healthcare system, RA patients with a high education level experienced less pain and less functional disability. Further, these patients achieved pain remission more often during the first year receiving standard care. Importantly, education background affected neither time to referral to rheumatologists, disease activity nor anti-rheumatic treatments. Low socioeconomic status (SES), measured in a variety of ways , has been associated with an increased risk of rheumatoid arthritis (RA), and a worse disease outcome , 2. DespOur aim was to evaluate whether SES, here measured as formal educational background, affects the chance of good control of RA during the first year in patients receiving standard care in Sweden. We used data from a well-established population-based RA cohort that has included incident cases captured before the initiation of the first disease-modifying anti-rheumatic drug (DMARD).The study participants were newly diagnosed, DMARD-naive RA patients from the Epidemiological investigation of rheumatoid arthritis (EIRA) study in Sweden (previously described in detail ), who we2). Formal educational background at diagnosis was categorized as having a university/college degree (high level of education) versus no university/college degree (low level of education). Several potential determinants of outcomes, including time to the first encounter with a rheumatologist, severity of disease at baseline, first and subsequent use of anti-rheumatic therapy, were recorded by rheumatologists and were accessible through SQR.Information on exposure  and several confounders , etc.) was collected through a self-administrated questionnaire (from the EIRA study) at baseline. Briefly, age at diagnosis was a continuous variable. Ever smokers were defined as current and former cigarette smokers while never smokers reported they had never smoked. Pack-years of smoking were calculated with one pack-year equivalent to smoking 20 cigarettes per day for one year. Ever drinking was captured by questions about present alcohol consumption and previous habitual consumption, and included both current and former drinkers. Total alcohol consumption was measured in drinks per week . BMI was calculated from self-reported height and weight , visual analog scale for pain , and health assessment questionnaire (HAQ) score (range 0–3). Please note that in all measures, a higher score represents a poorer outcome.We primarily classified all outcome measures into equal to/above median versus below median. We further separately categorized patients based on achievement (yes/no) of low disease activity (DAS28 ≤3.2), good response (DAS28 ≤3.2 and DAS28 decrease >1.2) and remission (DAS28 ≤2.6) according to European League Against Rheumatism (EULAR)/American College of Rheumatology (ACR) recommendations  and defiWe used modified Poisson regression to obtain the risk ratio (RR) with 95 % confidence interval (CI) of the outcomes associated with educational background . PatientAll analyses were adjusted for potential confounders, i.e., age at diagnosis , sex (binary), pack-years of cigarettes smoking (continuous), total alcohol assumption (continuous), BMI (continuous), and outcome measure at baseline . In addition, we performed analysis with additional adjustments for residential area (county), leisure time physical activity, anti-citrullinated protein/peptide antibodies (ACPA)-status, treatment at baseline, and study phase. We subsequently carried out stratified analysis based on ACPA status (ACPA-positive and ACPA-negative subgroups), and treatment (DMARDs and other treatments). All analyses were performed in SAS V.9.3.Basic characteristics of the patients are shown in Table p value <0.0001, HAQ 0.88 (0.50–1.38) vs. 1.00 (0.63–1.50), p value = 0.001). We observed no significant differences in anti-rheumatic treatments initiated at baseline or during the first year of disease (Table DAS28-based outcome measures showed comparable baseline levels between the exposed (patients with a university education) and unexposed (patients without a university education) groups but for VAS-pain and HAQ, slightly, although statistically significantly lower, median levels were observed among patients with a university education (VAS-pain 49 (28–67) vs. 53 (33–71), Throughout the follow-up period, patients with a high level of education had a decreased risk of having VAS-pain above the median compared with patients with a low level of education (RR (95 % CI) for the 3-month visit 0.82 (0.74–0.91); 6-month visit 0.86 (0.77–0.96); 1-year visit 0.81 (0.73–0.90)). They also had less functional impairment than patients with a low level of education ; 6-month visit 0.87 (0.78–0.97); 1-year visit 0.84 (0.77–0.92)) ; this did not remain significant after adjustment for potential confounders) and for remission at the 1-year visit (1.12 1.02–1.24)). Neither did we observe any significant associations for DAS28 components , and patient global assessment) in relation to educational background (data not shown). Higher education was associated with 15–25 % greater chance of achieving VAS-pain remission (3-month visit: 1.25 (1.13–1.38); 6-month visit: 1.14 (1.02–1.28); 1-year visit: 1.17 (1.07–1.28)). The results, however, did not remain significant at the 6-month visit after adjustment (Table ). NeitheHigher education was not associated with increased chance of improvement (more than the median) in VAS-pain Table . Thus, pIn addition to all the analyses above, we performed