Up to now, chronic low back pain without radicular symptoms is not classified and attributed in international literature as being "unspecific". For specific bracing of this patient group we use simple physical tests to predict the brace type the patient is most likely to benefit from. Based on these physical tests we have developed a simple functional classification of "unspecific" low back pain in patients with spinal deformities.Between January 2006 and July 2007 we have tested 130 patients  with spinal deformities  and chronic unspecific low back pain (pain for > 24 months) along with the indication for brace treatment for chronic unspecific low back pain. Some of the patients had symptoms of spinal claudication (n = 16). The "sagittal realignment test" (SRT) was applied, a lumbar hyperextension test, and the "sagittal delordosation test" (SDT). Additionally 3 female patients with spondylolisthesis were tested, including one female with symptoms of spinal claudication and 2 of these patients were 14 years of age and the other 43yrs old at the time of testing.117 Patients reported significant pain release in the SRT and 13 in the SDT (>/= 2 steps in the Roland & Morris VRS). 3 Patients had no significant pain release in both of the tests (< 2 steps in the Roland & Morris VRS).Pain intensity was high  before performing the physical tests  and low  while performing the physical test for the whole sample of patients. The differences where highly significant in the Wilcoxon test .In the 16 patients who did not respond to the SRT in the manual investigation we found hypermobility at L5/S1 or a spondylolisthesis at level L5/S1. In the other patients who responded well to the SRT loss of lumbar lordosis was the main issue, a finding which, according to scientific literature, correlates well with low back pain. The 3 patients who did not respond to either test had a fair pain reduction in a generally delordosing brace with an isolated small foam pad inserted at the level of L 2/3, leading to a lordosation at this region.® brace) and 13 with a sagittal delordosing brace (spondylogic® brace). There were patients with scoliosies and hyperkyphosiesbrace). Therefore a clear distribution of the patients from this sample to either chronic postural or chronic instability back pain was possible. In 2.3% a combined chronic low back pain from the findings obtained seems reasonable.With the exception of 3 patients (2.3%) a clear distribution to one of the two classes has been possible. 117 patients were supplied successfully with a sagittal realignment test-brace  should be used.Other factors than spinal deformities contribute to chronic low back pain. There is an increasing prevalence of low back pain, spinal stenosis and degenerative scoliosis in the aged population. Even though the exact percentage of patients with a symptomatology of spinal stenosis is not known, the main goal is to provide pain relief and improve functional lifestyle with minimum intervention . There aA sedentary lifestyle can lead to a loss of lumbar lordosis and this condition correlates with low back pain, spinal claudication, which may further have links with degenerative scoliosis in the adult population .Masiero et al.  have shoLow back pain has been seen in 1,416 out of 2,346 secondary school pupils (60%), and in 32% of the examined students. Statistical analysis has confirmed a correlation between LBP and such risk factors as the incorrect sedentary position , and smoking (p < .001 for students and p < .02 for pupils)  (related to the loss of lumbar lordosis) and instability low back pain [ILBP]  in patients with and without spinal deformities. Also a combination of both categories rarely seems possible. Simple physical tests are described to distinguish clinically between the two main categories .The strategy for physical rehabilitation and bracing differs essentially and can be separated into two basic categories:® brace  as can be seen on figure The bracing strategy for this condition consequently leads to a reduction of lumbar lordosis with the help of a simple 3-point system  leads to a scoliosis in some cases perhaps due to the reduction of the sagittal profile, which is supposed to destabilise the segmental configuration and its function .In individualised physical rehabilitation programs for low back pain, restoring function is the primary goal before specific bracing is offered, knowing that a loss of mobility correlates with an increase in pain intensity .The effectiveness of a classification-based low back pain program is yet to be established , but thiFurther investigations are necessary with patients not suffering from scoliosis or other spinal deformities, in order to reveal whether this classification also can be used in general low back pain patients.With the exception of 3 patients we have been able to distinguish between the two different types of 'unspecific low back pain' independent from the different kinds of spinal deformities. This finding seems to support the conclusion, as has been made in previous papers ,15, thatChronic unspecific low back pain is possible to clearly be classified physically in patients with spinal deformities. This functional classification is necessary to aid decision making as to which specific conservative approach  should be used.Other factors than spinal deformities contribute to chronic low back pain.Written informed consent was obtained from the patients for publication of their pictures.HRW is a consultant for Koob-Scolitech.MW does not declare any competing interests related to this paper.HRW: Patient acquisition, manuscript writing, statistics. MW: Patient acquisition, technical support.


The standard care in patients with a painful osteoporotic vertebral compression fracture (VCF) is conservative therapy. Percutaneous vertebroplasty (PV), a minimally invasive technique, is gaining popularity as a new treatment option. Many prospective and retrospective studies have reported on the effectiveness and safety of PV, but no large randomized controlled trial (RCT) has been published.To estimate cost-effectiveness of PV compared to conservative therapy in terms of: pain reduction, quality of life, complications, secondary fractures and mortality.The VERTOS II study is designed as a prospective, multicenter RCT. Patients with a painful VCF with bone edema on MR imaging, local back pain for 6 weeks or less, osteopenia and aged 50 years or older, after obtaining informed consent are included and randomized for PV or conservative therapy. In total 200 patients will be enrolled. Follow-up is at regular intervals during a 1-year period with standard questionnaires, addressing: clinical symptoms, pain medication, Visual Analogue Scale (VAS) score, quality of life and cost-effectiveness. Secondary fractures, necessary additional therapies and complications are recorded.The VERTOS II study is the first methodologically sound RCT designed to assess the cost-effectiveness of PV compared to conservative therapy in patients with an acute osteoporotic VCF., NCT00232466 Because of an aging population osteoporosis and associated fractures are becoming an important health issue, especially in Western societies. The incidence of a new vertebral compression fracture (VCF) in Europe is, at age 50–79 years, 1% per year in women and 0,6% per year in men and at age 75–79 years the incidence is 2,9% per year in women and 1,4% per year in men [Conservative therapy, bed rest, pain medication, physiotherapy and bracing, is considered the standard care in patients with symptomatic osteoporotic VCFs. Since the introduction of percutaneous vertebroplasty (PV) this minimal invasive therapy has gained popularity to stabilize osteoporotic VCFs and subsequently relief of associated local back pain. Despite the apparent lack of evidence, nowadays PV is considered an accepted therapy in many centres and acknowledged as a useful additional option in the care for these patients.In 1984 PV was developed in France for the treatment of painful aggressive vertebral angioma . In the Numerous prospective and retrospective studies on PV have been published and described a high clinical success rate -12. A reVERTOS, the first randomized controlled trial (RCT) with a limited group of 34 patients reports only on short-term results . Longer The development of new VCFs after PV in patients with osteoporosis is, in addition to pain relief and function, another important issue. It remains unclear whether PV is associated with a higher risk of secondary VCFs in adjacent vertebral bodies. Some authors believe in an increased risk of new VCFs after PV compared to the natural fracture incidence in osteoporosis, probably initiated by the increased stiffness of the cementated vertebral body -19. The Even now, after decades of performing PV no large RCT with mid-term follow-up has been published. Therefore, the VERTOS II study, a new RCT, was initiated to compare PV with conservative therapy in patients with osteoporotic VCFs.To estimate cost-effectiveness of PV compared to conservative therapy in terms of: pain reduction, QOL, complications, secondary fractures and mortality.VERTOS II is a multicenter RCT concerning the treatment of patients with a painful osteoporotic VCF. Patients are randomized to: (i) conservative therapy consisting of OPM, osteoporosis medication, physiotherapy or bracing; or (ii) PV with osteoporosis medication and analgesics, if necessary. Upon obtaining informed consent an independent central telephone operator completes the randomisation procedure, using a computer programme. The maximum allowed unbalance (block size) is six, with a maximum sample size of 84 for each participating centre. A total of 200 patients will be enrolled, 100 in each group. The enrolment of patients takes place in five centres: four centres in The Netherlands  and one in Belgium . Randomization started November 2005 with an expected completion of enrolment by March 2008. There is a one-year follow-up, with the possibility of an extended follow-up at two years. At present a total number of 111 patients is included.The overall Institutional Review Board approval was obtained at the St. Elisabeth Hospital in Tilburg. Each participating centre also obtained a local Institutional Review Board Approval. This study was registered in September 2005 at ClinicalTrials.gov [All patients, 50 years of age or older, visiting the hospital for an X-ray of the thoracic and/or lumbar spine, receive a short clinical questionnaire. Patients diagnosed with a VCF (Th5-L5), pain for six weeks or less and a Visual Analogue Scale (VAS) score of five and higher are contacted to participate in the study.After informed consent patients undergo a magnetic resonance imaging (MRI) scan of the spine, bone densitometry, blood sample screening and will visit the internist.All patients enrolled in the study comply with the following inclusion criteria: (1) VCF on X-ray of the spine , (2) level of VCF Th5 or lower, (3) back pain ≤ 6 weeks at time of X-ray, (4) ≥ 50 years of age, (5) bone edema on MRI of the fractured vertebral body, (6) focal tenderness on VCF level and (7) decreased bone density T-scores ≤ -1. The exclusion criteria are: (1) severe cardio-pulmonary condition, (2) untreatable coagulopathy, (3) systemic or local infection of the spine , (4) indication of alternative underlying disease  and (5) radicular and/or myelum compression syndrome. All patients contacted to participate in the study are registered in order to obtain an overview of the total patient population.MRI is performed in all patients prior to randomization using a 1 or 1,5 Tesla MRI scanner. The following MRI sequences are employed: sagittal T1 , T2 Turbo Spin Echo  and STIR  and transverse T2 TSE  at the level of the affected VCF. Bone edema in the VCF is defined as increased signal intensity at the STIR images and decreased signal intensity at the T1 weighted images. The shape and grade of every VCF is scored by two radiologists using the visual semiquantitative system according to Genant . When thThe pre-procedural work-up consists of: ECG, X-thorax and blood sampling. One hour prior to the procedure 2 g cefazolin is administered intravenously as prophylaxis.All vertebroplasties are performed by experienced radiologists in the angio suite under optimal  fluoroscopic guidance. The procedure takes place under sterile conditions. Local anaesthesia is administered from skin to the periosteum of the targeted pedicle. In two centres patients also receive fentanyl intravenously prior to the procedure. In one centre patients get propofol as intravenous anaesthetic.