Currently available sodium channel blockers lack selectivity, leading to cardiac and central nervous system side effects. Lacosamide is an anticonvulsant, which blocks Nav1.3, Nav1.7, and Nav1.8, and stabilizes channels in the slow-inactivation state. Since multiple Nav1.7 mutations in small fiber neuropathy showed impaired slow-inactivation, lacosamide might be effective.Small fiber neuropathy generally leads to considerable pain and autonomic symptoms. Gain-of-function mutations in the SCN9A- gene, which codes for the NaSCN9A-associated small fiber neuropathy, with the primary objective to evaluate the efficacy of lacosamide versus placebo. Eligible patients (the aim is to recruit 25) fulfilling the inclusion and exclusion criteria will be randomized to receive lacosamide (200 mg b.i.d.) or placebo during the first double-blinded treatment period (8 weeks), which is preceded by a titration period (3 weeks). The first treatment period will be followed by a tapering period (2 weeks). After a 2-week washout period, patients will crossover to the alternate arm for the second period consisting of an equal titration phase, treatment period, and tapering period. The primary efficacy endpoint will be the proportion of patients demonstrating a 1-point average pain score reduction compared to baseline using the Pain Intensity Numerical Rating Scale. We assume a response rate of approximately 60 % based on the criteria composed by the Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) group for measurement of pain. Patients withdrawing from the study will be considered non- responders. Secondary outcomes will include changes in maximum pain score, the Small Fiber Neuropathy Symptoms Inventory Questionnaire, sleep quality and the quality of life assessment, patients’ global impressions of change, and safety and tolerability measurements. Sensitivity analyses will include assessing the proportion of patients having ≥ 2 points average pain improvement compared to the baseline Pain Intensity Numerical Rating Scale scores.The Lacosamide-Efficacy-‘N’-Safety in Small fiber neuropathy (LENSS) study is a randomized, double-blind, placebo-controlled, crossover trial in patients with SCN9A-associated small fiber neuropathy. The findings may increase the knowledge on lacosamide as a potential treatment option in patients with painful neuropathies, considering the central role of Nav1.7 in pain.This is the first study that will be evaluating the efficacy, safety, and tolerability of lacosamide versus placebo in patients with NCT01911975. Registered on 13 July 2013.ClinicalTrials.gov, The online version of this article (doi:10.1186/s13063-016-1430-1) contains supplementary material, which is available to authorized users. Neuropathic pain is described as “pain caused by a lesion or disease of the somatosensory system” . The prev1.7, which is predominantly expressed in the small nociceptive and autonomic neurons. In addition to being associated with SFN, gain-of-function mutations in the SCN9A- gene have been described in the following human pain disorders: inherited erythromelalgia (IEM) and paroxysmal extreme pain disorder (PEPD) [V1.7 appears to be an appropriate target for treatment of different human neuropathic pain conditions, including the SCN9A-associated SFN.Voltage-gated sodium channels have been described to play an important role in neuropathic pain . In apprr (PEPD) , 14. Gair (PEPD) . TherefoV1.7, thereby frequently causing intolerable side effects involving the heart and central nervous system.Current treatments for pain in patients with SFN are far from satisfactory . Less thv1.3, Nav1.7, and Nav1.8 by targeting the slow-inactivation state and sparing channels with normal activity [SCN9A-associated SFN, multiple mutations in the SCN9A- gene have shown an impaired slow-inactivation [Lacosamide is a functionalized amino acid molecule that selectively enhances the slow inactivation of voltage-gated sodium channels and interacts with the collapsin-response mediator protein-2 . Lacosamactivity , 20. In To date, no studies with lacosamide have been performed in patients with SFN. Some evidence exists of lacosamide reducing neuropathic pain and being well tolerated in patients with a painful diabetic neuropathy , 22. TheSCN9A-associated SFN.The primary objective of this study is to determine the efficacy and safety of lacosamide versus placebo in patients with The Lacosamide-Efficacy-‘N’-Safety in SFN (LENSS) study is a randomized, placebo-controlled, double-blind, crossover-design study Fig. . The stuThe use of drugs such as lamotrigine, carbamazepine, oxcarbazepine, mexiletine, amitriptyline, and topical analgesics  that act on sodium channels is not allowed during the study period. Participants using these drugs require a washout period of at least five half-lives  prior to the screening visit. Other pain medications can be continued provided the dose and frequency of dosing have been stable over the previous 30 days prior to screening and remains unchanged during the study period. Additional medication is recorded.Each treatment phase is preceded by a titration phase. The dose of lacosamide is increased weakly, starting with 50 mg b.i.d. in the first week, followed by 100 mg b.i.d. in the second week, and concluding with 150 mg b.i.d. in the third week. After these 3 weeks, the treatment phase begins for 8 weeks. Based on previous studies and on the dose-related side effects, a dose of 200 mg b.i.d.  has been chosen as the maintenance dose . The subA convenient treatment period of 8 weeks was chosen based on literature findings and assuming that a positive effect of lacosamide should be seen within this period, thereby limiting the burden for patients .SCN9A-associated SFN are being recruited into the trial. SCN9A mutations classified as certainly, probably, or potentially pathogenic are eligible for inclusion [A total of 25 subjects with genetically proven Informed consent is obtained from all participants before any study procedure  is performed.Male and/or female subjects between 18 and 80 yearsBurning feetAllodyniaDiminished pain and/or temperature sensationDry eyes or mouthOrthostatic dizzinessBowel disturbances Urinary disturbancesSweat changes (hyperhidrosis/hypohidrosis)Visual accommodation problems and/or blurred visionHot flashes/palpitationsImpotence or diminished ejaculation or lubricationPresence of a clinical diagnosis of Small Fiber Neuropathy (SFN), with at least two of the following clinical symptoms not otherwise explained:and a mutation in the SCN9A- gene, confirmed by sequencing. Where possible, in vitro confirmation of the functionality of the mutation should have been performed and documented as has been demonstrated previously [In addition to the clinical diagnosis of SFN, presence of confirmed abnormality on intra-epidermal nerve fiber density evaluation (IENFD) and/or Quantitative Sensory Testing (QST) , 7 and aeviously , 9.Presence of pain due to SFN for at least 3 months prior to screening and an average self-reported pain score of at least 3 during this time.If on analgesic medication, subject must have a stable analgesic medication regimen for a minimum of 30 days before the start of the study and should continue with the same unchanged regimen throughout the study.Evidence of a personally signed and dated informed consent document indicating that the subject  has been informed of all pertinent aspects of the study.Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.Subjects must fulfill the following inclusion criteria to be eligible:Subjects with predominantly signs of large nerve fiber involvement , or clinically significant abnormal nerve conduction studies (NCS)History or presence of illnesses known to cause SFN (excluding diabetes mellitus), including liver, kidney, or thyroid dysfunction, monoclonal gammopathy, connective tissue disorders, sarcoidosis, Sjögren syndrome, amyloidosis, Fabry disease, celiac disease, HIV, and neurotoxic drugs Subjects with other severe pain conditions, which may impair the self-assessment of pain due to SFNAny condition possibly affecting drug intake and absorption History of known alcohol, analgesic, or illicit drug abuse within 12 months of screeningSubjects taking medications with potential effect on sodium channel functions, including lamotrigine, carbamazepine, oxcarbazepine, mexiletine, amitriptyline, and topical analgesics . These medications are prohibited until the end of the study period and require a washout period of at least five half-lives  prior to the screening visitTwelve-lead ECG demonstrating QTcF (Fridericia’s correction) > 450 or a QRS interval > 120 msec at screening. If the QTcF exceeds 450 msec or the QRS exceeds 120 msec, the ECG should be repeated two more times and the average of the three QTcF values should be used to determine the subject’s eligibility.Severe renal impairment (creatinine clearance ≤ 30 mL/min).Treatment with an investigational drug within 30 days  or five half-lives preceding the first dose of study medication. Participation in other studies during the period of current study participation or has surgery planned during the course of the study. Pregnant females, breastfeeding females, or females of childbearing potential not using effective and medically reliable contraception or not agreeing to continue effective contraception for at least 28 days after the last dose of the investigational product. Other clinically significant or unstable, or severe acute or chronic medical, or psychiatric/psychological condition or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the subject inappropriate for entry into this study. In the case of incidental findings, the patient and his/her treating physician will be informed and asked to undertake action if necessary. If a patient does not want to be informed about possible incidental findings and does not want his treating physician to be informed, the patient cannot participate in this study.Subjects presenting with any of the following cannot be included in the study:http://www.tenalea.com/). The randomization is computer- controlled based on the electronic case report form that is used. A blinded message is send to the investigator and an un-blinded message is send to the pharmacy. Patients are stratified based on the type of the SCN9A variant ((1) genetic variant and (2) genetically and functionally confirmed) and on the clinical diagnosis of SFN ((1) abnormal skin biopsy, (2) abnormal temperature