analysis with extra adjustments for residential area, leisure time physical activity, ACPA-status, treatment at baseline and study phase, but the results did not alter substantially and those variables were not kept in the final analyses. We subsequently carried out the stratified analysis based on ACPA status, but found no differences between the two subgroups. We also performed stratified analysis based on treatments, and again found no differences.In this population-based cohort with early RA, receiving standard care in a country with a tax-financed, generally accessible healthcare system, educational background affect neither the time to diagnosis nor treatment during the first year. Furthermore, we found that educational background was not associated with disease activity (DAS28), but patients with a high educational level had slightly less pain (VAS-pain) and less functional disability (HAQ) at baseline and during the first year receiving standard care. Consequently, they were also more likely to achieve pain remission and improvements in functional impairment.Methodological advantages of our study are its large sample size, the population-based design, the inclusion of incident cases, and the extensive information available. These features made it possible to adjust for several potential confounders. The general welfare system in Sweden provides health care to all citizens irrespective of SES, and the similar symptom duration observed among patients with different educational levels indicates that the system does not systematically favor earlier attention to individuals with higher education. Limitations in this study include self-reported educational background, which could have introduced non-differential misclassification. This misclassification was probably small as participants can be expected to remember their highest achieved education relatively easily. Not all EIRA study patients were followed in the clinical quality register, SRQ. However, the proportion of university-educated patients in the EIRA study was very similar (23 % and 20 %) regardless of inclusion in the SRQ.To some extent our results confirm previous findings on the relationship between low SES and worse disease outcome for some subjective measures , 6–11. HDespite accumulating evidence demonstrating the contrasting etiology between the two serologically defined RA groups based on ACPA , our finTo summarize, we found that higher-educated newly diagnosed RA patients had less pain and less functional impairment at diagnosis and throughout the follow-up period, although those statistically significant differences were of limited clinical relevance. Consequently, the patients with a higher level of education had a slightly greater chance of achieving pain remission, and improvement in physical function. Our study demonstrates that RA patients with different educational levels have the same opportunity to access healthcare including treatment; and that in this context, educational background has a very limited influence on the disease course.


To investigate what a geriatric assessment in general practice adds towards previous findings of prevalence, location, impact and the dyadic doctor-patient perception of pain in this age group.kappa statistics.Cross-sectional study. Consecutive patients aged 70 and over underwent a comprehensive geriatric assessment in general practice that included a basic pain assessment . Patients with pain and their doctors then independently rated its importance. Pain was correlated with further findings from the assessment, such as overall health, physical impairments, everyday function, falls, mood, health related lifestyle, social circumstances, using bivariate and multivariate statistics. Patient-doctor agreement on the importance of pain was calculated using 219 out of 297 patients (73.7 %) reported pain at any location. Pain was generally located at multiple sites. It was most often present at the knee (33.9 %), the lumbar spine (33.5 %) as well as the hip (13.8 %) and correlated with specific impairments such as restrictions of daily living (knee) or sleep problems (spine). Patients with pain and their physicians poorly agreed on the importance of the pain problem.A basic pain assessment can identify older patients with pain in general practice. It has resulted in a high prevalence exceeding that determined by encounters in consultations. It has been shown that a geriatric assessment provides an opportunity to address pain in a way that is adapted to older patients’ needs – addressing all sites, its specific impact on life, and the patients’ perceived importance of pain. Since there is little doctor-patient agreement, this seems a valuable strategy to optimize concrete treatment decisions and patient centered care.DRKS00000792)This study is registered in the German Clinical Trial Register ( Pain is a central health issue for the majority of older people. It is the number one trigger for contacting a general practitioner (GP) in older patients , and conA geriatric assessment, as used for the present study, provides a good opportunity to examine pain in general practice. Its main purpose is to determine older peoples’ health in a standard way. It focuses on relevant and frequent conditions, such as impaired functions, limitations in daily activities, symptoms, mental and psychological state as well as on disease monitoring . This diFirstly, it allows GPs to identify pain whether previously reported or