®, COOK Medical, Bloomington, Indiana, USA) is injected under continuous fluoroscopic imaging guidance using 1,0 cc syringes and 11 or 13 Gauge bone biopsy needles. The amount of injected cement in each treated vertebral body and any cement leakage is recorded. After the procedure a computed tomography (CT) scan of the treated vertebral bodies is performed to identify cement leakage or other possible local complications.Polymethylmetacrylate bone cement  Paracetamol (acetaminophen), (2) Tramadol, (3) Tramadol and Paracetamol, (4) Morphine. Non Steroid Anti Inflammatory Drugs (NSAID) are only prescribed if patients are intolerant for opiate-derivatives or in situations when already used. Corrections in dose and classification of pain medication are made if necessary by the internist. In most cases physiotherapy is prescribed. All patients receive osteoporosis medication, such as bisphosphonates together with supplemental calcium and vitamin D.All patients are asked to fill out standard questionnaires before and at one day, one week, one month, three months, six months and twelve months after PV or when conservative treatment is started by the internist.All standard questionnaires (except the questionnaire after one day) consist of the VAS score, QOL Questionnaire of the European Foundation for Osteoporosis , EQ-5D, Roland Morris Disability (RMD) Questionnaire. Cost-effectiveness is assessed and questions concerning use of pain medication, pain location, pain type are included.The VAS score is a pain score ranging from 0 (no pain) to 10 (worst pain ever) . The QuaThe RMD questionnaire is a disability questionnaire that measures the functional status of patients with back pain ,25.EQ-5D is a standardized instrument utilized as a measure of health related quality of life outcome . FurtherProcedural costs, other medical treatment and visits to alternative medical specialists, GP's and physical therapists are recorded and compared between groups. The questionnaire at day one post-procedural is a short questionnaire with a VAS score and questions about pain medication use, pain location, pain type and cost-effectiveness. All patients visit the internist at one and three months follow-up. All patients receive a pain diary. Patients are asked to fill out the VAS score and use of analgesics is recorded on a daily basis up until one month after randomization.At one, three and twelve months follow-up an X ray of the thoracic and lumbar spine, including antero-posterior and lateral views, is performed and compared to the X-ray at baseline. Secondary fractures are recorded. The shape and grade of every VCF is scored by two radiologists using the visual semiquantitative system according to Genant . When thBased on pilot data and literature we expect a difference of 25% in significant pain relief. If we assume that 20% withdraws from intervention we need approximately 100 patients in each group (α = 0.05 and β = 0.20).The data will be analysed according to the intention-to-treat principle. Standard statistical techniques will be used to describe characteristics of patients in both groups. We will compare baseline characteristics in the two treatment groups and if incomparability appears, we will in secondary analysis adjust for differences. The main outcome, significant pain relief will be compared with the Kaplan Meier survival analysis. Adjustment for possible baseline incomparability will be done with the Cox proportional hazards model.A cost-effectiveness analysis will be performed at four weeks and one year. Medical costs, time without burdensome pain and quality adjusted survival time will be compared. Bootstrapping and in case long-term modelling is required for comprehensive evaluation multivariate probabilistic sensitivity analysis will be used to evaluate uncertainty in the cost-effectiveness ratios.To the best of our knowledge the VERTOS II study is the first consistent RCT designed to assess the cost-effectiveness of PV compared to conservative therapy in patients with an acute osteoporotic VCF with mid-term follow-up.The author(s) declare that they have no competing interests.


Acute herpes zoster is a prevalent condition. One of its major symptoms is pain, which can highly influence patient's quality of life. Pain therapy is limited. Acupuncture is supposed to soften neuropathic pain conditions and might therefore act as a therapeutic alternative. Objective of the present study is to investigate whether a 4 week semi-standardised acupuncture is non-inferior to sham laser acupuncture and the anticonvulsive drug gabapentine in the treatment of pain associated with herpes zoster.Three-armed, randomised, placebo-controlled trial with a total follow-up time of 6 months. Up to estimated 336 patients  with acute herpes zoster pain (VAS > 30 mm) will be randomised to one of three groups (a) semi-standardised acupuncture (168 patients); (b) gabapentine with individualised dosage between 900–3600 mg/d (84 patients); (c) sham laser acupuncture. Intervention takes place over 4 weeks, all patients will receive analgesic therapy . Therapy phase includes 4 weeks in which group (a) and (c) consist of 12 sessions per patient, (b) visits depend on patients needs. Main outcome measure is to assess the alteration of pain intensity before and 1 week after treatment sessions . Secondary outcome measure are: alteration of pain intensity and frequency of pain attacks; alteration of different aspects of pain evaluated by standardised pain questionnaires ; effects on quality of life (SF 36); analgesic demand; alteration of sensoric perception by systematic quantitative sensory testing (QST); incidence of postherpetic neuralgia; side effects and cost effectiveness. Credibility of treatments will be assessed.This study is the first large-scale randomised placebo controlled trial to evaluate the efficacy of acupuncture compared to gabapentine and sham treatment and will provide valuable new information about the clinical and physiological effects of acupuncture and gabapentine in the treatment of acute herpes zoster pain. The study has been pragmatically designed to ensure that the study findings can be implemented into clinical practice if acupuncture can be shown to be an effective treatment strategy in acute herpes zoster pain.NCT00885586 Herpes zoster is a distinctive syndrome caused by reactivation of varicella zoster virus (VZV). It is characterized by a painful, blistering skin eruption following dermatomal distribution. As cellular immunity to VZV decreases with age, stress or because of immunosuppression, the virus reactivates and travels along the sensory nerves to the skin, causing distinctive prodromal pain followed by eruption of rash . The diaHerpes zoster can occur at any age but most commonly affects the elderly population. It is estimated that approximately 1 in 3 people will develop herpes zoster during their lifetime. The incidence of herpes zoster and the rate of herpes zoster-associated complications increase with age ,3.Symptoms that herald herpes zoster include pruritus, dysesthesia and pain along the distribution of the involved dermatome. The most distressing symptom is typically pain and the most feared complication beside CNS or ocular involvement is postherpetic neuralgia (PHN), the persistence of pain after rash healing. PHN is defined as pain persisting more than 3 months after the rash has resolved -6. In paThe development of effective strategies for the prevention and treatment of pain associated with herpes zoster and PHN is therefore an unmet public health need . Early rThe evidence base supports the oral use of tricyclic antidepressants, certain opioids, and gabapentinoids to prevent or treat PHN . AuthorsAcupuncture might figure as an alternate. There is some evidence, that acupuncture might be favourable in the treatment of neuropathic pain conditions . In addiThe primary objective of the trial presented is to investigate whether a 4 week semi-standardised acupuncture is non-inferior to the anticonvulsive drug gabapentine and sham laser acupuncture as placebo control in the treatment of pain associated with herpes zoster in addition to standardised analgesics. Secondary objectives include alteration of pain intensity and frequency of pain attacks, alteration of different aspects of pain evaluated by standardised pain questionnaires , effects on quality of life (SF 36), analgesic demand, alteration of sensoric perception, incidence of postherpetic neuralgia, side effects and cost effectiveness.The ACUZoster study is a three-armed, partially blinded randomised placebo-controlled trial investigating the efficacy of (a) acupuncture versus (b) gabapentine or (c) sham laser acupuncture in the treatment of pain associated with acute herpes zoster in addition to a standardised analgesic regimen respectively Figure . PatientThe ACUZoster trial aims to recruit up to a maximum of 336 patients. Recruitment for the trial started in November 2008. For inclusion patients must meet the following criteria: confirmed diagnosis of acute herpes zoster , pain intensity > 30 mm on a visual analogue scale (VAS 0–100 mm), standardised antiviral therapy with either brivudin (125 mg/d p.o.) or aciclovir (3 × 5–10 mg/kg/d KG i.v. or 5 × 800 mg/d p.o.).Main exclusion criteria are: Patients with insulin-dependent diabetes mellitus or other diseases influencing the peripheral sensibility ; patients under age (< 18 years); non-compliance; pregnancy or lactation; surgery within the last 3 month; severe heart/lung/kidney disease; diseases influencing the quality of life; psychiatric diseases ; chronic intake of analgesics, neuroleptics, antidepressants, corticoids, alpha-agonists; acupuncture, transdermal electric neurostimulation or other Complementary and Alternative Medicine treatment within the last 4 weeks; contraindications according to the summary of product information against analgesic treatment  or the investigational medicinal products .Participating trial physicians form part of the Multidisciplinary Pain Centre, Department of Anaesthesiology, University of Munich, Germany. All are experienced in pain treatment. Their acupuncture training reaches at least the level of "A-diploma" from one of the major German acupuncture societies (140 hours of curricular teaching) such as more than two years practical skills training at the Multidisciplinary Pain Centre. All physicians are experienced in working in clinical trials.