threshold testing, and (3) abnormal skin biopsy and abnormal temperature threshold).After the screening period, the patients return to our center. To ensure that eligible subjects are compliant, we will verify that at least 5 of the last 7 days of the pain diary are completed. This is important because the pain diary of the screening period is used as the baseline measurement of the primary outcome. Randomization is performed using ALEA data management. This software is provided by the Trans European Network for Clinical Trials Services  is provided in its approved marketed product dress. All medication dispensed to the subjects are to be returned to the investigator and double-checked by the monitor to assure study compliance.The following compliance calculation will be applied:Subjects are coded as being a noncompliant if the percentage compliance according to the above formula is less than 80 % or greater than 120 % study drug compliance.The daily Pain Intensity Numerical Rating Scale (PI-NRS) consists of an 11-point numerical scale ranging from 0 to 10, where 0 represents no pain and 10 the worst pain possible. The subjects are asked to complete the PI-NRS twice daily, in the morning and evening, preferably at fixed time points. In addition, the daily sleep interference scale (DSIS) is completed every day on awakening in the morning. The DSIS consists of an 11-point numerical scale ranging from 0 (pain does not interfere with sleep) to 10 (pain completely interferes with sleep) and is used to determine sleep quality. At each assessment, the following additional questionnaires are completed: the Neuropathic Pain Scale (NPS), Small Fiber Neuropathy Symptom Inventory Questionnaire (SFN-SIQ), Patient’s Global Impression of Change (PGIC), and the generic Short Form (36) Health Survey (SF-36).The chosen outcomes are largely based on the international criteria advised by the IMMPACT group for measurement of pain .The primary efficacy endpoint is defined as the proportion of patients demonstrating a 1-point average pain score reduction compared to baseline using the PI-NRS. A 1-point change on the PI-NRS is considered the minimum clinically important difference (MCID) according to the unified rule of ½ x standard deviation (SD) and recommendations given by the IMMPACT group , 27.Secondary outcomes include changes seen in the maximum pain score on the PI-NRS, the NPS, DSIS, PGIC, SFN-SIQ, SF-36, adverse events, laboratory safety tests , blood pressure (BP), pulse rate (PR), and electrocardiogram (ECG).Sensitivity analyses include assessing the proportion of patients having ≥ 2 points average pain improvement compared to their baseline PI-NRS scores.www.infermed.com). Assessments start at the screening visit. In addition, assessments at site visits and by phone are performed according to the scheme presented in Fig. An electronic case report file (eCRF) is used for each patient to collect all data. To host the eCRF, MACRO electronic data capture is used, powered by InferMed Ltd, London, UK. It has been designed to support compliance with the requirements of relevant regulatory bodies including International Council for Harmonisation (ICH) Good Clinical Practice . The SPIRIT checklist and figure for this study protocol are shown in Additional files Adverse events are recorded and monitored. The principal investigator is to be informed immediately in case of any serious adverse event (SAE). Every SAE is reported to the Ethics Committee. Suspected unexpected serious adverse reactions (SUSAR) are also reported. Furthermore, all SUSARs are expedited to the competent authorities in other Member States, according to the requirements of the Member States.SCN9A-associated SFN is limited, a crossover design was chosen to fulfill sample size requirements with the inclusion of 25 subjects.A 1-point change on the average PI-NRS compared to baseline is considered as the MCID , 27. We The analyses are performed on the intention-to-treat (ITT) population, defined as all patients who received at least one dose of randomized study medication and had at least one post-baseline assessment. Patients withdrawing from the study are considered as nonresponders. The comparison of the proportion of patients in both groups (lacosamide versus placebo) reaching the predefined cut-off is estimated using Kaplan-Meijer serial time series graphs with a log-rank test.For secondary efficacy endpoints, the treatment differences for change from baseline in selected outcome measures, according to the predefined inquiries, are analyzed using nonparametric tests. The statistical tests used depend on the type of data. Analyses of safety parameters are performed on the safety set (SS), which includes all randomized patients who took at least one dose of trial medication. Individual missing data are assigned using a last observation carried forward approach. Other missing-data treatment methods are performed (for example single and multiple imputation) to test which of these methods is the best according to sensitivity analyses.SCN9A-associated SFN are studied. Despite earlier studies performed with lacosamide in painful conditions, no study to date has been done in patients with SCN9A-associated SFN. This is interesting because most of them harbor an electrophysiological mechanism of pain induction through impaired slow-inactivation of the voltage-gated sodium channel NaV1.7 [In this study, the efficacy, safety, and tolerability of lacosamide in patients with pain due to l NaV1.7 , which ml NaV1.7 . TherefoSCN9A-associated SFN.With lacosamide, we hope to find a new treatment option for the excruciating pain often reported by patients with SFN. This is the first pilot study that aims to show the efficacy, tolerability, and safety of lacosamide in this specific cohort of patients with v1.7 mutation, this might be a viable option for patients with painful neuropathies or with neuropathic pain in general, considering the central role of Nav1.7 in pain. The first results of the study are expected in mid-2017.If lacosamide proves to be effective in SFN patients with a NaParticipant recruitment for this trial is ongoing. Recruitment began in November 2014 and is expected to end mid-2016.v1.7, voltage-gated sodium channel 1.7; NCS, nerve conduction studies; NPS, neuropathic pain scale; PEPD, paroxysmal pain disorder; PGIC, patient global impression change; PI-NRS, Pain Intensity Numerical Rating Scale; PR, pulse rate; QST, quantitative sensory testing; SAE, serious adverse event; SCN9A-associated SFN, gain-of-function SCN9A mutation-related small fiber neuropathy; SD, standard deviation; SF-36, Short Form (36) Health Survey; SFN, small fiber neuropathy; SFN-SIQ, Small Fiber Neuropathy Symptom Inventory Questionnaire; SS, safety set; WBP, Wet Bescherming Persoonsgegevensb.i.d., bis in die (twice daily); BP, blood pressure; DRG, dorsal root ganglion; DSIS, Daily Sleep Interference Scale; ECG, electrocardiogram; eCRF, electronic case report file; FSH, follicle-stimulating hormone; ICH, International Council for Harmonisation; IEM, inherited erythromelalgia; IENFD, intraepidermal fiber density; IMMPACT, Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials; ITT, intention-to-treat; LENSS study, The Lacosamide-Efficacy-‘N’-Safety in Small fiber neuropathy study; MCID, minimum clinically important difference; MUMC, Maastricht University Medical Center; Na


There is a need for a way to measure success in multi-modal pain therapy that researchers and clinicians can agree upon. According to developments in health services research, operationalizing success should take patient-reported outcomes into account. We will present a success criterion for pain therapy that combines different patient-reported variables and includes validity measures. The usable criterion should be part of a statistically significant and satisfactory model identifying predictors of successful pain therapy.Routine data from 375 patients treated with multi-modal pain therapy from 2008 to 2013 were used. The change scores of five constructs were used for the combined success criterion: pain severity, disability due to pain, depressiveness, and physical- and mental-health-related quality of life. According to the literature, an improvement of at least ½ standard deviation was required on at least four of the five constructs to count as successful. A three-step analytical approach including multiple binary logistic regression analysis was chosen to identify the predictors of therapy success with the success criterion as the dependent variable.2 (8) = 52.585; p < .001) that explained 17.6 % of the variance identified the following predictors of therapy success: highest pain severity in the last 4 weeks, disability due to pain, and number of physician visits in the last 6 months.A total of 58.1 % of the patients were classified as successful. Convergent and predictive validity data show significant correlations between the criterion and established instruments, while discriminative validity could also be shown. A multiple binary logistic regression analysis confirmed the feasibility; a significant model  with routine data that can be used in a predictor analysis in multi-modal pain therapy. The criterion was based on basic constructs used in pain therapy and used widespread validated self-rating instruments. Thus, it should be easy to transfer this criterion to other institutions. Measuring therapy success is one of the most traditional tasks in clinical research. This also applies to the area of pain therapy. The operationalization of successful pain therapy is handled in diverse ways: There are research groups that use pain levels as a measure of success e.g. , 2), whe, whe2]),Thus, an agreement on the measurement and operationalization of successful multi-modal pain therapy would be very helpful from a research perspective because this would make comparisons of effects of different pain centers much easier and more reliable both nationally and internationally.Health Services Research agrees that success (i.e. the “outcome”) of a therapeutic approach should no longer be solely expert-rated , 11. Thihttp://www.proqolid.org/.For reasons of validity and reliability, more than one variable/construct should be used as the criteria for success since each individual construct will not have the same importance for every patient. From a methodological view, such variables should be measured with reliable and objective instruments. The use of