yet “hidden”. Secondly, it facilitates the disclosure of pain at multiple locations. This is relevant, because the focus tends to be on single pain sites in the elderly , althougAs pain is usually not part of any routine assessment for older patients in German general practices, this paper intends to inform about the prevalence, location and impact of pain in general practice patients of 70 years and over, and to investigate and compare the relevance of pain from the patients’ and GPs’ views.The present study is nested in the PräfCheck project (Check preferences: Proactive and shared treatment planning with older patients), study phase B . The proThe procedure in part B was as follows: In the practices, study nurses performed a geriatric assessment with each participating patient. It included a basic pain assessment. Immediately afterwards, patients and their corresponding GPs independently rated each disclosed problem according to its deemed importance. This was done to create an awareness of the subjective relevance of concurrent patient problems. Whereas the control doctors merely discussed the assessment results with their patients in the following consultation, the intervention doctors additionally received the importance ratings of their patients, on the basis of which they performed a “PräfCheck” consultation to discuss priority problems , 10. TheRecruitment of GPs was based on zip codes. Initially, 43 GPs agreed to participate (response rate 18.6 %). In the practices, the reception staff consecutively approached every older patient who came to the office for whatever reason during a defined week. Inclusion criteria for patients were an age of 70 years or older and at least one contact with the GP in the previous three months. Exclusion criteria were long-term care dependency level II or III , dementiIn this study the STEP instrument was used (Standardised Assessment for Elderly Patients in Primary Care). It was developed as a comprehensive assessment for older patients in general practice in an EU-Concerted Action. It consists of 76 single questions and two short performance tests characterizing 44 health and everyday problems . STEP taFor the present analysis, we used the data from the control and intervention participants. This included the data on all patient problems uncovered by STEP and the associated importance ratings by doctors and patients.The pain assessment in STEP included a question that originates from the Medical Outcome Study (36-item Short-Form Instrument): “How much bodily pain have you had during the past 4 weeks?”  . PatientIn order to correlate the presence of pain with other conditions uncovered by the assessment, we focussed on the following set of n = 14 variables from STEP. They were chosen as they may have an association with pain according to literature reviews and clinical experience. These included eleven dichotomous variables: presence of functional disabilities .In order to determine the agreement between the importance ratings of patients and their GPs, we first established the observed frequencies of agreement. Then we calculated the chance-corrected agreement and employed the Cohen’s kappa co-efficient (κ). Values between 0 and 1 are interpreted in a range of agreement: 0.0-0.2, slight agreement; 0.21-0.4, fair agreement; 0.41-0.6, moderate agreement; 0.61-0.8, substantial agreement; and 0.81-1.0, nearly perfect agreement .A total of 297 patients participated in the study, 219 of which (73.4 %) suffered from pain at any site. Patients were on average 77 years old. Age, educational status and income were not significantly different between the pain and non-pain group. In the pain group, however, there was a higher proportion of women (64.8 %) compared to the non-pain group . The pain group also revealed a higher number of health problems and rated their health significantly worse compared to the non-pain group  and corresponding confidence intervals (CI) in Table In multivariate analysis, some of the significant effects of the bivariate analyses were not sustained (see Table = 0.09) when doctors considered the importance for their care. The agreement was slightly higher when doctors put themselves in the patients’ position: 73.7 % (129/175) agreement, κ = 0.17. Overall, physicians overrated the importance of pain in both situations compared to the patients’ assessment.Of the 219 patients suffering from pain at any site, 80.3 % (n = 175) rated their pain as moderate to severe and/or restricting their daily activities. These patients were then asked to rate the importance of pain along with their other health problems. 130 of these 175 patients rated their pain as “important” (74.3 %). Their physicians also rated the importance, once for their medical care and once when putting themselves in the patients’ position. The physicians classified the pain as important for their care in 146 patients (83.4 %). They presumed that the pain was important for 154 patients (88.0 %). Doctors and patients agreed on the importance of the pain in 69.1 % (121/175) of cases . However, in our study, the occurrence of falls was very low so that inference statistics show no significant differences between groups. The Women’s Health and Aging Study reported an association merely in women with widespread pain or lower extremity pain [depression after adjustments. In population studies [We found no significant associations of pain with fity pain . We also studies , 37 depr studies .The importance