®) which after including the patient to the trial allocates subjects to the respective arms balancing their age and genderThe randomization to one of the three arms of the study has been carried out by the Institute of Medical Information Technology, Biometry and Epidemiology, University of Munich, Germany (IBE). The investigators established a computer-based randomisation procedure  against a reference therapy (gabapentine) by simultaneous placebo control (sham laser acupuncture). The sample size estimation was based on the approach of Pigeot, Schäfer, and Röhmel . FollowiE = 15 mm• VAS change under acupuncture treatment: μR = 15 mm• VAS change under gabapentine (reference treatment): μP = 5 mm• VAS change under sham treatment: μ• Noninferiority margin: θ = 50% of the difference between the reference and the sham treatment (i.e. 5 mm VAS)• σ = 15,6 (estimated standard deviation within groups)• α = 0,025 (one-sided)• β = 0,2 (power: 80%)The necessary sample size under these assumptions was estimated as n = 336, with an optimal allocation of 168 patients to the acupuncture group and 84 patients each to the reference and placebo group. The dropout rate should not be higher than 10%.To allow for early termination, the study was designed to be assessed in four equally spaced interim analyses and one final analysis. Therefore, α-levels were adjusted according to O'Brien-Fleming to maintain the assumed 0,025-level for the overall study analysis .Interim analysis 1 : 0,00000Interim analysis 2 : 0,00039Interim analysis 3 : 0,00368Interim analysis 4 : 0,01102Overall study analysis : 0,02113Establishing noninferiority of the experimental therapy E (acupuncture) to the reference therapy R (Gabapentin) requires hierarchical testing of the following hypotheses using t tests :H0 is tested, using the same alpha level. If H0 is rejected, noninferiority is established. If the first step does not lead to the rejection of In a first step, All patients are treated by the attending dermatologists immediately after diagnosis of herpes zoster with a standardised antiviral therapy with either brivudin (125 mg/d p.o.) or aciclovir (3 × 5–10 mg/kg/d KG i.v. or 5 × 800 mg/d p.o.) as well as a symptomatic therapy of rash with local antiseptics according to the guidelines of the German Dermatological Society .In addition all patients have the possibility to receive a standardised analgesic treatment, according to WHO recommendations: step 1: nonopioid analgesics (Metamizol 4 × 1.0 g p.o. (4 × 40 gtt). Paracetamol 4 × 1.0 g), step 2: additionally moderate opioids , step 3 recommends use of stronger opioids (morphine). Escape medication available for step 2 and 3 are tramadol respectively morphine drops. Patients are not allowed to use other analgesics or analgetic therapies.Patients in the acupuncture group and the sham laser group will receive an acupuncture treatment. Acupuncture treatment is semi-standardised. Obligatory basic points with and without electrical stimulation have to be chosen. In addition facultative individual points can be chosen according to the diagnostic pattern and its corresponding meridian systems Table . DetaileDeutsche Ärztegesellschaft für Akupunktur, DÄGfA).The treatment strategies for acupuncture were developed based on a consensus process with experienced acupuncture experts representing members of the faculty of one of the major German societies for medical acupuncture: German Medical Acupuncture Association (Both treatment groups (needle and sham laser) consist of 12 sessions within 4 weeks (3 sessions/week). Each session is supposed to last 20 minutes. Resting time after both treatments is 20 minutes.® 0.15 × 20 mm or 0.3 × 30 mm and Asiamed® 0.25 × 40 mm) at defined acupuncture points and treatment areas. After needle insertion, the needle is manipulated until the subject obtains the deqi response (a deep aching or full feeling at the needle). Needle techniques include very point technique and dry needling. Further manipulation can be obtained applying an electro acupuncture device .(1) The needle acupuncture technique (a) used in this trial is performed using expendable needles (Seirin(2). Sham laser acupuncture (c) is applied at equivalent points as needle acupuncture, approaching a non-functioning laser pen which had been deactivated before by the manufacturer . Only red light is emitted. For emphasis of the imaginary power of this sham procedure, visual and acoustic signals are accompanying the red light emission. Patients are treated 45 sec. without skin contact.Patients are treated individually with gabapentine 900 mg/d – 3600 mg/d. According to the recommended scheme given by the manufacturer Table , the iniPatients are scheduled for re-assessment at least once a week.The trial has been approved by the Ethics Committee of the University of Munich such as the national component authority (Bundesinstitut für Arzneimittel und Medizinprodukte BfArM). The study protocol is in accordance to the declaration of Helsinki and the „ICH E6 Guideline for Good Clinical Practice”. Written informed consent is obtained from all patients.), including certification by an external audit according to ICH-GCP at the Institute for Medical Informatics, Biometrics and Epidemiology (IBE), Ludwig-Maximilians-University, Munich, Germany. Data protection such as adequate quality and safety control according to the guidelines for good clinical practice (CPMP/ICH/135/95) is assured. Trial registration is EudraCT 2006-004698-86.The study will be conducted according to common guidelines for clinical trials ; effects on quality of life SF 36), alteration of sensoric perception by systematic quantitative sensory testing (QST); incidence of postherpetic neuralgia; side effects and cost effectiveness. QST measurements are taken before and 1 week and 6 months after treatment. For detailed information please refer to Table 6, alteraExpectations about outcome are the main modifying variables of the placebo effect according to Strauss-Blasche . Patient® Software  All data entry will be carried out twice.Data entry is done with SPSS statistical software system . Data analysis will be done with SAS/STATTo our knowledge, the ACUZoster study is the first clinical study to investigate the effectiveness of an acupuncture treatment for acute herpes zoster pain in direct comparison to a standard analgesic treatment with gabapentine and to a sham laser acupuncture treatment in a three-armed, randomised controlled clinical trial. Compared to previous studies of acupuncture in the treatment of herpes zoster, this study has a more rigorous methodology and will include more patients.As pain in Herpes zoster is a prevalent symptom, zoster neuralgia figures an established model to investigate neuropathic pain therapies . TherefoInclusion and exclusion criteria were hold pragmatic in order to facilitate screening and recruitment. Exclusion criteria (besides standard items such as pregnancy or contra indications to the study medication) are diseases interfering with the patients' sensory perception. Our inclusion and exclusion criteria are based on further trials evaluating sensations and on recommendations found in the literature ,25,26.No single treatment has been shown to be completely effective for all sufferers of acute herpes zoster pain, and in the practical clinical scenario combinations of analgesic drugs are usually required to achieve partial relief of pain. Although there is an increasingly large number of trials that compare various analgesics to placebo, very few directly compare single therapies for which an evidence base exists, or address the issue of combining treatments . CurrentEven as the use of acupuncture has been reported being promising by smaller trials in neuralgia , neuropaTo our knowledge, this is the first study evaluating the effectiveness of acupuncture in a large scaled trial proofing its non-inferiority in comparison to the commonly used analgesic gabapentine, both in comparison to sham treatment.There is a controversial discussion on the subject of control procedures for clinical acupuncture trials ,30,31. TIn contrast, the choice of sham laser avoids activation of non-specific physiological effects such as stimulation of Aβ-fibres or C-fibres. Blinding of patients is easily achieved. Blinding both therapist and patients has been performed successful in a precedent trial , but wasA limitation is that the therapist is still familiar with the difference of needle versus laser. In addition, technical devices are not directly comparable to the manual skill of acupuncture, and they are also liable to evoke different patient belief in treatment effects .Given that the resolution to this controversy remains in doubt, the use of the sham laser methodology in this randomised single blinded study design avoids these mentioned concerns while still providing a valid control. Assessment of expectations is therefore still needed to demonstrate the level of belief in the treatments supporting our contention ,37.We chose sham laser acupuncture as a control as this is suggested to provoke only unspecific treatment effects . For theThis study is the first large-scale randomised placebo-controlled trial to evaluate the efficacy of acupuncture compared to gabapentine and sham treatment. It can be expected to provide valuable new information about the clinical and physiological effects of acupuncture and gabapentine in the treatment of acute herpes zoster pain. The study has been designed pragmatically to ensure that its findings can be implemented into clinical practice if acupuncture or gabapentine are found to be effective treatment strategies in acute herpes zoster pain.The authors declare that they have no competing interests.JF helped conceiving of the study and drafted the manuscript. SK, PL, LL and GMS participated in the design of the study. Parts of the study constitute the topics of the medical thesis of PH and ST. FP, JR and JP participated in the design of the study and coordinate the study in their departments. AC performed the sample size estimation. KJS organises internal and external monitoring. UM conceived of the biometrical study design. DI conceived of the study, he participated in the design and coordination of the study and supervised drafting the manuscript. All authors read, and approved of the final manuscript.The pre-publication history for this paper can be accessed here:


