N-acylethanolamina involved in neuroinflammation and pain-generating processes. Formulations containing ultra-micronized palmitoylethanolamide (um-PEA) are available but their effectiveness on chronic pain in highly heterogeneous geriatric patients is not clear and probably not generalizable. We planned to adopt the N-of-1 trial approach to test the effectiveness of um-PEA objectively at the individual level in our older outpatients.Chronic pain in older people is highly prevalent, often underestimated, and associated with adverse outcomes. Most available analgesic drugs are often either ineffective or not tolerated, with many side effects. Palmitoylethanolamide (PEA) is an endogenous widely distributed N-of-1 approach on the physician’s management plan and confidence will be assessed. We will secondarily meta-analyze the performed N-of-1 trials to obtain an estimate of the average effect of um-PEA compared with placebo using a frequentist and Bayesian approach.Persons 65 years or older referring to the Geriatric Unit of the Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico of Milan complaining of noncancer chronic pain of any origin will be eligible. Each trial will be a placebo-controlled randomized crossover trial including two um-PEA (600 mg twice a day) and placebo treatment pairs. The um-PEA or placebo 3-week periods will be separated by 2-week washout intervals to overcome possible carryover effects. Pain intensity, need of on-demand analgesic medications, and impact on daily activities will be evaluated. Cognitively impaired patients will be eligible as long as an expression of pain can be recognized and its frequency assessed by a caregiver. Trial results will be discussed with the patient or caregiver and the treating physician to decide whether to continue the treatment. The impact of the N-of-1 trials on PEA will bring the principles of evidence-based medicine into the care of patients not usually represented in conventional randomized controlled trials, and realize a patient-centered outcome approach necessary to improve appropriate prescribing in elderly patients with multimorbidity and polypharmacy.While pursuing an ultimate clinical objective, i.e. to empirically and objectively decide the best treatment choice for an individual older patient with chronic pain, these series of geriatric NCT02699281. Registered on 3 March 2016.ClinicalTrials.gov The online version of this article (doi:10.1186/s13063-016-1496-9) contains supplementary material, which is available to authorized users. Pain prevalence increases with age. In particular, the prevalence of chronic or persistent pain among older people ranges from 45 % to 80 % . PersistPersistent pain and its inadequate treatment are associated with adverse outcomes in older people: functional impairment, falls, slow rehabilitation, mood changes, and sleep and appetite disturbances, resulting in a higher consumption of healthcare resources .Achieving pain control in geriatric patients is complicated by many issues. First, older people may underreport pain, and in this population persistent pain has often complex and multifactorial manifestations. Self-reporting is deemed to be the gold standard in pain assessment but older people might find difficult to complete self-reported questionnaires of pain and functional status, developed and validated in younger patients , 9. PainSecond, the somatosensory system changes with aging , throughThird, pharmacological management of chronic pain is particularly challenging in the elderly. Owing to age-related body changes affecting drug pharmacokinetics, and because of multimorbidity and polypharmacy, older patients are generally more likely to experience drug-related adverse effects . In partSo called adjuvant (or pain-modulating) drugs, co-administered with other analgesics, have been found to be effective in attenuating pain perception, particularly in the treatment of neuropathic pain . They inAll pain-modulating therapies target neurons, the principal component of the pain unit. However, a growing body of evidence suggests that immune cells, in particular mast cells and microglia, play a substantial role in the somatosensory system, being the primary interlocutors for pain neurons, both in the periphery and at the spinal and supraspinal levels . Immune N-acylethanolamina widely distributed in different tissues [et al. [Palmitoylethanolamide (PEA) is an endogenous  tissues . It is s tissues . In muri tissues , 32. Mic tissues –37. Rece [et al.  confirmeNormast®, are available in Italy only out-of-pocket and a treatment cycle at the doses recommended by the product information sheet would cost the patient about € 60. Given that the required treatment for persistent pain would probably be longer, the cost should be balanced by the actual effectiveness. These reasons represented the rationale to adopt a randomized N-of-1 trial as a more objective and personalized prescribing approach, compared with the conventional trial (i.e. ‘prescribe and see’) [N-of-1 trials are within-patient randomized multi-period crossover trials to compare, in a double-blind fashion, therapeutic strategies , with time periods as randomization units and the patient as control for herself or himself. This study design can be theoretically used to test new drugs along their way to marketing authorization. In our case, we will adopt this approach to determine the best therapeutic choice for a certain patient in clinical practice, objectively and empirically, with randomization