of pain is usually not part of a pain assessment, in which intensity, functional restrictions and distress are typical measures. It has been argued that information about the personal importance should be included in pain assessments to identify patient needs and priorities more comprehensively . Indeed,This is a post-hoc analysis of a cross-sectional study on pain locations and its associations in an older general practice population. One novel aspect of our study is the sampling technique as each patient underwent a geriatric assessment that included pain avoiding the presence of pain as key question for inclusion of patients. The prevalence of pain therefore exceeds that of other general practice studies, which rely on more self-motivated patient reports, indicating the presence of underreporting. Also, pain assessment as part of an overall geriatric assessment facilitates a comprehensive association with other common health related conditions and everyday problems of older patients in primary care. Finally, to our knowledge the dyadic comparison of the importance of pain between doctors and patients has not been investigated before.One of the limitations of the current study is that it was a cross-sectional analysis portraying the concurrent relationship between pain and other health related conditions. Therefore the findings cannot contribute towards clarifying the complex causal relationships of pain locations and health related problems. The study does not provide any information on other health conditions or patient characteristics than those collected as part of the geriatric assessment. Further data might have enriched our analyses, e.g. BMI or coping skills. Moreover, due to our geriatric assessment procedure, the association of pain with other health related conditions was only possible for the (large) subgroup of patients with more severe pain (trigger was pain assessed as moderate to severe or impeding daily activities). Finally results of the current study are not easily comparable with other findings for very different reasons, e.g.: the level of care, inclusion criteria, definition and measurement of pain, and inclusion of different factors to be associated with pain.Our findings suggest the necessity of a pro-active doctor-driven diagnostic approach for older patients in general practice as pain is seemingly not reported by all pain sufferers in this age group. GPs should also pay particular attention to multisite pain, as only a minority of older patients have single site pain, even if just the main pain site is mentioned. The findings also point towards a considerable discordance of patients’ and doctors’ views on the importance of pain. When decisions on pain treatment emerge, GPs should also consider the patient perception on importance and establish treatment preferences within a wide range of treatments that co-exist in the presence of multiple health problems. As different pain locations are associated with different limitations in quality of life, complex rehabilitation and support might be required beyond the prescription of universal “pain killers”.


This study aimed to identify key symptoms that could be associated with the diagnosis of acute forms of symptomatic apical periodontitis (SAP) and symptomatic irreversible pulpitis (SIP), and to identify a diagnostic algorithm based on these symptoms.N = 103) and SIP (N = 70). Moreover, a decision tree was constructed based on recursive partitioning to identify a hierarchy in differentiating symptoms.In this prospective, observational study 173 emergency patients diagnosed with acute pain of endodontic origin and no swelling or fistula were included. Patients were asked 11 specific questions from a checklist with a possible discerning value between acute SAP and acute SIP. Pain levels were recorded using the numeric rating scale (NRS-11). Subsequently, the painful tooth was diagnosed. Logistic regression was used to evaluate the checklist regarding its differentiation between SAP (With identical median NRS-11 scores of 8, the teeth diagnosed with acute SAP and SIP were severely painful. The decision tree analysis resulted in a tree with splits according to pain on cold, perceived tooth extrusion, and pain duration. The overall sensitivity of the tree to detect SAP based on key symptoms was 95 %, its specificity was 31 %.The best indicator for SAP was a reported absence of pain to cold stimuli. In teeth that did have a history of pain triggered by cold stimuli, the decision tree correctly identified SAP in 72 % of the teeth that felt too high and had hurt for less than one week. Odontalgia is the main cause of oro-facial pain . Acute dThe socioeconomic importance of dental pain has long been recognized . It has In this prospective, observational study, adult patients seeking emergency care in a dental hospital because of inflammatory conditions caused by infection of the pulp space were assessed. The aim of the study was to identify key symptoms that could be associated with either SIP or SAP, and to identify a diagnostic algorithm based on these symptoms. Symptoms were related to clinical signs/findings.All patients attending the dental emergency unit at our institution from opening at 07:30 am to 10 am were considered. It was aimed to include all adult (18 years or older) patients presenting with acute pain from a permanent tooth caused by an endodontic infection. The emergency unit consisted of physicians and dentists from all dental