The minimal detectable change (MDC) and the minimal clinically important changes (MCIC) have been explored for nonspecific low back pain patients and are similar across different cultural settings. No data on MDC and MCIC for pain severity are available for neck pain patients. The objectives of this study were to estimate MDC and MCIC for pain severity in subacute and chronic neck pain (NP) patients, to assess if MDC and MCIC values are influenced by baseline values and to explore if they are different in the subset of patients reporting referred pain, and in subacute versus chronic patients.Subacute and chronic patients treated in routine clinical practice of the Spanish National Health Service for neck pain, with or without pain referred to the arm, and a pain severity ≥ 3 points on a pain intensity number rating scale (PI-NRS), were included in this study. Patients' own "global perceived effect" over a 3 month period was used as the external criterion. The minimal detectable change (MDC) was estimated by means of the standard error of measurement in patients who self-assess as unchanged. MCIC were estimated by the mean value of change score in patients who self-assess as improved , and by the optimal cutoff point in receiver operating characteristics curves (ROC). The effect on MDC and MCIC of initial scores, duration of pain, and existence of referred pain were assessed.658 patients were included, 487 of them with referred pain. MDC was 4.0 PI-NRS points for neck pain in the entire sample, 4.2 for neck pain in patients who also had referred pain, and 6.2 for referred pain. MCS was 4.1 and ROC was 1.5 for referred and for neck pain, both in the entire sample and in patients who also complained of referred pain. ROC was lower (0.5 PI-NRS points) for subacute than for chronic patients (1.5 points). MCS was higher for patients with more intense baseline pain, ranging from 2.4 to 4.9 PI-NRS for neck pain and from 2.4 to 5.3 for referred pain.In general, improvements ≤ 1.5 PI-NRS points could be seen as irrelevant. Above that value, the cutoff point for clinical relevance depends on the methods used to estimate MCIC and on the patient's baseline severity of pain. MDC and MCIC values in neck pain patients are similar to those for low back pain and other painful conditions. Minimal detectable change (MDC) is defined as the minimal change that falls outside the measurement error in the score of an instrument used to measure a symptom. Minimal clinicall important change (MCIC) is defined as the minimal change in the score that is meaningful for patients -12. DiffIt is useful to define MDC and MCIC for three main reasons: a) to calculate the sample size of studies aiming to assess the effectiveness or cost/effectiveness of interventions, b) to interpret the clinical relevance of results in studies on the effectiveness of treatments, and c) to help clinicians select among treatments with slight differences in their size effects, especially if they differ in their safety profiles, by allowing them to anticipate the clinical meaningfulness of the expected differences in their effects.MDC and MCIC for low back pain patients have been estimated in different cultural settings, with consistent results -9. In geIn patients with nonspecific neck pain (NP), MDC and MCIC have been explored for disability and quality of life -15. MDC Therefore, the primary objective of this study was to calculate the MDC and MCIC values for neck and referred pain severity in subacute and chronic NP patients treated in routine clinical practice. Additional objectives were: a) to explore if MDC and MCIC values for neck pain were different in the subset of patients who reported referred pain, b) to assess if MDC and MCIC values depended of baseline values, and c) to explore if they were different between subacute and chronic patients.This study was performed in the Balearic Health Service . The Ib-Salut is a public organization that belongs to the Spanish National Health Service, in which universal, tax funded health care services are provided to every citizen. The Ib-Salut covers all of the inhabitants of the Balearic Islands, who were about 916,500 when this study started. All of the 515 primary care physicians working at the 49 primary care centers belonging to the Ib-Salut were invited to participate in this study. No incentives were offered to the physicians or patients to participate.Data from patients recruited between January 1, 2004, and November 21, 2006, were included in this study. The study was approved by the Medical Ethics Committees of the participating institutions.The study population was defined as patients seeking care in the routine primary care practice of the Ib-Salut for subacute and chronic NP, with or without referred pain. Based on the available evidence for LBP patients, time limits to consider a patient as "subacute" and "chronic" were set at between 14 and 90 days, and longer than 90 days, respectively -20.In accordance with the current treatment protocol for neck pain in routine practice in the Ib-Salut, subacute and chronic patients were referred to a specialized Unit, where patients with a pain severity ≥ 3 points on a pain intensity numerical rating scale (PI-NRS) , underweInclusion criteria were: seeking health care at any of the primary care centers belonging to the Ib-Salut, for neck pain (NP) lasting 14 or more days, either with or without pain referred to the arm or arms, reporting a pain severity ≥ 3 points on a pain intensity numerical rating scale (PI-NRS) , and undExclusion criteria were : data suThe clinical condition of each patient was evaluated by the GPs at the primary care centers, who gathered data on duration of the current pain episode (in days); existence of referred pain (yes/no); diagnostic procedures performed in the previous 6 months, and current treatment. Patients were assessed on their first visit (baseline assessment) and three months later (12 week follow-up).At each assessment, patients rated, on their own and without assistance, two separate PI-NRS for current neck and referred pain, ranging from "0" (no pain) to "10" (worst imaginable pain). NP-related disability was not assessed since no validated instrument for that purpose is available in Spanish.At the 3 month follow-up, patients scored the change in their clinical status on the following scale: 1: Completely recovered, 2: improved, 3: unchanged, 4: worsened. Patients rated their clinical status on their own and without assistance.Since patients graded the evolution of their own clinical status, this classification was considered as the external criterion for a change to be "clinically important".The MDC and MCIC values in the PI-NRS for neck and referred pain were estimated for the follow-up period of 3 months.The Minimal Detectable Change (MDC) was calculated as 1.96 * √2 * SEM. ,12 The sThe following methods were used to estimate the MCIC :1. Mean Change Score (MCS): Mean change of PI-NRS in patients who scored "2" ("improved") on the external criterion. The changes of scores PI-NRS were calculated by subtracting the final values from the baseline values, so that positive scores correspond to improvement.2. Optimal cutoff point (ROC): Considering the PI-NRS change as a diagnostic test for discriminating between improved and not improved patients, and the external criterion as a gold standard, a ROC curve was developed describing the performance of changes in the corresponding scale to detect improvement . The optData from all recruited patients (both with and without referred pain) were included in the main analysis, in which MDC and MCIC values for neck pain were calculated. In a subgroup analysis, only patients with referred pain at baseline were included, and MDC and MCIC values for neck and referred pain were calculated.The effects of baseline scores and chronicity on MDC, MCS and ROC were estimated by defining subgroups. Values were estimated for patients with low baseline scores (lowest tertile) and high baseline scores (highest tertile). Values were also estimated for chronic and subacute patients, with the cut-off point for chronicity established at 90 days ,30. All In this study 678 patients were recruited and 20 (2.9%) were excluded because of refusal to sign the informed consent 15 cases), fever (3 cases) and patients feeling systematically unwell (2 cases). Therefore, 658 were included, and none were lost to follow-up. As seen in Table 5 cases, Three months later, 210 (31.9%) reported feeling completely recovered, 395 (60.0%) improved, 48 (7.3%) unchanged, and only 5 (0.8%) worse. Table Table As seen in those tables, MDC for neck pain is 4.0 PI-NRS points in the entire sample and it is 4.2 for patients who also complained from referred pain, and MDC for referred pain is 6.2 PI-NRS points. These values are not influenced by baseline pain severity or duration.MCS for neck pain is 4.1 PI-NRS points, both in the entire sample and in patients who also had referred pain, and it is also 4.1 PI-NRS for referred pain. MCS remains constant across subacute and chronic patients, but it is higher for patients with more severe baseline pain. Depending on baseline severity, MCS values range from 2.5 to 4.9 PI-NRS points for neck pain, and from 2.4 to 5.3 for referred pain ,  while otThe results of this study provide a reference for what "relevant" improvement means in terms of neck and referred pain for subacute and chronic neck pain patients treated in routine clinical practice. The values provided here may be useful for clinicians to interpret patients' evolution depending on the baseline severity of their symptoms and duration of pain. They can also assist researchers in selecting an MCIC value depending on the context in which it is going to be used.The author(s) declare that they have no competing interests.FK conceived the study and participated in its design, coordination and the drafting of the manuscript.VA, AR, AC, AM and JZ performed the statistical analysis and participated in the drafting of the manuscript. VA also participated in the design of the study.JC, LA, MT and MAM collaborated in coordination and data collection.MTG, MG and NM participated in the study design, and drafting and editing of the manuscript.All authors revised the design, revised the draft manuscript and read and approved its final version.This manuscript does not contain information about medical device(s).This study was funded by the Kovacs Foundation.The authors received no individual funding for their work.Th funding institution played no role in the study.No benefits in any form have been or will be received from a commercial party related directly or indirectly to the subject of this manuscript.The pre-publication history for this paper can be accessed here:


The Dutch Walking Stairs, Walking Ability and Rising and Sitting Questionnaires are three validated instruments to measure physical activity and limitations in daily living in patients with lower extremity disorders living at home of which no German equivalents are available. Our scope was to translate the Walking Stairs, Walking Ability and Rising and Sitting Questionnaires into German and to verify its concurrent validity in the two domains pain and activities in daily living by comparing them with the corresponding measures on the Visual Analogue Scale.We translated the Walking Stairs, Walking Ability and Rising and Sitting Questionnaires according to published guidelines. Demographic data and validity were assessed in 52 consecutive patients with Complex Regional Pain Syndrome 1 of the lower extremity. Information on age, duration of symptoms, type of Complex Regional Pain Syndrome 1 and type of initiating event were obtained. We assessed the concurrent validity in the two domains pain and activities in daily living by comparing them with the corresponding measures on the Visual Analogue Scale.We found that variability in the German Walking Stairs, Walking Ability and Rising and Sitting Questionnaires was largely explained by measures of pain and activities in daily living on the Visual Analogue Scale.Our study shows that the domains pain and activities in daily living are properly represented in the German versions of the Walking Stairs, Walking Ability and Raising and Sitting Questionnaires. We would like to propagate their use in clinical practice and research alike. Complex Regional Pain Syndrome (CRPS) is a painful condition that often results in substantial disability . Two typIn the past the focus of CRPS research was mainly on symptoms and pain. Little attention has been given to the disabilities associated with CRPS. As a consequence, little information is available on the problems CRPS patients encounter in activities in daily living, and specific measurement instruments to address these problems are lacking .http://www.trendconsortium.nl. Up to now, these instruments are only available in Dutch and English . In this paper we describe how we translated the Walking Stairs, Walking Ability and Rising and Sitting Questionnaires into German and how we verified its concurrent validity in the two domains pain and activities in daily living by comparing them with the corresponding measures on the Visual Analogue Scale (VAS).We are only aware of one instrument, which allows measuring the functional limitation of CRPS patients. In 2000, Oerlemans et al. developed and validated the Radboud Skills Questionniare (RASQ) to map alterations in the level of disability in patients with CRPS of the upper extremity . Today thttp://www.morbus-sudeck.ch, http://sudeck.foren-city.de). We included all eligible and consenting adult patients suffering from CRPS 1 of the lower extremity with fulfilled International Association for the Study of Pain (IASP) criteria, more than 18 years of age, illness duration of more than three months and the ability to complete the questionnaires. The study protocol was approved by the local Ethics Committee  and informed consent was obtained from all participants.We recruited patients from the outpatient clinic of Balgrist University Hospital, Zurich, Switzerland and through advertisements posted on two self-help homepages for patients afflicted with CRPS  living on the Visual Analogue Scale (VAS) . We hypothesized, that a higher score on the VAS (pain and ADL) is associated with a more severe functional impairment in CRPS 1 patients.Values are reported as mean ± SD, medians and interquartile ranges (IQR) or as absolute number and percentage. Linear regression analysis and mean prediction interval were used to assess the relationship between the three questionnaires and the VAS pain respectively VAS of activities in daily living. A probability value of p < 0.05 was considered statistically significant for all tests. We performed all statistical analyses with the SPSS 12 statistical software package .The wording of the questions and response options correspond to the original version. We did not add or remove items nor changed response categories.The demographic and clinical characteristics of the participants are shown in table Self perceived pain and restrictions in activities in daily living were 5.7 + 2.1 and 5.6 + 2.2 on the VAS. Average of the total score of the questionnaires was 29.4 + 13.2 . For the detailed analysis see table 2 = 0.25). Higher VAS pain scores indicated higher total functional limitation ). These results were consistent within the subdomains walking stairs ), walking ability ), and raising and sitting ). For details see table VAS pain scores explained a considerable amount of variability of the total score R = 0.25. 2 = 0.37). Higher VAS ADL scores indicated higher total functional limitation ). These results were consistent across the subdomains walking stairs ), walking ability ) and raising and sitting ).VAS ADL scores explained a substantial amount of variability of the total score  and the fulfilment of established diagnostic criteria . We onlyhttp://www.trendconsortium.nl).This validated German version will help to determine the disability of patients suffering from CRPS 1 of the lower extremity in German speaking countries in clinical practice as well as in research. This is important, if these questionnaires will be used to document follow up in longitudinal studies or intervention studies . In addiInvestigators in German-speaking countries now have the possibility to assess physical activity and limitations in daily living in patients with CRPS 1 of the lower extremity.Information about patients' disability can be used to enhance clinical decision making and to observe the course of the condition.Our study demonstrates a sufficient concurrent validity for the German versions of the Walking Stairs, Walking Ability and Rising and Sitting Questionnaires for the use in clinical practice as well as research. We would like to propagate their use in clinical practice and research alike.The authors declare that they have no competing interests.All authors participated in the study design. FB and LMB drafted the protocol and the manuscript. CH and AL assisted in patient recruiting. RK and FB obtained funding. CH, AGHK, RSGMP and JM critically reviewed the protocol and the manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2474/11/108/prepub


Due to tolerance development and adverse side effects, chronic pain patients frequently need to be switched to alternative opioid therapyTo assess the efficacy and tolerability of an alternative transdermally applied (TDS) opioid in patients with chronic cancer pain receiving insufficient analgesia using their present treatment.A total of 32 patients received alternative opioid therapy, 16 were switched from buprenorphine to fentanyl and 16 were switched from fentanyl to buprenorphine. The dosage used was 50% of that indicated in equipotency conversion tables. Pain relief was assessed at weekly intervals for the next 3 weeksPain relief as assessed by VAS, PPI, and PRI significantly improved (p < 0.0001) in all patients at all 3 follow up visits. After 3 weeks of treatment, the reduction in the mean VAS, PPI, and PRI scores in the fentanyl and buprenorphine groups was 68, 77, 74, and 69, 79, and 62%, respectively. Over the same time period the use of oral morphine as rescue medication was reduced from 27.5 ± 20.5 (mean ± SD) to 3.75 ± 8.06, and 33.8 ± 18.9 to 3.75 ± 10.9 mg/day in the fentanyl and buprenorphine groups, respectively. There was no significant difference in either pain relief or rescue medication use between the two patient groups The number of patient with adverse events fell during the study. After the third week of the treatment the number of patients with constipation was reduced from 11 to 5, and 10 to 4 patients in the fentanyl and buprenorphine groups, respectively. There was a similar reduction in the incidence of nausea and vomiting. No sedation was seen in any patient after one week of treatment.Opioid switching at 50% of the calculated equianalgesic dose produced a significant reduction in pain levels and rescue medication. The incidence of side effects decreased and no new side effects were noted. Further studies are required to provide individualized treatment for patients according to their different types of cancer. Opioids represent the principal therapy in chronic moderate to severe cancer pain treatment. The development of transdermal polymer matrix systems for opioid administration has resulted in several advantages compared to oral, sublingual or parenteral administration. These systems represent a non-invasive method, effective and well accepted by cancer patients who often have gastrointestinal problems and difficulties with oral medication  either due to the cancer itself or due to the side-effects on oral or parenteral concomitant medication . At presRecent studies have shown that opioid transdermal delivery systems have numerous advantages since they permit continuous controlled release of the opioid for 72, or even up to 96 hours depending on the product, thus reducing peaks in plasma drug concentrations resulting in consistent and long-term pain relief. In addition, they are associated with a lower rate of adverse events. Overall, they represent a very useful therapy since they offer adequate analgesia with comparably low side-effects and non-invasive administration. However, analgesic tolerance can develop with any long-term opioid treatment, requiring an increase in drug dosage in order to obtain the same analgesic effect. As a consequence this normally results in an increase in side effects . In caseConsidering the importance of this strategy, we carried out this study on opioid switching using two polymer matrix systems: transdermal buprenorphine (BTDS) and transdermal fentanyl (FTDS) substituting the opioid previously taken with the other type  in patients who were dissatisfied with their previous therapy with respect to inadequate analgesia, side-effects or both. Based on previously published data and considering the mechanisms which form the basis of tolerance phenomena, the aim of this study was to evaluate the switching dose between transdermal opioids, with regard to analgesic efficacy and the reduction of side-effects.Eligible patients, of either sex, were suffering from chronic pain and had been treated for the previous three months with either transdermal buprenorphine or transdermal fentanyl. Inclusion criteria required inadequate analgesia .Exclusion criteria included renal insufficiency (serum creatinine clearance less than 60 ml/min), moderate or severe hepatic disease , history of hepatitis B or C, or acute hepatitis A in the last three months, HIV, clinically significant cardiovascular and/or respiratory diseases, pregnancy, lactation, alcohol consumption, psychotropic drug consumption. Also excluded were patients expecting chemotherapy or radiotherapy cycles during the study, those with known allergy to the medicines or matrix patch components, those with extensive skin disease, and patients who were currently participating in, or had within the last 30 days participated in, other clinical trials. Patients with neurological and/or psychological conditions that might hinder completing daily diaries and pain scales were also excluded.The study was carried out according to the ethical principles of the current amended version of Declaration of Helsinki, after ethics committee approval. All the patients gave their signed informed consent before participation in the study.The four-week study was organized with a Screening visit (V0) followed by a Recruitment visit (V1) one week later, when treatment was initiated. Three control visits  at weekly intervals then followed.During the screening visit (V0) the age, sex and race of each patient was noted and a detailed history of the cancer disease and of the concomitant pain was taken. Each patient underwent a thorough a physical examination including height, weight and vital signs . The presence or absence of other concomitant disease and their treatment was registered. Haematochemical analyses were carried out to evaluate hepatic and renal function  . An ECG was performed together with a neurological examination. During the visit the type of transdermal patch and the dose were noted.At the end of the screening visit the patients were discharged and told to continue the