already existing instruments that are also used in other areas of clinical research would provide practical help to clinicians internationally. Such instruments should ideally be available in different language versions that have been validated. A large platform on available instruments already exists and is freely accessible for researchers and treatment providers: There are two relatively new aspects that should be taken into consideration when developing and suggesting such a measurement tool for wide use:The first aim of this work is to introduce such a possible measurement of success for multi-modal pain therapy that includes patient-reported data and is comprised of different constructs. The presentation should include empirical evaluation of the criterion.The second aim is to test the feasibility of the success criterion: Goal is to identify predictors of successful multi-modal pain therapy using the newly developed success criterion as the dependent variable.The overall goal of having a success criterion in pain therapy and knowing the predictors of success was to direct patients that are suitable and will likely profit of this intensive treatment into the therapy. For clinicians it would be helpful to have a-priori-estimation where they can expect success to be able to use tight resources in the most reasonable way. Furthermore, having a success criterion is a prerequisite for answering further research question such as comparison of different treatment centers or therapists.The data for the study constitute routine data from patients enrolled in semi in-patient treatment in the interdisciplinary pain center of the University Clinic in Erlangen. The patients participated in a five-week full-time multi-modal pain therapy. The data that we analyzed were collected within the time frame of January 1, 2008 to March 31, 2013. The patients were assessed medically by trained pain therapists  with self-reported questionnaires before patients began therapy (“t1”) and after they completed the treatment (“t2”). There were no extra data collected for study reasons. Thus, we developed the success criterion using only data that are already implemented in routine care. The patients were informed about the treatment and the kind of data collection that would accompany their therapy. They gave written consent to be treated and to have their data collected and anonymously analyzed for scientific use. The data were anonymized, and the person who implemented the data analysis did not see any person-related information in the data and also did not see any patients in person so that it would be impossible to form a connection between sensitive data and real persons. The data were treated according to the German and Bavarian legislative rules for data protection. Routine data collection accompanies therapeutic action at the University Clinic Erlangen as a matter of quality assurance. This is in accordance with the ethical commission of the Friedrich-Alexander-Universität Erlangen-Nürnberg.In the time period set aside for this study, a total of 417 patients with a chronic pain condition were enrolled in the 5 week multi-modal pain therapy. Data from 42 patients could not be included in the analysis because of poor data quality—more than 50 % of the assessed variables were missing for those people. Thus, a sample of N = 375 was available for analysis. Single missing data in the N = 375 sample was imputed using the EM-algorithm .The sample was comprised of 72.5 % females. The patients had a mean age of 46.9 years (standard deviation: 11.0), 36.3 % were employed/self-employed, 16.5 % were living alone, and 28.3 % had 12 or more years of education.According to the therapeutic procedures catalogue (“OPS”), multi-modal pain therapy is a multidisciplinary treatment that lasts for at least seven days. It is administered to patients with chronic pain conditions (including tumor pain) and compulsorily involves at least two disciplines.manifest or impending impairment of quality of life and/or ability to workfailure of a uni-modal pain therapy in the patient’s anamnestic history or failure of an operative procedure that was administered to relieve pain, or failure of a pain-medication withdrawal treatmentexisting pain medication dependency or abusepsychic comorbidity that contributes to manifesting the pain conditionserious somatic comorbidityTo be deemed suitable for this kind of treatment , patients are required to have at least three of the following characteristics:The prerequisites set forth by the German statutory health insurance for multi-modal pain therapy require interdisciplinary diagnostics by at least two disciplines  as well as the parallel application of at least three of the following active therapeutic approaches: psychotherapy, physiotherapy, relaxation methods, occupational therapy, medical training, sensorimotor training, work place training, therapies from the area of art , or other exercise therapies .Multi-modal pain therapy in Erlangen can be described as a semi-inpatient, intensive, interdisciplinary treatment. The program used in this study was conducted in groups of 8 patients and lasted for 4 to 5 weeks for 6 to 8 hours per day for a total of 5 days per week.A physical exercise program (every day): general fitness exercises, muscle strengthening exercises, stretchingEducation (every day): anatomy, pain, and physical and mental coping strategiesRelaxation training (every day): progressive muscle relaxation, applied relaxationOptional therapy-related drug treatment or physiotherapyIndividual physical counseling (once a week): vicious circle of pain, realistic goal determination, individually based medical therapyIndividual psychological counseling (once a week): cognitive-behavioral intervention, treatment of individual emotional distressThe program included:The use of valid, wide-spread and consented data in form of patient-rated outcome variables was a prerequisite.At the end a dichotomous variable should result for two reasons: a) facilitating clinical decision making in the future and b) definite classification of success and non-success for prognostic analysisThe algorithm resulting in a dichotomous success variable (yes/no) should be as easy as possible to integrate five different constructs.The change patients undergo in therapy should not only be minimally detectable , but ratBased on the literature, a distribution-based method that is consented should be used as benchmark for a minimal clinically important difference.To come up with the combined success criterion, following considerations were undertaken:Average pain severity in the last 4 weeks: 11-point numeric rating scale of pain severity referring to the “primary pain” ranging from 0 (no pain) to 10 (strongest imaginable pain) – visualized with equal distances between the steps of the scale.PDI: Pain Disability Index —using anADS: The General (in German: “Allgemeine”) Depression Scale  measureshttp://www.sf-36.org/). The physical and mental health summary measures  were used.SF-36: The SF-36 Health Survey  was usedThe following instruments were used to construct the combined success criteria for multi-modal pain therapy:The variables listed above were chosen because they are widely used both nationally and internationally in pain therapy. To operationalize the constructs of pain severity, disability due to pain, depressiveness, and quality of life, we employed validated and widespread self-report questionnaires to ensure that the measures could be easily transferred to other institutions .Difference values were computed for the five above mentioned constructs. Descriptive statistics for the difference values can be found in Table While pain severity, disability, and depressiveness should be reduced after therapy, health-related quality of life should be higher (i.e. to show improvement). The construct “depressiveness” was a special case: Here, we looked for improvement only in patients who had been identified as “depressive” at t1. People who had been below the cut-off for depressiveness at t1 were counted as successful as long as they were still below the cut-off after they completed therapy.The analysis of the five constructs resulted in a dichotomous variable incorporating a decision for each individual: successful—yes/no. Characteristics of the criterion including percentages of patients that are defined as successes are presented in the results section.In addition to the above-mentioned variables, the following constructs were assessed and used to predict successful pain therapy: age, sex, living situation, school education, employment, number of affected pain regions, localization of the primary pain, affective and sensory pain perception, frequency of primary pain, highest pain severity in the last 4 weeks, lowest pain severity in the last 4 weeks, actual pain severity, subjectively acceptable pain severity after treatment, persuasibility of pain, number of other symptoms accompanying the pain, number of psychic comorbidities, Park-Index*, number of times the personal physician was changed due to failures in pain treatment, number of pain-associated physician visits in the last six months, number of other pain-related treatments  in the last 6 months, total number of doctors involved because of pain, number of pain-associated hospital visits, number of pain-associated rehabilitation treatments, retirement request pending, current retirement payment, disability request pending, and a work accident as the reason for the pain condition.