and blindness as instruments to overcome those factors  that might bias conventional trials of therapies [N-of-1 trials on PEA for chronic pain in older patients will be part of the activity of the Geriatric N-of-1 Service, an experimental project that we have implemented, with the approval of the local ethical committee, following the pioneering experience of Guyatt and colleagues [The mechanism of action and the safety profile make PEA an appealing choice for pain relief in older people. However, the evidence base for its efficacy to treat chronic pain in the elderly is not fully convincing. In addition, formulations containing um-PEA, like nd see’) . In geneherapies –41. In plleagues  but in tlleagues .This study protocol has been realized according to the CONSORT extension for reporting N-of-1 trials (CENT) 2015  and the N-of-1 trial approach to test the effectiveness of um-PEA 600 mg (Normast®) twice a day for chronic pain in a certain patient referring to our geriatric unit in whom the treatment might be indicated, and to assist decisions on long-term treatment of that patient.The primary  objective of our study is to apply the N-of-1 trials performed for clinical purposes. Contextually, a classical frequentist meta-analytical approach will be compared with a Bayesian approach, and the potentialities of a Bayesian-based cumulative study design explored.As a secondary (research) objective, we aim to obtain an overall estimate of the effectiveness of um-PEA 600 mg twice a day compared with placebo and evaluate the possible determinants of between-trial heterogeneity, through a meta-analysis of the Each trial will be a blinded placebo-controlled randomized trial. Each trial’s duration will be 18 weeks, comprising two um-PEA and placebo treatment pairs assigned in a random order according to a pairwise randomization scheme. Thus, the sequence of each pair can be either um-PEA/placebo or placebo/um-PEA. Each treatment period will last 3 weeks. The treatment periods of each pair and the two pairs will be separated by 2-week washout intervals to minimize carryover effects. A run-in period will not be routinely performed, but will be considered when deemed appropriate . Figure This study design was conceived taking into account the available information on the product pharmacological characteristics, balanced with the need for a trial with an acceptable duration from the practical viewpoint. The onset time of PEA is not easily predictable from its pharmacokinetics or pharmacodynamics. According to the available literature, most people notice the effects within 1 week, but sometimes 6–8 weeks are required, especially for chronic pain syndromes. Regarding a possible carryover effect, no sufficient data are currently available, either from basic or clinical research studies, to make a definitive statement. However, given the type of mechanism of action, a possible residual effect might be expected. Concerning the dose, in the heterogeneous literature on the use of the product for pain control, different doses have been tested, from 300 mg a day to 2400 mg a day, either once or split into three doses per day. The product information sheet for Normast® 600 mg suggests ‘1–2 tablets a day for 20–30 days’.inclusion criteria are:Patient age ≥ 65 years.Pain is localized at the back (any level) or at the joints or at the limbs.The pain is chronic, i.e. it has been present for at least 6 months, even if with fluctuations.The pain is attributable to one or more of the following conditions: osteoarthritis or osteoarthrosis; spondylosis; radiculopathy; diabetic peripheral neuropathy; post-herpetic neuralgia; chronic idiopathic axonal polyneuropathy; fibromyalgia; or pain of uncertain origin or idiopathic, as long as it has had and it is expected to have a chronic nature, even if with spontaneous fluctuations.The treating physician deems PEA to be a possible treatment option for the patient, either alone or as an add-on medication on top of other analgesic drugs.Older patients complaining of chronic pain of likely osteoarticular or neuropathic origin will be eligible for the study. Detailed Case 1 (self-assessment): The patient is able to give an informed consent and to express the characteristics of the pain-like intensity and impact on function over a quantitative scale; the patient might be able to self-compile questionnaires, or to reliably answer questions administered by a caregiver.Case 2 (caregiver-based-assessment): The patient has a certain degree of cognitive decline that hinders the direct involvement of the patient in the consent process or in the outcome self-assessment, but an all-day caregiver willing to collaborate and consent to the trial is present. In this case, the pain has to be clearly expressed by the patient in a modality that can be assessed in its frequency and impact on function by someone other than the patient.Dealing with geriatric patients, and willing to offer the opportunity of a treatment option with an objective and empirical evaluation regardless of patient cognitive integrity, we will distinguish two cases:N-of-1 trials on case 1 patients will be candidates for the secondary objective of our study. The opportunity to meta-analyze case 2 trials will be judged according to the number and heterogeneity of the assessment instruments and modalities of completed trials.N-of-1 trial.Patients with cancer-related pain and patients with a clear ischemic pathogenesis for pain  will be excluded. There will be no exclusion criteria concerning the