previous therapy. They were asked to return to the department for the recruitment visit one week later. All the patients received a diary in which to rate their pain every morning on awakening on a VAS scale. Patients were permitted to continue with rescue medication  morphine) up to a maximum of three daily doses, which was recorded in the diary.During the recruitment visit each patient underwent a thorough physical examination: general appearance, eyes, lungs, heart, abdomen, musculoskeletal and vital signs were evaluated. The results of haematochemical examinations for renal and hepatic function and the results of the neurological and cardiological examinations were recorded. Adverse Events (AEs) were evaluated. The consumption of rescue medication in mg/day was recorded.Patients complying with the inclusion criteria were divided into two groups according to the administered therapy up to the recruitment visit. The method used for transdermal patch switching was to replace the first opioid patch with the alternative one, deducting 50% from the dose calculated according to equianalgesic tables.The FTDS group were patients at the screening visit who had taken buprenorphine TDS 70 μg/h and suffered side-effects and refractory pain and had taken this dose continuously during the pre-recruitment week. At the recruitment visit, the transdermal buprenorphine patch in these patients was replaced by a 25 μg/h transdermal fentanyl patch, positioned at different skin site on the thorax, arm or back.The BTDS group were patients at the screening visit who had taken fentanyl TTS 75 μg/h and suffered side-effects and refractory pain and had taken this dose continuously during the pre-recruitment week. The transdermal fentanyl patch in these patients was replaced by a 52.5 μg/h transdermal buprenorphine patch, positioned at different skin site on the thorax, arm or back.Rescue medication with 20 mg of immediate-release oral morphine was prescribed to each patient up to three times a day. At the end of the recruitment visit (V1) all the patients were asked to return after one week for the first control visit (V2), and to continue keeping their daily diaries.Mean weekly pain on the basis of the VAS scores in diaries (VAS 0 = no pain to VAS 100 = intolerable pain) was recorded throughout the 4 week period. The Present Pain Intensity  and Pain Rating Index (PRI) were assessed during each visit from V1 to V4. The PRI was taken from the Short-Form Mc Gill Pain Questionnaire and comprised 15 items investigating both the sensorial (11 items) and the emotional sphere of pain (4 items) with a score from 0 to 3 for each item (0–45). In all cases the necessity of rescue medication was registered as milligrams of oral morphine per day. Another parameter taken into consideration was the patients' satisfaction with the new therapy. It was evaluated by means of the simple question: "Are you satisfied with your analgesic treatment?" The patients could answer only "Yes/No".The primary efficacy measure was pain reduction as recorded by patients both in a daily dairy using VAS and during the visits by PPI and PRI. The secondary efficacy measure was the reduction of rescue mediation consumption as milligrams of IR oral morphine per day.In all patients, the presence (Yes) or absence (No) of AEs was evaluated and recorded in response to questions posed for nausea and/or vomiting, constipation, and dysphoria. The level of sedation was evaluated by a 4-point scale .For each of the two treatment groups, a paired Student t test was used to compare the mean values of the primary efficacy parameters  and rescue medication consumption for the same patients measured at Visits 2, 3, and 4 compared to baseline values (Visit 1). A Student t test for independent variables was used to compare the two independent treatment groups.In total, 40 Caucasian patients were screened and 32 were enrolled. All the enrolled patients completed the study. The demographic characteristics of the patients are shown in table There were no differences in vital signs and no respiratory depression was noted in either group. No significant differences were showed between Group BTDS and Group FTDS regarding VAS, PPI, PRI values, AEs incidence and rescue medication consumption on enrolment.In both groups of patients, there was a statistically significant reduction p < 0.0001) of the weekly VAS after 1, 2 and 3 weeks treatment compared to V1 values. The mean decrease in the FDTS group was 34% (V2), 57% (V3) and 68% (V4), and in the BTDS group was 33% (V2), 60% (V3), 69% (V4)  at each visit after commencing treatment. The mean decrease in the FTDS group was 54% V2), 71% (V3), and 77% (V4), and in the BTDS group 59% (V2), 75% (V3), and 79% (V4)  as showed in table In all patients there was a reduction in rescue medication at Visits 2, 3, and 4 as measured by the daily consumption of IR oral morphine . The number of patients with constipation was also reduced; BTDS group: V1 11 pts, V2 4 pts, V3 5 pts, V4 5 pts and similarly in the FTDS group: V1 10 pts, V2 6 pts, V3 4 pts, V4 5 pts . This applies not only to the therapeutic formulation but also to the side effect analysis, so that we can gain a better understanding of how much the adverse events are connected with the choice of opioid and how much they are related, or supported by, the underlying pathology of the disease.In our study we decided to change the drug and not the route of administration, because patients prefer a transdermal route as it does not interfere with their daily activities, it is easy to use, and is non invasive. Transdermal route patients only have to remember their opioid medication every 72 hours. Reduced constipation, nausea and vomiting result in a better quality of life. These factors account for better patient compliance and lead to the feeling of greater independency from treatment. All patients stated that they were satisfied with the therapy and this result is particularly important because, as the international literature underlines, psychological factors interfere with patients' quality of life and disease prognosis ,18-20.In contrast with our results, other studies discuss the necessity of using equianalgesic doses in opioid switching to obtain good pain control . These dIn conclusion, we think that further studies should be performed in order to find safe and effective opioid switching methods necessary to give greater insight into the difficult balance between analgesia and toxicity. It is also important to consider individual variables, such as psychological distress in cancer patients, as these are important as prognostic factors since they affect therapeutic results.The authors declare that they have no competing interests.A.C. as principal investigator of this study, had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analyses. Study concept and design: A.C., P.M.C. Acquisition of data: S.P., P.V., B.M., G.E. Analysis and interpretation of data: S.P., P.V. Drafting of the manuscript: S.P., P.V., B.M., G.E. Critical revision of the manuscript for important intellectual content: A.C., P.M.C., P.M.B. Study supervision: A.C., P.M.C., P.M.B. All authors read and approved the final manuscripts


Numerical rating scales (NRS), and verbal rating scales (VRS) showed to be reliable and valid tools for subjective cancer pain measurement, but no one of them consistently proved to be superior to the other. Aim of the present study is to compare NRS and VRS performance in assessing breakthrough or episodic pain (BP-EP) exacerbations.In a cross sectional multicentre study carried out on a sample of 240 advanced cancer patients with pain, background pain and BP-EP intensity in the last 24 hours were measured using both a 6-point VRS and a 0-10 NRS. In order to evaluate the reproducibility of the two scales, a subsample of 60 patients was randomly selected and the questionnaire was administered for a second time three to four hours later. The proportion of "inconsistent"  evaluations was calculated to compare the two scales capability in discriminating between background and peak pain intensity and Cohen's K was calculated to compare their reproducibility.NRS revealed higher discriminatory capability than VRS in distinguishing between background and peak pain intensity with a lower proportion of patients giving inconsistent evaluations (14% vs. 25%). NRS also showed higher reproducibility when measuring pain exacerbations (Cohen's K of 0.86 for NRS vs. 0.53 for VRS) while the reproducibility of the two scales in evaluating background pain was similar (Cohen's K of 0.80 vs. 0.77).Our results suggest that, in the measurement of cancer pain exacerbations, patients use NRS more appropriately than VRS and as such NRS should be preferred to VRS in this patient's population. The importance of pain measurement in routine cancer patient assessment and in research is advocated by experts and scientific associations -5, and sSubjective pain intensity is the most often considered among the dimensions of pain that should be assessed , both inFor these reasons VAS was not considered in our study, which instead focused on VRS and NRS; both scales are easy to use with most patients and have shown good psychometric properties  but no sIn developing a new questionnaire for breakthrough or intense episodic pain (BP-EP) evaluation, both an 11-point NRS and a 6-level VRS were included in the questionnaire with the aim of comparing their performance in evaluating pain exacerbations in terms of reproducibility and of discriminatory capability to distinguish pain exacerbations over a background of less severe pain.This analysis is based on data from 240 patients consecutively enrolled in a cross sectional Italian multicentre study aimed at estimating BP-EP prevalence in a population of advanced cancer patients with pain. The results on prevalence are going to be presented elsewhere. Patients were included if they had a diagnosis of cancer, had cancer-related chronic pain, were at least 18 years of age, and were able to provide written informed consent. Patients were excluded if their pain was exclusively due to a surgical procedure.The questionnaire for BP-EP evaluation was administered as an interview to the patients by a nurse or a physician; patients were asked to assess their background pain intensity referring to the previous 24 hours and, if they reported to have also episodes of pain exacerbations , they were asked to rate the intensity of their most severe episode during the previous 24. Only for the aims of the present study, the questionnaire for BP-EP evaluation contained a double evaluation both for background pain and for pain intensity exacerbations; one evaluation was performed using a 6-point VRS and patients were asked to rate their pain intensity choosing from the following descriptors: None, Very mild, Mild, Moderate, Severe, Very severe ; the secThe sample size of 240 patients was calculated based on the main outcome of the study . 