*The Park-Index refers to a publication by Park et al.  who descTo provide an empirical evaluation of the success criterion percentages of patients who fulfilled a certain number of subcriteria  are presented. As a sensitivity analysis the required change was set to one SD for each single criterion—theoretically doubling the minimal clinically important difference.To provide figures for evaluating validity of the success criterion, convergent validity was checked with a) nine scales of the FESV (Questionnaire to assess pain reduction) at the end of treatment; b) with the subjective patient satisfaction at the end of treatment , c) with percentage of patients that reached a subjectively tolerable pain level which they defined at the start of their treatment. The FESV  is a selFurthermore predictive validity was analyzed with a) subjective patient satisfaction with treatment one year after discharge and b) with rating of pain severity one year after discharge. For both correlation and inference statistics with the success criterion at the end of treatment are shown.Discriminative validity was checked by correlation and inference statistics with the MPSS (Chronicity state according to Gerbershagen) rating . This isA three-step analytical approach was chosen to predict successful pain therapy: I) Pre-analysis: Univariate analyses involving binary logistic regressions for 37 potential predictor variables  and success (dichotomous yes/no) as the dependent variable were carried out. We decided to keep variables for further analysis if they showed a significant (p < .05) or at least a trend toward a significant association (p ≤ .10) with therapy success. II) Multicollinearity: We assessed whether the in Step I significant/trend significant variables were correlated with the other potential predictors. To develop a parsimonious model, we decided to eliminate variables if they had associations with other predictors of r > .500, indicating medium and high degrees of association. The decision about which of two variables had to be eliminated in cases of multicollinearity was based on the degree of association with other variables in the model. The variable that showed higher associations with all other variables was omitted. Thus, the remaining variables were used in the final model. III) Final model: A multiple binary logistic regression analysis was computed with the success criterion as the dependent variable and the predictor variables that were not associated with each other more than r = .500 and that at least showed a trend toward being significantly associated with therapy success in the univariate analysis.Furthermore, as a sensitivity analysis the variables that had been eliminated in the above described Step I were included in the final model one at a time, thus resulting in analyses with 8 + 1 predictors. This analysis was conducted to account for the very rare possibility that a variable that had a non-significant univariate association with a dependent variable could turn out to have a significant association when it was combined with a certain set of variables. This sensitivity analysis was computed to provide hints about other potentially important variables that might be associated with therapy success.A combined success criterion incorporating the five variables pain severity, pain disability, depressiveness, and health-related quality of life  was developed.Per definition 58.1 % of patients were counted as successful (at least 4 out of 5 fulfilled criteria). Table The single criterion that had the highest success rate was depressiveness. A total of 223 patients (59.5 %) were above the cut-off before therapy, thus counting as depressive. Of those, 85.0 % improved after therapy Fig. . HoweverThe combined success criterion correlates significantly with eight of nine scales of the FESV Table . Except Therapy success correlates significantly with subjective patient satisfaction at the end of treatment . The mean values in satisfaction between successes (M = 1.71) and non-successes (2.13) differ significantly .2 = 18.666; p < .001)Therapy success also correlates significantly with the percentage of patients that reached a subjectively tolerable pain level . While of those classified as successful reached 38.5 % their subjective tolerable pain level, in the group of non-successes reached this only 17.8 % . Successful patients have a significantly higher rated satisfaction   one year after finished treatment.Furthermore a significant correlation between pain severity one year after discharge and the definition as a succeed is evident . Thus patients defined as successful have significantly lower pain severity one year after discharge (M = 6.9) than patients defined as not successful (M = 7.7) .The Gerbershagen rating describing the chronicity of pain is neither with the sum score (r = .046) nor with the stadium (r = .056) significantly or clinical relevantly correlated with therapy success. Successes and non-successes do not differ in their mean sum score significantly .Step 1 – Pre-Analysis: The binary-logistic regression analyses revealed the following 9 significant predictors of success: affective pain perception , average pain severity in the last 4 weeks , highest pain severity in the last 4 weeks , lowest pain severity in the last 4 weeks , actual pain severity , disability through pain (PDI) , depressiveness (ADS) , mental-health-related quality of life (SF-36) , and number of pain-associated physician visits in the last six months ,. Furthermore, the two variables age  and school education  were significant at an alpha-level of .10. Detailed results for each of the 37 regression analyses can be found in Table Step 2 – Multicollinearity Analysis: the following variables were eliminated from the final model: depressiveness , average pain severity in the last 4 weeks , and actual pain severity in the last 4 weeks . Thus, 8 variables remained in the final modal.2 (8) = 52.585; p < .001) that explained 17.6 % of the variance identified a total of three variables predicting success  in multi-modal pain-therapy: disability due to pain , highest pain severity in the last 4 weeks , and number of pain-associated physician visits . Patients who were more impaired and had a smaller number of pain-associated physician visits in the last 6 months  had a higher probability of success. The detailed results for the 8 predictors that were included are shown in Table Step 3 – Full model—multiple binary logistic regression analysis: A significant model  remained significant in all cases. The variable age was a further significant predictor in the models with the additional predictors “number of pain-associated hospital visits” (age: p = .047) and “number of symptoms accompanying the pain” (age: p = .048). All other chosen variables remained unchanged in their associations. Only one additional predictor had a significant association with success when included in the full multivariate model: “disability request pending”. It was associated such that success in therapy was more probable when there was no disability request pending (p = .008).This work originated in the practical routine care of chronic pain patients. After every block of multi-modal pain therapy in the pain therapy center, therapists claimed that they “somehow knew” who had benefitted and who had not—however, this was more of a gut instinct rather than a measurable effect. Thus, a need to be able to operationalize success in multi-modal pain therapy was evident. A further goal was to optimize patient recruitment and allocation to an expensive specialized treatment such as semi-inpatient multi-modal pain therapy. It was important to know who was benefitting from such therapy—but in order to answer that question; agreement about what was meant by “benefitting” was needed first.Thus, first, there was agreement that success in multi-modal pain therapy needed to be measured multi-modally and thus with different constructs. Second, the measurement should be implemented with constructs that had been assessed as valid and relevant for the patient; therefore, patient reported outcomes were utilized. Third, the measurement should be feasible, easy to implement within routine care , valid, reliable, and objective; therefore, we used well-known measures with tested quality criteria that were widely used (at least in Germany). Fourth, literature-based knowledge on minimally clinical important difference should be incorporated.As a consequence, we developed a combined success criterion including five single criteria . We defined success as improvements of at least ½ standard deviation on at least four of the five single criteria.A first empirical evaluation showed evident convergent validity, predictive and discriminant validity. Patients defined as successes had more favourable values than patients defined as non-successes in the instruments used for convergent and predictive validity. The strength of the correlations seems to be low. However, this can be explained by the concept: correlation of a multi-domain-construct with a single criterion. Thus, the combined success criterion is to heterogenic to show high correlation with for example pain severity.A critical point is that the success criterion does not include the social aspect of re-establishing the ability to become gainfully employed or to work, which has been used as a single success criterion in many international studies e.g. , 4). How. How4]).Reflecting the results concerning therapy success, it has to be stated that immediately after therapy completion, more than half of the patients improved markedly on at least four of the five constructs. However, to judge the effectiveness of multi-modal pain therapy, this result is insufficient and needs to be validated with follow-up data. This is a limitation at the moment. We plan to do this as soon as the routine data are available, and the results will be published consequently. However, the mean amount of change in the single criteria is comparable to results reported in the literature with pain patients treated with several diverse treatments concerning the mental health related quality of life , 31, phyA further limitation is, besides that it concerns in this manuscript data of a single center, that we were bound to the assessment instruments implemented in routine pain care. The advantage of this on the other hand is that those instruments are used in all multimodal pain therapy centers in Germany because of the dissemination of the German Pain Questionnaire  and thusWith the decision for ½ standard deviation as minimal clinically important difference (MCID) there might be a certain amount of change that is undetected since the MCID is not equivalent with the minimally detectable change . For theThe presented combined success criterion has to be seen as a first (pilot) version. Adaption of the criterion concerning number and kind of included single criteria might be necessary depending on the results of further examination: a) in other treatment centers, b) with follow-up data c) when routine assessment instruments are changed.Up to now our approach of measuring success does not reflect individual patient preferences and/or goals. It would also be an adaptation possibility to define success in the single criteria more dependent on the change goals of the patient himself.In conclusion, we developed a feasible, combined, PRO-success criterion