comorbidities the patient might have. Patients can take other medications or undergo non-pharmacological therapies  for chronic pain control as long as they are not newly commenced; generally, no therapy modification that can affect pain must have been made soon before or concomitantly with the enrollment in the The study will be conducted at the Geriatric Unit of the Fondazione IRCCS Ca’ Granda – Ospedale Maggiore Policlinico in Milan, Italy, which is an academic tertiary hospital unit that serves inpatient and outpatient referrals.Patients will be mainly recruited from the geriatric outpatient clinic. Referrals might also be generated in the inpatient clinic but, to be enrolled in the study, patients need to have recovered from any acute illness.Normast® 600 mg or placebo will be administered orally twice daily during the treatment periods. No study drug will be administered during the washout period.One tablet containing either The patient will be allowed to take on-demand painkillers during the entire trial duration. At the baseline visit, the patient will be recommended according to our usual geriatric practice, i.e. to take acetaminophen at a maximum dose of 2 g daily if not contraindicated or in case of drug allergy or intolerance; if acetaminophen is insufficient, to combine or replace it with codeine or tramadol; to use ibuprofen when pain is not eventually controlled, trying to avoid, in general, nonsteroidal anti-inflammatory drugs. The patient will be given instructions on how to report on-demand analgesia according to the outcome assessment instruments and modalities.N-of-1 trial will be the daily intensity of pain, the daily need of on-demand analgesic medications, and the impact of pain on daily activities measured over a week time .Outcome measures evaluated in each In the cases in which self-assessment is not feasible  the daily frequency with which the patient complains of pain measured by the patient’s caregiver will be adopted as the outcome measure, since the measurement of the frequency of pain complaints by someone other than the patient is expected to be more feasible than the quantification of pain intensity. The daily need of on-demand analgesic medications and the impact of pain on daily activities over a week will also be evaluated in case 2 trials.primary outcome measure; the daily need of on-demand analgesic medications, and the impact of pain on daily activities will be the secondary outcome measures.For the purpose of deciding for the optimal treatment in the patient, all the listed outcome measures will be valued. For meta-analytical purposes, the daily intensity of pain (case 1) or the daily frequency of pain symptoms (case 2) will be the Pain intensity will be assessed daily using an 11-point (from 0 to 10) visual numeric scale . To helpAt the baseline visit, the ability of the patient to compile the questionnaire unaided after instructions will be verified. If any limitation arises, the patient’s caregiver will be engaged and trained to take responsibility for completing the assessment.The participating caregiver and treating physician will be asked to identify the pain symptoms and to measure the daily frequency with which the patient complains of them using a five-point scale: 1 corresponds to ‘never’, 2 to ‘once’, 3 to ‘sometimes’, 4 to ‘often’, and 5 to ‘continuously’.The impact on daily living will be measured by identifying those patient activities most affected by chronic pain  and building a personalized instrument through which the impact on each activity will be measured using a five-point scale similar to the one used for case 1 patients.The use of on-demand analgesic medications will be reported daily by the participating caregiver, specifying the type of drug taken and its dosage.N-of-1 trial on the physician’s management plan, we will preliminarily ask each physician if he or she would treat the patient with um-PEA independently of the N-of-1 trial; once the N-of-1 trial results become available, we will ask how the physician intends to treat the patient. Management plan options will include continuing or withdrawing um-PEA. We will also investigate the level of the physician’s confidence in the management plan, both before and after the N-of-1 trial, using a seven-point scale. The physicians will be asked the following [To assess the impact of the ollowing :Totally comfortable; certain it is the right thing for the patient.Almost totally comfortable; very probably it is the right thing for the patient.Quite comfortable; it is probable that the treatment plan is best for the patient.Not totally comfortable; but treatment likely to be as good as alternatives.Mildly uncomfortable; some uncertainty whether treatment plan is best for the patient.Moderately uncomfortable; feeling that the treatment plan might not be the best for the patient.Extremely uncomfortable; uncertain about treatment plan and, if wrong, patient may suffer.How comfortable do you feel now about your treatment plan?The study timeline is reported in Fig. At the enrollment visit, eligibility criteria will be checked, informed consent will be obtained, and data regarding patient socio-demographics, pain characteristics, comorbidities, and pharmacotherapy will be collected. The clinical investigators will also evaluate the ability of the patient and the caregiver to assess pain intensity, and appropriate training for questionnaire fulfilment will be performed.After allocation, the study drug will be delivered to the patient (case 1) or