60 patients were enrolled in the retest phase to ensure a 0.18 precision for the estimates of the reproducibility indexes . This last calculation was performed in the hypothesis that the reproducibility indexes to be estimated were 0.8 [The capability of the two scales to discriminate between background pain and pain exacerbations intensities, was measured calculating the proportion of "consistent" and of "inconsistent" evaluations; the evaluation provided by a patient was defined as "consistent" if background pain intensity was lower than peak intensity, otherwise it was defined as "inconsistent" . A higher percentage of inconsistent evaluations on one scale with respect to the other indicates that the former is less adequate for pain exacerbation measurement. The difference between the percentage of inconsistent evaluations obtained through NRS and through VRS, along with its 95% Confidence Interval (95% CI), was estimated to compare the two scales.Scales reproducibility was evaluated through weighted Kappa (with quadratic weights) and its 95% CI, as a measure of agreement between the first and the second administration of the same scale in the subsample of 60 patients. The strength of the agreement was defined as poor (K < 0.40), moderate (0.41-0.60), substantial (0.61-0.80) and almost perfect (0.81-1.00) .The study was approved by the ethics committees of each of the 8 participating centers. It was carried out in accordance with the Declaration of Helsinki, and with Italian laws regarding clinical research. All patients provided written informed consent.A study sample of 240 consecutive cancer patients with cancer-related chronic pain Table  was enroFig. Fig Table Table This study, comparing NRS and VRS psychometric properties in the assessment of pain exacerbations, reveals a significantly higher discriminatory capability of NRS in distinguishing between background and peak pain intensities referred to the pain experienced in the previous 24 hours; patients gave inconsistent evaluations in 23 cases with NRS (14%) versus 40 cases with VRS (25%). NRS also showed higher reproducibility when measuring pain exacerbations (Cohen's K of 0.86 for NRS vs. 0.53 for VRS) while the reproducibility of the two scales was similar in evaluating background pain (Cohen's K of 0.80 vs. 0.77).In agreement with previous studies ,13,26 NRMoreover the wider range of NRS scores at any value of VRS suggests that patients benefit from the greater sensitivity offered by the higher number of response levels possible with NRS. The possibility to increase the number of verbal descriptors in VRS scales has also limitations. A study by Rosier et al.  showed tIn this experience no data were missing for both scales. This is probably due to the fact that the pain evaluations were not self-completed by patients but administered by a trained nurse or physician, who could properly help patients in understanding questions. Some patients who did not give consent may have had physical or cognitive impairment and this could have contributed to increase the compliance with pain assessment. Although good compliance with the use of NRS is confirmed also in the clinical use, the two scales applicability should be verified in different conditions such as self-administration and repeated use in time.One limit of the study could be that the two scales have different upper anchor descriptors: "The worst possible pain" for the NRS and "Very severe" for the VRS. The two scales formats have been chosen because they both have undergone specific validation studies in Italian and other languages ,31,32 anThe ability of the patient to report his/her pain assessment over the same 24 hours period 3 to 4 hours after the first administration, could be questionable. This choice is aimed to avoid reproducibility overestimation due to memory effect of the first assessment. Furthermore the potential bias introduced by a 3 to 4 hours interval, should have resulted in an underestimation of reproducibility while the indexes obtained (Cohen's K of 0.80 and 0.77 respectively for baseline NRS and VRS) indicate substantial agreement.In addition, these results should be considered within the limits of the study methods which required the assessment of previous 24 hours pain in a population of advanced cancer patients with no clinically evident cognitive impairment and in relatively good general conditions (38% of patients were out patients and only 14% were admitted to hospice or home care programs).Previous studies have already compared various scales for pain measurement and gave different results ,26,33-35The data from the literature favoring the use of NRS for pain measurement are based on its intrinsic measurement properties , its croOur results suggest that in the measurement of cancer pain exacerbations, patients use NRS more appropriately than VRS and as such NRS should be preferred to VRS in this patient's population.(VAS): Visual Analogue Scale; (NRS): Numerical Rating Scale; (VRS): Verbal Rating Scales; (BP-EP): Breakthrough or intense Episodic Pain; (CI): Confidence Interval.CB, EZ, CM, and AC have undertaken consultancy work for Dompé SpA. LL and MB are employees of Dompé SpA, Milan, Italy.CB participated in the design of the study, performed the statistical analysis and drafted the manuscript. EZ, CM, TC, EF, participated in the design of the study, collected data and revised the drafted manuscript. MB, LL participated in the design of the study and revised the drafted the manuscript. AC conceived and coordinated the study, participated in its design and drafted the manuscript. All authors read and approved the final manuscript.


Postherpetic neuralgia (PHN) is a painful and difficult to treat complication of acute herpes zoster. Current treatment options provide only partial relief and are often limited by poor tolerability. We evaluated the safety and efficacy of a single 60-minute application of NGX-4010, an 8% capsaicin patch, in patients with PHN.This multicenter, double-blind, controlled study randomized 155 patients 2:1 to receive either NGX-4010 or a 0.04% capsaicin control patch. Patients were at least 18 years old with PHN for at least 3 months, and an average Numeric Pain Rating Scale (NPRS) score of 3 to 9. The primary efficacy endpoint was the percentage change in NPRS score from baseline to weeks 2-8.The mean percent reduction in "average pain for the past 24 hours" NPRS scores from baseline to weeks 2-8 was greater in the NGX-4010 group (36.5%) compared with control (29.9%) although the difference was not significant (p = 0.296). PGIC analysis demonstrated that more NGX-4010 recipients considered themselves improved  compared with control at weeks 8 and 12, but the differences did not reach statistical significance. Post hoc analyses of patients with PHN for at least 6 months showed significantly greater reductions in "average pain for the past 24 hours" NPRS scores from baseline to weeks 2-8 in NGX-4010 patients compared to controls . PGIC analysis in this subgroup demonstrated that significantly more NGX-4010 recipients considered themselves much or very much improved compared with control at week 12 .Although treatment appeared to be safe and well tolerated, a single 60-minute application of NGX-4010 failed to show efficacy in this study which included patients with PHN for less than 6 months. Large reductions in pain observed among control patients with pain for less than 6 months may have been due to spontaneous resolution of PHN, may have confounded the results of the prespecified analyses, and should be taken into account when designing PHN studies.NCT00068081 Postherpetic neuralgia (PHN) is a painful complication of acute herpes zoster (shingles) that is caused by reactivation of the varicella zoster virus usually contracted in childhood. Acute herpes zoster is often very painful. Usually this pain subsides, but if it persists beyond healing, it is referred to as PHN. Transition from acute herpes zoster to PHN occurs when the pain in the affected area persists months after crusting of the skin lesions. Definitions of PHN vary from as short as 1 month to as long as 6 months after lesion crusting -4.The treatment of peripheral neuropathic pain syndromes commonly requires the use of more than one neuropathic pain medication -7 such aSensitization of peripheral nociceptors that express transient receptor potential vanilloid 1 receptor (TRPV1), a ligand-gated non-selective cation channel, is thought to play a role in PHN . TreatmePatients 18 years or older with a diagnosis of PHN and an average Numeric Pain Rating Scale (NPRS)  score ofExclusion criteria were as follows: use of any topically applied pain medication on the painful area within 21 days before the day of application of the study patch; current use of any investigational drug or class 1 anti-arrhythmic drug; uncontrolled diabetes mellitus or uncontrolled hypertension; significant pain of an etiology other than PHN; painful PHN areas located only on the face, above the scalp hairline, or near mucous membranes; and hypersensitivity to capsaicin, local anesthetics, oxycodone hydrochloride, hydrocodone, or adhesives. As prior use of high-dose opioids could limit the responsiveness to the optional oral opioid rescue analgesics used during the treatment procedure, patients using concomitant opioid medication that were not orally or transdermally administered or exceeded a total dose of 60 mg/day morphine equivalent were excluded.The study was approved by Institutional Review Boards at all participating sites, and conducted in accordance with the ethical principles of the Declaration of Helsinki, Good Clinical Practice guidelines, and applicable regulatory requirements. Written informed consent was obtained from all participating patients before initiating study-related procedures.2, 8%, NeurogesX Inc., San Mateo, CA) or an identically appearing low-concentration capsaicin control patch  for 60 minutes according to a randomization scheme prepared by Cardinal Health . The low-concentration capsaicin control patches were used in place of placebo patches to provide effective blinding in the study since topical capsaicin can produce local erythema and a burning sensation. All patients were pre-treated with a topical anesthetic cream  for 60 minutes before the application of the study or control patch(es) which were applied directly to the painful area(s) (up to 1000 cm2). After patch removal, the area was cleansed with a proprietary cleansing gel formulated to remove residual capsaicin. Patients were monitored for 2 hours after patch removal. Local cooling as well as oxycodone hydrochloride oral solution (1 mg/mL) or equivalent could be administered at the onset of treatment-associated discomfort and as needed. Patients could take opioid rescue medication (hydrocodone bitartrate/acetaminophen 5 mg/500 mg) every 8 hours for up to 3 days after patch application for treatment-associated discomfort as needed. Topical pain medications were not permitted during the 12-week study period. Patients were allowed to take acetaminophen up to 2 g/day as needed for aches and pains.A baseline screening period was followed by a treatment day (day 0), a 12-week post-treatment assessment period with clinic visits at weeks 4, 8, and 12. Eligible patients were randomized 2:1 to receive either NGX-4010  scores throughout the 12-week study period. The NPRS is an 11-point scale (0 to 10) with 0 indicating no pain and 10 indicating the worst possible pain . PatientThe primary efficacy endpoint was the percentage change in "average pain for the past 24 hours" NPRS scores from baseline to weeks 2 through 8. To avoid the potential confounding effect of allowed opioid rescue medications