for multimodal pain therapy. However, the challenge will be to raise awareness in practical working pain therapy centers that there is a need for such a criterion and a need for comparable outcome measures. Even though the pain research community frequently asks “that a standard outcome be used across pain studies”  and “forConcerning the predictors, we found that the patients with especially heavy burdens profited the most. Patients with more severe pain when therapy began and with larger impairments in their daily life functioning due to their pain were associated with a higher probability of therapy success. There could be two reasons for these findings. One is a methodological one: People with high scores on the pain severity and pain impairment scales had better chances of improving substantially than patients who began with low scores (ceiling effect). The second reason is a motivational one: pain therapists frequently report that patients who are seriously impaired and bothered by their dysfunction have the highest levels of motivation to change their lives. To a large degree, multi-modal pain therapy is about changing habits. Changing habits is not easy and is often inconvenient. Thus, a patient must be motivated  to bridLike our study, a study from the Netherlands also found that high scores on disability were associated with recovery five and 12 months after therapy in patients with chronic nonspecific low back pain . A GermaThe third significant predictor of success after completing therapy in our study was the number of pain-related physician visits in the last six months. Success was higher for patients with a smaller number of doctors visits. The interpretation could be that highly impaired pain patients had stopped visiting doctors for out-patient care because they had decided that such visits were not helping them. So perhaps they were focusing on this planned intensive semi-inpatient 5-week multi-modal treatment and had put a lot of their hopes in that specific therapy and were therefore highly motivated to succeed. One early study also reported results in this direction: especially non-depressed patients with chronic pain seemed to profit from treatment if they had fewer previous types of treatment . In anotThere is a frequently recycled discussion in pain therapy about whether patients who are in the process of applying for disability pension should be included in multi-modal pain therapy. The hypothesis is that those patients will not/cannot improve because of their conflict of interest. There are studies from Denmark supporting this hypothesis , 48. HowIn our study, younger age showed a trend toward being associated with a higher probability of therapy success. This direction of association has also been reported in other studies e.g. , 44)..44]).Interestingly, the Patient-Reported Outcome (PRO) that we focused on in this study with regard to the success of multi-modal pain therapy still seems to be different from therapy satisfaction as one Australian study had suggested .In conclusion, there are not many published works that have focused on the predictors of success in multi-modal pain therapy. The works cited in our discussion make reference to other pain management strategies, unimodal approaches, or rather unspecific pain therapy concepts. As Morasco and colleagues stated in their review: “Limited data are available to identify predictors of treatment outcome” .From the perspectives of both researchers and clinicians, a combined “PRO” criterion for assessing success in multi-modal pain therapy is desirable. There are two reasons for this: 1) it models the multifactorial genesis and therapy of chronic pain better than one single category criterion, and 2) a decision about whether a patient is considered a success or not is necessary for almost all analyses that would follow such as differences in outcomes between different patient collectives, observation of long-term outcomes of applied health services, etc. The combined success criterion that we developed involves well-established constructs whose measurement is implemented in routine care in pain treatment centers. A first empirical evaluation confirms evidence of content validity.


Most people referred to rapid access chest pain clinics have non-cardiac chest pain, and in those diagnosed with stable coronary heart disease, guidance recommends that first-line treatment is usually medication rather than revascularisation. Consequently, many patients are not reassured they have the correct diagnosis or treatment. A previous trial reported that, in people with non-cardiac chest pain, a brief discussion with a health psychologist before the tests about the meaning of potential results led to people being significantly more reassured. The aim of this pilot was to test study procedures and inform sample size for a future multi-centre trial and to gain initial estimates of effectiveness of the discussion intervention.This was a two-arm pilot randomised controlled trial in outpatient rapid access chest pain clinic in 120 people undergoing investigation for new onset, non-urgent chest pain. Eligible participants were randomised to receive either: a discussion about the meaning and implication of test results, delivered by a nurse before tests in clinic, plus a pre-test pamphlet covering the same information (Discussion arm) or the pre-test pamphlet alone (Pamphlet arm). Main outcome measures were recruitment rate and feasibility for a future multi-centre trial, with an estimate of reassurance in the groups at month 1 and 6 using a 5-item patient-reported scale.Two hundred and seventy people attended rapid access chest pain clinic during recruitment and 120/270 participants (44%) were randomised, 60 to each arm. There was no evidence of a difference between the Discussion and Pamphlet arms in the mean reassurance score at month 1 (34.2 vs 33.7) or at month 6 (35.3 vs 35.9). Patient-reported chest pain and use of heart medications were also similar between the two arms.A larger trial of the discussion intervention in the UK would not be warranted. Patients reported high levels of reassurance which were similar in patients receiving the discussion with a nurse and in those receiving a pamphlet alone.ISRCTN60618114 (assigned 27.05.2011).Current Controlled Trials The online version of this article (doi:10.1186/1471-2261-14-138) contains supplementary material, which is available to authorized users. Chest pain is a common reason why people access health services, with over 400,000 people per year being referred to rapid access chest pain clinics (RACPCs) in England . RACPCs Psychological factors have been targeted for treatment of NCCP. A recent review of randomised controlled trials (RCTs) of psychological interventions for symptomatic management of non-specific chest pain in patients with normal coronary anatomy showed modest to moderate success in terms of reduced chest pain frequency, particularly for those using cognitive behavioural therapy . This suplus a brief pre-test discussion with a health psychologist re-iterating the same information. People receiving the pre-test discussion were more reassured at one month after the test than patients randomised to the pamphlet alone or to the usual care arm (results explained after the test). Only the difference between the discussion and usual care arms reached statistical significance when considering mean reassurance score . The proportion of patients reporting chest pain at one month decreased significantly from baseline in the discussion group and pamphlet-only group, but not in the usual care group. It is possible that a key element in the relative success of the NZ pre-test interventions was the fact that they were delivered before the test. Donkin et al. found that, in people with NCCP, patients’ beliefs before an exercise stress test predicted the amount of reassurance they felt once they had received their negative test result [Petrie et al. (2007) undertook a small RCT in New Zealand (NZ) to assess whether it was possible to improve people’s preparedness for negative results, and so increase reassurance . The stut result .It is not only those who get a negative result in RACPC that may require reassurance; patients who receive a positive result (CHD) may also need reassuring. According to guidance from the National Institute for Health and Care Effectiveness (NICE), initial treatment for people diagnosed with stable CHD should be optimal pharmacotherapy to control symptoms together with effective secondary prevention. Interventions such as percutaneous coronary intervention or coronary artery bypass graft surgery should be restricted to those in whom optimal medical treatment fails to reduce symptoms, or if further testing by non-invasive imaging or by angiography shows left main stem or severe three-vessel disease . This paThe NZ study was limited by small sample size and short duration of follow-up (one month), and it only included people with NCCP. The clinical pathway for patients with chest pain differs between NZ and the UK and the discussion intervention was delivered by a health psychologist, a profession which is not routinely available in NHS outpatient clinics.The aim of this study was to adapt the discussion intervention for delivery in UK RACPCs and conduct a 2-arm pilot RCT comparing discussion (plus pamphlet) versus pamphlet alone. The pre-test pamphlet had already been recommended for use at the study site, as part of the chest pain pathway. The aim of the pilot trial was to test study procedures and gain data to inform the choice of primary outcome measure and the sample size calculation for a future, multi-centre RCT of effectiveness and cost-effectiveness. A preliminary investigation into whether the face-to-face discussion with a nurse may improve patient reassurance was also made. If a simple discussion intervention was found to be effective and cost-effective when delivered by a nurse to people with both NCCP and with a diagnosis of CHD in UK RACPCs, then it could be relatively easily incorporated into the clinical pathway.The NZ discussion intervention and pamphlet were adapted so that they covered both positive and negative test results, and the different treatment options. This was undertaken by an expert reference group with input from service users and RACPC staff. The pamphlet  versus the pamphlet alone in patients attending RACPC with new onset chest pain. The study was conducted at the