caregiver (case 2) and baseline pain intensity and functional status will be recorded.The patient or caregiver will be contacted by telephone after the first week of treatment to investigate possible issues concerning therapeutic adherence, adverse effects, and questionnaire completion. A visit with the patient and caregiver will be scheduled before the beginning of each period, to deliver the study drug and acquire the completed questionnaires, checking their correct fulfilment. At the end of the last period, the last questionnaires will be collected.A final visit with the patient will be scheduled at the end of the trial, once the study results are available. The patient, the caregiver, the treating physician, and the study investigators will discuss the study results.www.randomizer.org. Two sets of two random numbers , with each number in a set remaining unique, will be generated for each patient. Pharmacists will be recording the allocation sequence and will provide the study drug  to the clinical investigators at the beginning of each study period. Patients, participating caregivers, treating physicians, and clinical investigators  will be blinded to the treatment sequence.The sequence will be generated by the pharmacist using the web site Unblinding will be permissible at any time that the trial will be considered concluded. Reasons for which the trial will be deemed concluded other than its completion will be: the patient withdraws consent; the patient or the treating physician is convinced that drug effectiveness has been established or refuted before the end of the designed trial; and safety concerns.N-of-1 trial, the sample size is represented by the number of periods of treatment. The choice to design each trial including two treatment pairs is not based on a formal power calculation, considering that N-of-1 trials with a practicable number of pairs can rarely reach the conventional level of statistical power of 80–90 % [N-of-1 trial, two treatment pairs seem a reasonable choice, given the starting good level of confidence on the treatment effectiveness that our geriatric team derived from the brief experience with the product  we preliminarily had in our practice.For each  80–90 % . The choN-of-1 trials to estimate an overall population treatment effectiveness and evaluate the possible determinants of the effect heterogeneity between trials will be a proof-of-concept study. Given the explorative nature of this secondary objective, the number of N-of-1 trials that will be meta-analyzed is not dictated by a specific sample size calculation. A first meta-analysis will be performed on those completed N-of-1 trials initiated during the first 12 months from the start of the first N-of-1 trial, as long as there are at least three trials. A second meta-analysis will be performed including all the N-of-1 trials initiated within 24 months from the start of the first N-of-1 trial (study duration).A meta-analysis of the performed The posterior probability that um-PEA is better than placebo for a certain patient  and for the population  will be provided through a Bayesian approach.N-of-1 trial and, secondarily, we will combine results across them.According to the objectives of the study, we will first analyze results within each t test will be used for the statistical comparison of period mean scores within treatment pairs.Results on daily pain intensity will be summarized, calculating first the mean symptom score of each week in each period, and then the mean score in each period. The week and period mean scores will be paired with the treatment administered in each period, in a cross-tabulation and in a graph. A similar synthesis will be used for the scores on the week impact on function. A paired t test will be repeated after having excluded from the calculation of the period mean scores the measures made during the first week of each period.At first, the analyses will be performed assuming that the washout periods were sufficient to overcome the possible carryover effect of PEA. If a slow onset time or a residual carryover effect are suspected from the qualitative (‘at a glance’) evaluation of the week (mean) outcome measures including those made during the washout periods, a sensitivity analysis will be conducted. In this second analysis, a paired If more than three measures of the daily pain intensity in the same week are missing for at least one week, the period mean score will be computed, weighting each week mean score according to the inverse-variance method .N-of-1 trial will first be evaluated by the physician and the patient or caregiver (when feasible), keeping the nature of the two treatments covered (i.e. naming the treatments simply A and B); then, the code will be broken and the nature of treatments revealed.To make the final treatment decision as objective as possible, the results of each A linear mixed effect model  will be Patient-level (or study-level) variables will also be tested in the analyses as possible explanatory variables of treatment effect heterogeneity.In addition to the classic (frequentist) analysis, results of the individual trials and their combination will be approached using Bayesian hierarchical methods, as described by Zucker et al. . Non-infN-of-1 trials, each trial will be classified according to:completeness, defining as complete those trials conducted to the term; as incomplete with clinical decision those trials interrupted before the completion of the planned treatment pairs because the physician and patient