during days 0 to 3, week 1 NPRS scores were not included in the primary analysis. Other efficacy measures included: percentage change in NPRS scores from baseline to weeks 2-4 and 2-12; the percentage of patients with a ≥ 30% and ≥ 50% reduction in NPRS score from baseline to weeks 2-4, 2-8 and 2-12; the percentage of patients considered improved  on the PGIC and CGIC at weeks 4, 8 and 12; changes from screening in the BPI questionnaire collected at weeks 4, 8 and 12; and changes from screening in the SFMPQ questionnaire collected at weeks 4, 8 and 12. Weekly changes in NPRS scores were also performed.Efficacy analyses were based on the intent-to-treat population that consisted of all patients who received any study treatment and had at least 3 days of available NPRS scores during the baseline period. The NGX-4010 group was compared to the control group using a gender-stratified ANCOVA model with baseline pain as the only covariate. The same method was used to analyze the differences between the NGX-4010 groups and the control group in NPRS scores for weeks 2-4 and 2-12. Logistic regression with gender and baseline as covariates tested the difference in the proportion of patients with a ≥30% and a ≥50% mean decrease from baseline in NPRS scores during weeks 2-4, 2-8 and 2-12. For the Short-Form McGill Pain Questionnaire and BPI, a t-test was used to test for differences in change from screening to week 8 between treatment groups. For PGIC and CGIC, Fisher's exact test was used to test for differences between treatment groups in the percentage of patients considered improved . To assess the potential impact of enrolling patients with disease of less than 6 months duration, post hoc analyses were performed on the subgroup of patients with PHN duration of at least 6 months (180 days). Treatment comparisons were performed using gender-stratified ANCOVA to test for a difference between the NGX-4010 and control groups, with baseline pain, pre-anesthetic pain score, and percent change in NPRS score from pre-anesthetic to pre-patch application time point as covariates. The percent change in pain following application of the topical anesthetic and the pain score reported immediately before application of the topical anesthetic were found to be significant covariates in these post hoc analyses and included in the model.Missing post-treatment NPRS scores were imputed using a modified last-observation-carried-forward approach. If the NPRS score was missing on days 0-8, the baseline score was imputed for that day. If the NPRS score was missing for any day past day 8, then the latest available non-missing score collected before that day was imputed for that missing value. If NPRS scores were missing for all post treatment study days (including day 0), then the baseline score was imputed for all missing scores. No imputation was used for the calculation of weekly scores. For the calculation of NPRS baseline scores, all available screening scores which were not biased by pain medication changes were used. For changes in non-SSRI antidepressant or anticonvulsant medications, pain scores up to 14 days after the medication change were considered biased. For changes in other pain medications, pain scores up to the day of medication change were considered biased. Changes in minor OTC analgesics  were ignored.It was estimated that to achieve 90% power at the 0.05 significance level, a total of 150 patients, with 100 designated for NGX-4010 and 50 designated for control treatment, were required to detect a difference of 15% in change from baseline in NPRS scores between the NGX-4010 and control group.Safety was assessed by continuous monitoring of adverse events and periodic assessments of clinical laboratory parameters, vital signs, physical examinations, dermal assessments (0- to 7-point severity score) , pain ext-tests, as appropriate. The proportions of patients reporting each level of maximum dermal response on the day of treatment were compared between the active group and the control group using Fisher's exact test. The results of the allodynia assessments at each visit were compared using a t-test while the rest of the neurologic sensory exams were compared using a Cochran-Mantel-Haenszel test for trend.Adverse events were coded using the Medical Dictionary for Regulatory Activities . Rescue medication use from days 0 to 5, the number of patients completing the intended patch duration, demographics, and baseline clinical characteristics were compared between groups with Fisher exact tests or A total of 155 patients were enrolled into the study and received double-blind treatment: 102 patients received NGX-4010 and 53 patients received control  were similar between treatment groups Table .Patients treated with a single 60-minute application of NGX-4010 reported a mean 36.5% reduction in pain during weeks 2 to 8 compared with 29.9% in the control group . Results for this subgroup were similar to the results from the subgroup with PHN duration of less than 6 months with regard to patients treated with NGX-4010 who showed a mean percent change from baseline during weeks 2 to 8 of -36.8% (data not shown); however, control patients with PHN duration of 6 months or more had a smaller mean percent change from baseline during weeks 2 to 8 compared to control patients in the subgroup with PHN duration of less than 6 months .To assess the potential impact of enrolling patients with disease of less than 6 months duration, post hoc analyses were performed on the subgroup of patients with PHN duration of at least 6 months (180 days). Sixteen (16%) patients enrolled in the NGX-4010 group and 10 (18%) patients in the control group had PHN duration between 3 and 6 months and were excluded form these analyses. A summary of the "average pain for the past 24 hours" NPRS scores for weeks 2-8 and 2-12 as well as the results of the responder and PGIC analyses for this subgroup are presented in Table Analysis of PGIC in the subgroup of patients with PHN for 6 months or longer demonstrated that significantly more NGX-4010 recipients considered themselves to have much or very much improved compared with the control group at week 12  in the NGX-4010 group completed at least 90% of the intended patch application duration. Those patients that did not complete the intended patch application duration had the patches removed early due to application site pain or burning. All patients in the control group completed at least 90% of the intended patch application duration. On the day of treatment, mean "Pain Now" NPRS scores decreased following topical anesthetic and increased following patch application in both treatment groups Figure . PatientTreatment-related pain was manageable in most patients with the use of local cooling or short-acting oral opioids. Thirty-four percent of NGX-4010 patients and 9% of control patients received oxycodone on the day of treatment. The mean dose of oxycodone used was 10.6 ± 5.43 (SD) mg for patients treated with NGX-4010 and 5.6 ± 1.34 (SD) mg for patients treated with control (p = 0.0010). Few patients used hydrocodone/acetaminophen for treatment-related pain from days 0-5: 12% of NGX-4010 patients and 2% of controls.A total of 76 NGX-4010 patients (75%) and 28 (53%) control patients reported adverse events. The most frequently reported adverse events were related to local application site reactions . These application site reactions occurred more commonly in NGX-4010 patients . Two hours after patch removal, 52% of NGX-4010 patients had dermal scores of 2 or more compared to 4% of controls. Few NGX-4010 patients (< 3%) had a dermal assessment above 2 at any time point. By week 4, the majority of patients in the both the NGX-4010 (92%) and control (89%) groups had no evidence of dermal irritation (score = 0) and no patients in either the NGX-4010 or control groups had dermal assessment scores ≥ 2.2) compared to control (-25.1 cm2), the results were highly variable and not statistically significantly different.There were no statistically significant differences between the treatment groups in light brush, pinprick, vibration, and warmth sensations at screening, week 4, week 8, or week 12. No trends consistent with a decrease in sensory function were observed in either group over the 12-week study period. Though patients treated with NGX-4010 demonstrated a larger reduction in mean surface area of allodynia from screening to week 8  and a 28% difference in NPRS score reduction between NGX-4010 and control during weeks 2-4 . SubsequTreatment with NGX-4010 was well tolerated in the majority of patients, with nearly all patients completing the full duration of treatment. Although an initial increase in pain was evident during and after NGX-4010 patch application, pain returned to near pre-procedure levels within 85 minutes after patch removal and by the evening of the day of treatment, patients had on average less pain compared with baseline. Mild, transient dermal irritation was observed in a majority of patients after patch removal. Capsaicin-related local application site reactions were the most common adverse events and were transient, mostly mild to moderate, and self-limited. Application site pain could be adequately managed by pre-treatment with a local anesthetic and local cooling or, if needed, short-acting oral opioid analgesics. Small transient increases in systolic and diastolic blood pressure seen during or shortly after treatment were likely due to treatment-associated discomfort.No reduction in sensory function following NGX-4010 administration was observed suggesting that capsaicin treatment can lead to pain reduction without clinically relevant changes in protective sensation. Indeed, when used as a topical analgesic, capsaicin's mechanism of action involves the selective and reversible defunctionalization of cutaneous sensory nerve endings expressing TRPV1, which have been shown to be hyperactive in painful peripheral neuropathies. The high selectivity of capsaicin for the TRPV1 receptor, coupled with the selective expression of TRPV1 in nociceptive sensory nerves, suggests that even with defunctionalization of cutaneous nociceptors, other skin sensory nerve endings that are capsaicin-insensitive, including those that arise from Aβ-fibers that transduce tactile and proprioceptive stimuli, will be intact and functional ,26. In aAlthough treatment appeared to be safe and well tolerated, a single application of NGX-4010 failed to show efficacy in this study which included patients with PHN for less than 6 months. Spontaneous resolution of PHN, which is primarily observed during the first 6 months, may have confounded the results. Therefore, when designing PHN studies, the potential for spontaneous resolution should be taken into account.LRW, MT and RR were compensated by NeurogesX for their roles as principal investigators. LRW and RR are consultants for Neurogesx and Astellas. JKT and GFV are employees of NeurogesX and own NeurogesX stock.LRW, MT and RR were principal investigators in the study and made substantial contributions to acquisition of data and drafting of the manuscript. JKT and GFV interpreted the results and drafted the manuscript. All authors read and approved the final manuscript.The pre-publication history for this paper can be accessed here:http://www.biomedcentral.com/1471-2377/10/92/prepub