University Hospital of South Manchester  RACPC. It was approved by North West 9 Research Ethics Committee – Greater Manchester West (reference no. 10/H1014/82) and the R&D Directorate of UHSM NHS Foundation Trust.Patients were sent information about the trial with their RACPC appointment letter and asked on arrival at clinic if they wished to take part. Patients were eligible if they were: attending RACPC for assessment of new-onset, non-urgent chest pain; able to read written English; able to comprehend spoken English; aged 18 years and over and able and willing to give informed consent. Patients were excluded if they: had a previously diagnosed cardiac pathology; had no symptoms of chest pain; were undertaking the exercise test as part of a pre-surgical medical examination; were pregnant; were involved in another research study; had a severe documented psychiatric disorder or had a life-threatening co-morbidity. Eligible patients gave written informed consent.Patients were randomised by a research nurse telephoning a remote randomisation service , University of York, UK). Random permuted blocks (block sizes of four and six) were used to allocate patients in a 1:1 ratio.Patients were told that the study was to compare two different ways of giving information about possible test results and treatments but not what the two formats were (pamphlet and discussion), or that one (the pamphlet) was considered to be the control arm. Staff treating patients in the RACPC appointment were not informed of treatment group allocation.After randomisation, all patients were given the pre-test pamphlet by the research nurse and were allowed sufficient time to read it. Patients allocated to the Discussion arm were then engaged in a brief (5–15 min) discussion with the research nurse. After receiving the pamphlet and discussion (Discussion arm), or the pamphlet alone (Pamphlet arm), patients returned to clinic and underwent assessment and tests as usual. All patients received the usual advice and information from staff during the initial RACPC appointment and any visits for further tests.Assessment in clinic was led by a senior cardiac specialist nurse according to UHSM’s protocol. It included an assessment of risk factors, typicality of symptoms (symptom score 0 to 3), Diamond and Forrester percentage score  and the At the end of the initial appointment patients were either given a diagnosis (CHD or NCCP) or, if a particular test  could not be performed on the day, they were asked to return for further tests. In each case, test results/diagnosis were explained to the patient by a clinic nurse, face-to-face, before leaving clinic. Patients with NCCP were reassured that there was no evidence of coronary disease and were advised to see their GP within the next week for reassessment for other causes of the chest pain. Other possible causes of the chest pain were suggested if the patient asked, but the nurse emphasised that they should go to their GP. If patients were at high risk of developing heart disease, lifestyle-change advice and leaflets were provided to the patient, and their GP was informed that aggressive risk factor management was needed. A CHD diagnosis resulted in the initiation of appropriate treatment: medication with review after 3 months or referral for an angiogram (possibly followed by angioplasty or surgery).As this was a pilot study, primary outcomes included recruitment rate and process, proportion of patients attending RACPC randomised, and reasons for non-participation. The study was powered to give initial estimates of effectiveness using the patient-reported 5-item reassurance questionnaire used in the NZ study  Table 11. OutcomSecondary outcomes included the feasibility/acceptability of the discussion intervention, follow-up rates, questionnaire completion rates, and patient-reported chest pain, heart-related drug use, Hospital Anxiety and Depression Scale (HADS) , Brief IAs a pilot trial, the main aim was to inform the feasibility and sample size of a future multi-centre trial, however a sample size calculation was carried out in order to obtain reasonable estimates of effectiveness within the study. Petrie et al.  observedAll analyses were conducted on an intention to treat basis, including all patients in the arms to which they were randomised, assuming data were available. No imputation was carried out in this pilot analysis. Analyses were conducted in SAS version 9.3 .The reliability and validity of the 5-item reassurance questionnaire was investigated using standard psychometric tests. Internal consistency between items was tested using Cronbach’s alpha, where >0.7 was considered acceptable . The disThe proportion of patients reassured  was sumPatient-reported data on resource use  and health related quality of life (EQ5D) were summarised by intervention arm and timepoint in order to preview future cost-effectiveness analysis issues, such as the accuracy and completeness of the data collection methods and the need to account for censored/missing data in a future trial.120 patients (60/arm) were recruited in 8 months (Oct 2011 to May 2012). Figure Forty-three 35.8%) patients received a diagnosis at their initial clinic visit, whilst 65 54.2%) returned for further tests and got their diagnosis at a second visit. The remaining 12 (10.0%) patients were invited to return for further tests but declined. Cardiac tests performed are presented in Table 5.8% pati.2% returReturn rates for the reassurance questionnaire were good, with 80% of participants returning a questionnaire at month 1 and at month 6. However, the timing of questionnaire return varied considerably, with month 1 questionnaires being completed at a median of 6 weeks (range 4 to 17) and month 6 questionnaires at a median of 28 weeks (range 24 to 41).The validity of the reassurance questionnaire was investigated in this sample as previously it was used for NCCP patients only . AlthougDifferences between the arms in the proportion of patients classed as reassured were not consistent over time . Other questionnaires ranged from 28-100% completed Table . ResultsAt baseline 92/113 (81%) patients reported some chest pain in the previous seven days. At month 1 a smaller proportion of the Discussion arm reported chest pain in the period since they last completed a questionnaire, 24/45 (53%) compared to 29/47 (62%) of the Pamphlet arm. At month 6 these proportions were more similar (59% in the Discussion arm vs 52% in the Pamphlet arm).Data from a 7-day chest pain diary completed at month 1 and month 6 showed a similar reduction in the proportion of patients reporting chest pain over time in both arms . At month 6 the proportions were 40% of the Discussion arm and 29% of the Pamphlet arm.The discussion intervention, assessed through qualitative interviews, was found to be acceptable to patients and staff. This will be reported more fully elsewhere. Change from baseline in treatment satisfaction from the SAQ-UK, showed a trend towards improvement at month 1 for the Discussion arm (median 8 points) with a return to baseline levels by month 6, whilst the Pamphlet arm showed no change at either timepoint. For other secondary outcomes, the intervention arms showed similar trends over time. Tables for secondary outcome data are available in Additional file Completion rates for resource use questions and EQ5D are summarised in Table An aim of the pilot was to provide information regarding the feasibility of conducting a large-scale trial in this patient population. Prior to the pilot, during the development of the interventions, patients received information about the study by letter and were asked to telephone a YTU researcher if they were interested in taking part. The response rate for this strategy was very poor and so it was altered for the pilot RCT. Rather than having actively to telephone a researcher, patients were asked by clinic staff on arrival at RACPC if they wanted to take part. This was much more successful, with an uptake rate for patients attending RACPC to recruitment into the pilot trial at around 40%.We considered that the discussion intervention could improve reassurance in all patients attending RACPC, so patients with both positive (CHD) and negative (NCCP) test results were included in this pilot. Consistent with other studies, the majority of the patients recruited in RACPC received an NCCP diagnosis. Only 14% of patients were diagnosed with CHD so our numbers were too small to investigate effectiveness in the CHD subgroup separately. For example, we wished to investigate how satisfied patients receiving a CHD diagnosis were with their proposed treatment, measured by the treatment satisfaction scale within SAQ-UK, however this was not possible due to low numbers. Future trials would have to be considerably larger to recruit a reasonable number of CHD patients from this setting.Return rates for the reassurance questionnaire were reasonable (80%) but many participants required one or more reminders. Up to three reminders were sent: reminder letters after 3 and 4 weeks with a final telephone reminder after 4 to 5 weeks. This led to some questionnaires being completed much later than planned. An earlier telephone reminder to encourage the return of primary outcome data should be considered for future trials. However, we do not think this altered our main outcomes following a sensitivity analysis including all patients with a questionnaire returned within a two week window either side of month 1.Completion rates for other patient-reported questionnaires were lower . This was partly because patients’ responses to the reassurance questionnaire were collected during the reminder telephone call, but not the other questionnaires. Also, it is possible that the other questionnaires seemed less relevant to patients at month 1 and month 6, particularly if they were no longer experiencing chest pain. For example the BIPQ refers to the patient’s “illness”, whilst SAQ-UK and Guys and St Thomas’ questionnaire refer to chest pain or tightness. For future studies in this area, only the most relevant questionnaires should be included, focussing on those with high compliance. Additional instructions within the questionnaire could be included to improve completion rates.This pilot study included investigations into the effectiveness of the discussion intervention, in terms of providing reassurance to patients about their test results in RACPC. According to a recent review “there is no generally