specialties. After a short first examination by an oral surgeon, patients diagnosed with pericoronitis or temporomandibular joint pain were referred to the Oral Surgery department. All other patients were referred to the Department of Preventive Dentistry, Periodontology and Cariology for further examination. Patients who did not present with spontaneous pain, but merely reported slight discomfort to stimuli indicative of reversible pulpitis were not considered as’acute’. These patients did not enter the study. The remaining patients presenting with acute pain from a permanent tooth were asked to participate in the study . The different inflammatory endodontic conditions  were established according to the recommended diagnostic terminology of the Consensus Conference of the AAE . In a deU test. The alpha-type error was set at 5 %. To assess the diagnostic value of the 11 symptoms (other than pain) between SAP and SIP, a multiple logistic regression model was fitted to the outcome variable SAP. All of the variables of the checklist were included in order to obtain a predicted probability for SAP for each individual patient. Because some teeth were bridge abutments and the question did thus not make sense, the variable “Tooth feels too high” had 11 missing values. These were multiply imputed with 5 replications. Results of the logistic regression are based on the pooled estimates of the 5 imputed data sets. The area under the receiver operating characteristic (AUC) curve was used to evaluate the discriminative ability of the regression model.Descriptive statistics included counts and percentages for the questions on pain history. Categorical data was compared between groups using the Chi-squared test. NRS-11 pain levels, which are non-interval ratings, were compared between groups using Mann–Whitney In an alternative approach recursive partitioning was used to construct a decision tree. The focus of the tree was to facilitate the diagnostic decision between SAP and SIP. All variables of the checklist were included in the tree model. All analyses were conducted using R statistical software .P > 0.05).From January 2013 over a period of 15 month (64 weeks) 368 adult patients attended the dental emergency unit at our institution with severe pain on a permanent tooth. One hundred and forty-seven were not eligible to enter the study because they did not meet the criteria for inclusion  for both conditions under investigation. Median NRS-11 ratings were 8 for both SAP and SIP, with similar inter-quartile ranges: 2 for SAP, 1 for SIP. There was also no difference (P > 0.05) in pain levels between male and female patients. Eighty-one percent (81 %) of the patients used analgesics within the last 24 h before seeking emergency treatment. There was no statistical difference between the two conditions under investigation in this regard either.Pain levels were statistically similar  of the 173 patients included to this study had consumed analgesics within the past 24 h before seeking emergency treatment, 79 % (N = 136) of them reported severe pain at levels between 7 and 10 on a NRS-11 scale [N = 159) featured a painful response to percussion. In contrast the influence of analgesics on pulpal sensitivity test has shown to be negligible [It is known that the intake of analgesics can affect endodontic diagnosis. The pain perception itself can decrease, or the response to clinical test like tooth percussion can be reduced . However11 scale . Moreovegligible . Consequ % N = 13 of them gligible . Furthergligible . These c9 % N = 1 of them 9 % N = 1 of them Earlier authors concur with the present results in that pain to cold stimuli  and the duration though. Teeth affected by pulpits apparently hurt for more than one week before the pain reached a level that caused the patient to seek emergency care.Numerical rating scales have been validated, and are commonly used for the assessment of pain intensities , 41. TheThe current approach to facilitate the diagnostic decision between SAP and no SAP (SIP) has been two-fold. Initially, a prediction model including all available clinical information was constructed to assess the discriminative ability of the full checklist as measured with the AUC. The resulting AUC was nearly 80 %, which is an indication that the full model is in some degree valuable for the distinction between patients with SAP and SIP. However, the use of a prediction model based on 11 variables may be difficult to implement in a clinical setting unless a respective computer algorithm will be made available, e.g., in the form of a software application. For that reason, the decision tree analysis, which facilitates the distinction into the groups of SAP and SIP following a specific order of questions/key symptoms, was added in a second step Fig. . The oveThis study confirmed that in severely painful teeth, the most specific single symptom to differentiate between SIP and SAP was pain to cold stimuli. In addition, however, decision analysis identified a set of key symptoms to diagnose SAP also in teeth with a history of pain to cold stimuli. If these felt too high and had hurt for less than one week, the probability that SAP was diagnosed was still 72 %.AAA, acute apical abscess; AAE, American Association of Endodontists; AUC, area under the receiver operating characteristic curve; CBCT, cone beam computed tomography; NRS, numeric rating scale; SAP, symptomatic apical periodontitis; SIP, symptomatic irreversible pulpitis