or caregiver were at that point convinced of the effectiveness or lack of effectiveness of PEA (notwithstanding the blinding); and as incomplete for other reasons those trials interrupted before the completion of the planned treatment pairs because of other reasons ;its achievement of statistically significant results, setting P ≤ 0.1 as the criterion to define a statistically significant mean effect difference between PEA and placebo;the direction of results, i.e. a beneficial or harmful effect of PEA compared with placebo when a statistically significant mean effect difference is found.the To evaluate the usage and usefulness of the performed Owing to the small amount of data to be managed and to the absence of funding, a data monitoring committee is not recruited. Data will be managed and monitored directly by the study investigators. The correct use of the study drug and instruments, and possible adverse effects will be monitored at each phone or in person contact with the patient. Patients will be encouraged to report any possible adverse effect or concern about the study for the whole study duration through the provided investigators’ phone contacts.Data will be stored in an electronic database, protected by password.N-of-1 approach to a geriatric population. Research and clinical practice become intimately intertwined on the ground of geriatric N-of-1 trials. Indeed, while they borrow typical research instruments  to achieve their ultimate clinical objective, i.e. to determine the best therapeutic choice for patients, reliably and empirically, they also meet the aims of innovative and timely research. They bring principles of evidence-based medicine into the care of older patients scarcely represented in conventional randomized controlled trials. Moreover, N-of-1 trials promote and exploit a patient-centered research that goes beyond the need of generalizability and even beyond the limits of the comparative effectiveness research. In particular, they embody the spirit of patient-centered outcomes research necessary to prioritize medicaments and improve appropriate prescribing in older patients with multimorbidity and polypharmacy [Um-PEA might represent an effective and safe option for older patients with chronic pain. We opted to investigate this hypothesis at the individual level, in our routine practice, applying the pharmacy . Patientpharmacy .N-of-1 trials on PEA will help to enhance our capabilities to interpret, measure, and treat pain in its alternative expressions.We also expect that putting the patient at the center of our practice and research, modifying the trial design according to patient expectations, needs, and difficulties, might help to mitigate those well-known barriers concerning participant enrollment and adherence encountered in the conduction of trials involving older persons. Learning how to listen to the patient’s needs, even when not traditionally expressed, makes patient-centered practice and research possible even with cognitively impaired people. In particular, this series of N-of-1 trials on PEA we conduct will provide aggregate information on the product that can be used to inform treatment decisions for other patients not participating in the trials.The meta-analysis of the Finally, the project, in its entirety, will represent a way of filling the gap between science and practice, facilitating the involvement of patients and clinicians in the production of evidence, and promoting the creation of ‘a real clinical learning community’ .At the time of manuscript submission, four patients have been enrolled and randomization has begun.CONSORT, Consolidated Standards of Reporting Trials; PEA, palmitoylethanolamide; um-PEA, ultra-micronized palmitoylethanolamide; SPIRIT, Standard Protocol Items: Recommendations for Interventional Trials


Currently, it is common practice in the emergency department (ED) for pain relief in hip-fracture patients to administer pain medication, commonly systemic opioids. However, with these pain medications come a high risk of side effects, especially in elderly patients. This study investigated the safety profile and success rate of fascia iliaca compartment block (FICB) in a busy ED. This ED was staffed with emergency physicians (EPs) and residents of varying levels of experience. This study followed patients’ pain levels at various hourly intervals up to eight hours post procedure.Between September 2012 and July 2013, we performed a prospective pilot study on hip-fracture patients who were admitted to the ED of a teaching hospital in the Netherlands. These patients were followed and evaluated post FICB for pain relief. Secondary outcome was the use of opioids as rescue medication.Of the 43 patients in this study, patients overall experienced less pain after the FICB (p=0.04). This reduction in pain was studied in conjunction with the use and non-use of opioids. A clinically meaningful decrease in pain was achieved after 30 minutes in 62% of patients ; after 240 minutes in 82% of patients ; after 480 minutes in 88% of patients . No adverse events were reported.In a busy Dutch ED with rotating residents of varying levels of experience, FICB seems to be an efficient, safe and practical method for pain reduction in patients with a hip fracture. Even without the use of opioids, pain reduction was achieved in 64% of patients after four hours and in 72% of patients after eight hours. In current emergency department (ED) practice, pain management in hip-fracture patients is hampered by a high risk