accepted instrument to measure the level of reassurance” . We usedWe found no evidence of a difference in reassurance (both proportion of patients classed as “reassured” or mean score) between the discussion and pamphlet-only arms at month 1 or 6. The NZ study reported a significantly higher proportion of reassured patients in the discussion group (69%) compared to both the pamphlet-only group (40%) and a usual care control (35%) at month 1. Their results using mean reassurance score, however, were more similar to our pilot study; at month 1 the mean score was higher in the discussion group  compared to both the pamphlet-only  and control group , but only the difference between discussion and control groups reached statistical significance. The NZ study was just in patients who received a negative (NCCP) test result, whereas this UK pilot also included patients diagnosed with CHD. Our sensitivity analyses on the NCCP subgroup showed a possible trend for higher reassurance in the Discussion arm  and interaction with different staff for the different tests. It is possible that the usual care advice/information and explanation of test results in the UK RACPC was of a standard such that no additional benefit could be gained from a pre-test discussion. The discussion intervention was delivered by a research nurse who was not trained in psychological techniques and this may have contributed to the ineffectiveness of the discussion intervention. The target is to see UK patients in RACPC within 2 weeks of their GP visit, although this was not measured in this study, whereas patients had to wait longer for their clinic appointment in the NZ study (median 6 weeks). The NZ patients had more time to build up negative beliefs, which can influence reassurance in people with NCCP .A limitation to this pilot was the absence of a third “no pre-test information” control arm. This was because Greater Manchester, where the study was conducted, had recommended that a Petrie-style pre-test pamphlet should be usual care in RACPC. As a result, we have no information on whether a pre-test pamphlet alone is better than no pre-test information in a UK setting. Since RACPCs are likely to send an information pamphlet with the appointment letter anyway, for example explaining what clothes to wear and what tests the patients may have in RACPC, it may be that RACPCs in regions other than Greater Manchester should consider including information regarding possible test results and ensuing treatments.An additional face-to-face discussion with a nurse, which re-iterated information given in a pre-test pamphlet, did not significantly improve reassurance in patients. Whilst there was a possible trend in the NCCP subgroup for improved reassurance with a discussion, the difference was not considered to be clinically important and does not warrant a larger trial of the discussion intervention in UK RACPCs.Pretest pamphlet. All patients in the study received this pre-test pamphlet  at the start of their RACPC appointment. (PDF 469 KB)Additional file 1:Responses to 5 reassurance questions.doc. Plots of patients’ responses to the five questions (Questions 1 to 5) in the reassurance questionnaire at baseline (Questions 1 and 2 only), post-clinic, month 1 and month 6. Answers on a 0–10 scale. (DOCX 65 KB)Additional file 2:Chest pain diary data. Table presenting patient-reported chest pain in a 7-day period at month 1 and month 6, collected from chest pain diaries. (DOCX 15 KB)Additional file 3:Secondary outcome data_HADS_BIPQ_SAQ-UK_Guys and St Thomas. Three tables: (i) Change from baseline, at month 1 and month 6, for HADS, BIPQ and SAQ-UK; (ii) Individual item scores from the Brief Illness Perception Questionnaire at baseline, month 1 and month 6 and (iii) Guys and St Thomas’ chest pain score at baseline, month 1 and month 6. (DOCX 27 KB)Additional file 4:Reassurance Question 3. Patients’ response to Question 3 of the Reassurance Questionnaire (How reassured were you by the test?) for those categorised as “reassured” and “not reassured” according to the method of Petrie et al., 2007. (DOCX 15 KB)Additional file 5:NCCP subgroup results. Proportion of patients reassured and reassurance score at month 1 and month 6 for NCCP patients only. (DOCX 13 KB)Additional file 6:


Traumatic pseudoaneurysm of the axillary artery combined with brachial plexus injury is extremely rare. The factors that influence the symptoms and functional recovery related to this condition are unclear. Nine patients who had sustained this trauma were surgically treated at our unit between June 1999 and November 2010. The cause of trauma, symptoms, signs and examinations of neurological and vascular deficits, and the surgical findings of the involved nerves and vessels were recorded in detail. The functional recovery of vessels and nerves, as well as the extent of pain, were evaluated, respectively. The average length of patient follow-up was 4.5 years . After vessel repair, whether by endovascular or operative treatment, the distending, constant, and pulsating pain was relieved in all patients. Furthermore, examination of the radial artery pulse on the repaired side appeared normal at last follow-up. All patients showed satisfactory sensory recovery, with motor recovery rated as good in five patients and fair in four patients. The symptom characteristics varied with the location of the damage to the axillary artery. Ultrasound examination and computed tomography angiography are useful to evaluate vascular injury and provide valuable information for operative planning. Surgical exploration is an effective therapy with results related to the nerve injury condition of the brachial plexus. Traumatic pseudoaneurysm of the axillary artery combined with brachial plexus injury is extremely rare and has been reported in only a few cases Because previous reports on this condition have been limited to case reports, factors that influence the symptoms and functional recovery related to the condition remain unclear. For example, both endovascular repair and operative treatment of axillary artery pseudoaneurysm have been described in different reports The aims of this study were to assess the cause of trauma, treatment type, and treatment outcomes in a series of patients who had undergone surgery from traumatic pseudoaneurysm of the axillary artery combined with brachial plexus injury.This research has been approved by the Huashan Hospital Institutional Review Board.Because all patient's data (including the follow-up data) had been collected before we decided to start this study, and this retrospective data analytical research didn't influence the treatment and prognosis of the participants, the written informed consent from participants was exempted by the Institutional Review Board.From June 1999 to November 2010, nine patients  who had sustained a pseudoaneurysm of the axillary artery combined with brachial plexus injury were treated in our department. The patients had an average age of 28.7 years . Eight patients sustained injuries to the left upper limb and one patient to the right. Injury was caused by penetrating trauma in four patients and by blunt trauma in the other five. And in the five blunt trauma patients, four suffered injury from a traffic accident and the other one from a fall accident. All had sustained different kinds of neurologic deficits in the injured upper extremities . Seven pTwo patients had a clear thrill mass in their axillary fossa or infraclavicular region . Four paPatients' pain was evaluated using a visual analogue scale (VAS). The characteristics of the pain and its influence on daily living were also recorded .Patients were grouped by procedure type: in Group 1 (patient nos. 1–7), the pseudoaneurysm and brachial plexus injury were treated as part of the initial surgical exploration; and in Group 2 (patient nos. 8 and 9), a vascular stent-graft was inserted for the pseudoaneurysm before the surgery for the brachial plexus injury.The surgery was performed under general anesthesia. Each patient was placed in the supine position with a sandbag under their posterior chest. An infraclavical incision followed the deltopectoral interval, and as the anterior axillary fold was crossed, the incision continued in a zigzag fashion, entering the axilla and arm to explore the brachial artery. When an injury was found in the first or second portion of the axillary artery or was combined with a clavicular fracture preoperatively, a transverse supraclavical incision was occasionally also made .The proximal and distal parts of the axillary artery, vein, and brachial plexus were identified and retracted with elastic tapes, and the soft tissues covering the pseudoaneurysm were detached. If an injury was found in the first or second portion of the axillary artery, it was beneficial to identify the distal part of subclavian artery through the transverse supraclavical incision to control the blood supply of the pseudoaneurysm. The proximal and distal parts of the axillary artery were clamped by atraumatic vessel clamps. The capsule of the pseudoaneurysm was opened directly. After the thrombus and accumulated blood were removed, the axillary artery injury was evaluated . DependiAfter the pseudoaneurysm sac was removed, the brachial plexus was explored, and the method of repair was determined by the grade of the nerve injury. Only patient no. 4 sustained a partial severance injury of the medial cord. The continuities of brachial plexus in the other six patients were intact. Contusion of brachial plexus could be observed in all seven patients. Particularly in Patient no. 7, an obvious epineurium laceration on the medial cord was observed. If the brachial plexus had a contusion but its continuity was still maintained, microsurgical neurolysis was undertaken , as was Some patients with bone fractures also underwent open reduction internal fixation (ORIF). Following the operative procedures, drainage tubes were used to prevent hematoma formation.Low-dose heparin 5000 IU was administered with a hypodermic syringe, and low molecular weight dextran was administered in an intravenous drip infusion every 12 hours for 5 days. The use of anticoagulants was discontinued after 5 days.The surgery was performed under general anesthesia with the patient placed in an identical fashion to that of Group 1 patients. An infraclavical incision followed the deltopectoral interval to an extent necessary for nerve exploration only; vascular surgery was not necessary in this subgroup. The brachial plexus was regularly explored, and the method of repair was determined by the grade of the nerve injury. In patient no. 9, the lateral cord of the brachial plexus was embedded by a thickened scar but continuity was still maintained; thus microsurgical neurolysis was performed. In patient no. 8, the posterior cord of the brachial plexus could not be separated from the solid hematoma mass, and an intraoperative electrophysiological examination showed complete injury of the posterior cord. The segment of the posterior cord that was embedded in the hard scar tissue was thus abandoned and 6 cm length cable nerve grafting was performed.Because a stent was used for pseudoaneurysm before the surgery, the patients were asked to take aspirin 100 mg and clopidogrel 75 mg daily for at least 6 months. The day before surgery, the oral drugs were suspended and then reinitiated on postoperative day.Postoperatively, patients were reviewed daily until discharge, and then at approximately 1, 3, and 6 months postoperatively. Subsequently, the patients were advised to have follow-up examinations every 6 months. Follow-up examinations were as follows:According to the VAS, pain symptoms, which included the initial pain and the pain at the time of admission, were assessed preoperatively. Then, the pain intensity was measured every 4 hours in the first postoperative week until discharge. The characteristics of the pain and its impact on daily life were also recorded. The intensity and characteristics of pain were further assessed during routine follow-up .The radial artery pulse, skin temperature (monitored with a transistor thermoscope), color, swelling, and capillary blood refill of the relevant upper extremity were examined every 4 hours for 5 days postoperatively. Then, the radial artery pulse was palpated during routine follow-up, and CTA or ultrasound were used to further check the condition of the axillary artery unconventionally .The neurological function was assessed according to the British Medical Research Council System. The grade of nerve function recovery was evaluated according to Birch R's grading system The follow-up duration ranged from 24 to 135 months .Before the vessel repair, whether by endovascular or operative treatment, the characteristics of pain were described by all patients as being constant, distending and pulsating in the axillary region and upper extremities. The degree of pain became more intense with time. On admission, all patients had somnipathy and required analgesics to control the pain.For patient nos. 1–7, the degree of pain decreased markedly on postoperative day 1 and the type of pain changed to a stabbing pain. Analgesics were not required postoperatively. For patient nos. 8 and 9, pain decreased markedly after the endovascular treatment. The chief complaint changed thereafter to numbness and weakness prior to the nerve surgery. No patient complained of pain at last follow-up.Eight patients had a good vascular condition after the vessel repair, whether by endovascular or operative treatment. Only one patient (no. 7) presented with a slowed capillary blood refill and the radial artery pulse could not be detected on postoperative day 3. An emergency DSA examination was performed and it showed that the repaired axillary artery was unobstructed but that the subclavian artery was occluded by a 3 cm long thrombus. Thrombolytic therapy and stent-grafting was then performed by a vascular surgeon, and the radial artery pulse was recovered. The patient required anticoagulant medicines for 6 months. All patients maintained a good radial artery pulse during the follow-up period .The recovery of motor function was rated as good in five cases and fair in four cases, and the recovery of sensory function was good in all patients  Figure  and 7.In the five patients with good results , the continuities of brachial plexus were intact, and only neurolysis were undertaken. On the other hand, the four patients with fair motor function recovery  were those with definite nerve injuries: Patient no. 4 sustained a partial severance injury of the medial cord. In patient no. 7, an obvious epineurium laceration on the medial cord was observed. The patient nos. 8 and 9 with delayed nerve surgery, the brachial plexus was embedded by a thickened scar.Traumatic pseudoaneurysms of the axillary artery are rarely encountered in civilian clinical practice, with case reports comprising the majority of the literature on this condition. Penetration trauma, such as stab wounds and gun missile wounds, is the most common cause of pseudoaneurysms In general, traumatic axillary pseudoaneurysms arise from partial laceration of the axillary artery and subsequent bleeding from the lumen into the surrounding soft tissue. As the pseudoaneurysms expanded, pain or neurological deficit presents. However, although the surrounding bone and muscular girdle does provide considerable coverage and protection, it may obscure physical signs of vascular injury and hinder rapid operative exposure and vascular control. Some classic signs and symptoms of a pseudoaneurysm, such as expanding hematoma, continuous thrill, and a diminished radial artery pulse pressure, may be absent or unclear in this region. In our series of patients, only two (22.2%) had clear thrill masses and two (22.2%) had clear pulseless symptoms. For patient nos. 1–7, a diagnosis of pseudoaneurysm was missed during the initial evaluation in the primary hospitals.Based on our findings, it would appear that constant pain, especially distending and pulsating pain, may be an important indicator of an injury of the axillary artery. All nine patients had constant, distending, and pulsating pain, which became more serious over time. After the vessel repair, whether by endovascular or operative treatment, the pain decreased markedly and the VAS pain score decreased from a preoperative value of 5.9 to 2.4. These changes in pain were characteristic and may be helpful for future diagnosis and confirmation of resolution of the condition.If a pseudoaneurysm is suspected clinically, imaging modalities such as ultrasonic examination, CTA, MRA, or DSA may be useful to assist in diagnosis Digital Subtraction Angiography (DSA), when employed as the initial diagnostic modality for vascular injury, has the advantage of enabling the placement of a stent or occluding balloon as an endovascular treatment as required. However, conventional diagnostic DSA also has the disadvantage of being time-consuming and invasive, and may be associated with serious complications. CT angiography (CTA) is emerging as a novel modality to study arterial anatomy, with the additional advantages of being non-invasive and able to evaluate arterial trauma rapidly and reliably, reducing the delay before repair of the injury We did not use MRA in this study. Kapoor et al reported their experience and suggested that it may be useful as an alternative to CTA in patients who are contraindicated for CT contrast, e.g., those with an iodine allergy or reduced renal function Neurological compression may present as a complication in 10% to 30% of patients with a pseudoaneurysm 3  compared to 160 to 2400 cm3  in the latter. Therefore, the injured portion of the axillary artery played an important role in the clinical symptoms of the traumatic axillary artery pseudoaneurysm combined with the brachial plexus injury.Based on our findings, pain or signs of a neurological deficit may present more severely and dramatically when a pseudoaneurysm is present in the first or second portion of the axillary artery with a narrow space beneath the pectoralis minor, as was seen in patient nos. 2 and 5–9. Further, if the axillary artery injury occurred in the third portion, it would not compress the brachial plexus until the pseudoaneurysm became greatly enlarged in the axilla space over time, as was seen in patient nos. 1, 3, and 4. The range of intervals from trauma to neurological dysfunction was 0 to 9 days  in the former group of patients, compared with 0 to 60 days  in the latter. Further, the range of volumes of the pseudoaneurysms in the former group was 33 to 240 cmRoganovic et al reported their experience in treating peripheral nerve lesions associated with missile-induced pseudoaneurysms, stating that the resulting nerve damage could be severe if surgery was delayed for more than 3 to 4 days after symptoms of neurological decline Therefore, the key prognostic indicators of brachial plexus injury may be the nerve injury condition of brachial plexus and the treatment method, rather than the duration of the nerve compression.As endovascular repair techniques increase in popularity An extended interval between these two treatments may lead to surgical challenges during the secondary procedure: firstly, use of anticoagulation after the endovascular treatment carries a risk of hemorrhage in the operative area; and secondly, the hematoma in the pseudoaneurysm may become organized and form a solid mass after endovascular therapy, which is much harder than the sac of a pseudoaneurysm, leading to great difficulties in freeing the brachial plexus from the scar tissue and providing complete decompression of the brachial plexus, as was seen with patient nos. 8 and 9.Based on our experience with this cohort, open surgical exploration was the preferable treatment option to treat the axillary artery pseudoaneurysm combined with brachial plexus injury. Endovascular procedures can be viewed as a backup treatment option if the open procedure fails, as occurred with patient no. 7. The patient achieved reasonable nerve function recovery and good radial artery pulse during the follow-up period.In summary, both penetration and blunt trauma can cause an axillary artery pseudoaneurysm combined with brachial plexus injury. Violent blunt trauma has a high likelihood of causing immediate and serious neurological symptoms and fractures which could comprise the symptom of a pseudoaneurysm easily. Constant and expansive pain may be an important indicator in the diagnosis of a pseudoaneurysm. The characteristics of the symptoms are likely to correlate to the location of the injured axillary artery. Ultrasound examination and CTA are useful modalities to evaluate vascular injury and provide valuable information for operative planning. Open surgical exploration is an effective therapy, the results of which are linked to the nerve injury condition of brachial plexus.