of side effects. These side effects are particularly noticeable in elderly patients. Twenty-four hours after a hip fracture, 50% of patients aged 50 and up reported “severe to very severe” pain.3One of the goals of the ED in the OLVG is safe, rapid and effective pain management to insure avoidable complications. To achieve this, fascia iliaca compartment block (FICB) can be a good option. FICB using the “two pop technique” is found to be safe and relatively easy to perform.14Prior studies have shown good results from FICB in hip-fracture patients. These studies, however, all have small numbers, use different cut offs in evaluating pain, and pain scores are usually documented for short periods. Our objective was to investigate the success rate of administration of FICB in a busy Dutch ED with a standardized cut off for pain and a follow up of eight hours. The additional component in this busy ED is the always-rotating interns and residents. In the Netherlands, there have been no studies performed which investigated FICB in hip-fracture patients. Our study was initially designed in anticipation of a randomized double blind placebo-controlled trial (RCT).This prospective pilot study was carried out on hip-fracture patients, presenting to the ED of the OLVG, between September 2012 and July 2013. The institutional review board approved the study.Eligible patients were over the age of eighteen with clinical or radiological signs of a hip fracture. They presented with an intact cognitive status on admission and were able to give informed consent. We eliminated patients from the study if they displayed any cognitive impairment such as dementia or delirium or when surgery was planned within one hour. Patients were also excluded if they had any known allergy to local anesthetics, if an infection at the injection site was present, or if there was a history of femoral bypass surgery or an elevated International Normalized Ratio (above 4.5), or if they were admitted by the orthopedic department instead of general surgery. In the Netherlands, hip-fracture patients are treated by orthopedic and surgical teams. In the ED, patients are assigned to a specialty team based on day of the week rather than fracture type. During this study, for practical purposes, we only paired up with the surgical team. We included patients in the study when they met all inclusion criteria.The study investigators  trained EPs and residents with different levels of experience in how to perform the FICB. The form of teaching was through lectures and assisting physicians in performing the procedure until competency was demonstrated. EPs and residents were supervised three times in the performance of FICB until the study investigators felt they were competent to perform it independently. The lecture was comprised of background information, anatomy, technique, drug interactions and study protocol. The study investigator gave multiple demonstrations in the ED. EPs and residents were encouraged to ask any questions. All physicians were provided with a pocket card containing information about FICB, such as procedure protocol and details of the medications to be administered.A standardized FICB technique was used on all eligible patients. The patient was placed in a supine position, the inguinal ligament was identified and the femoral artery was palpated. After the skin was cleaned with chlorhexidine, FICB was given with a SonoPlex Stim cannula 22G×50mm needle without the use of a nerve stimulator. The needle was inserted perpendicular to the skin at a point 1cm below the juncture of the lateral and medial two-thirds of a line that joins the pubic tubercle to the anterior superior iliac spine. The needle was inserted until a loss of resistance was felt as the fascia lata was passed, and further advanced until a second loss of resistance occurred when the fascia iliaca was pierced (often described as “two pops”). This technique was first described by Dalens et al.All of the patients had a peripheral intravascular access and were supplied with oxygen as needed. Electrocardiogram, non-invasive blood pressure and oxygen saturation were monitored and documented. Any change in cognitive functioning after the administration of the FICB was recorded in each patient’s chart. EPs and residents were interviewed by the investigator after finishing two or more FICBs to ascertain whether they felt they had mastered the technique. Nurses were interviewed and asked to give feedback on whether the FICB was successful in patients’ pain management. Other collected data included patient demographics and type of fracture.Nurses performed pain assessment during the first hour in the ED and until eight hours on the surgical ward. We used a 10-point numeric rating scale (NRS). This assessment was done before any medication was given, during FICB, and after the FICB was performed at 30, 60, 120, 240 and 480 minutes. The need for and use of supplemental analgesia was documented. Patients received a short-acting opioid in the ambulance or in the ED if pain was rated NRS≥7. In our analysis, we rated these patients “positive” for one hour because these short-acting opioids are usually active for more or less one hour. If patients received a long-acting opioid, for example morphine, we rated them “positive” for opioids for the duration of four hours. All patients received one gram of acetaminophen and 50 mg of diclofenac , when there were no contra indications for the use of these medicines.For the analysis, we put patients in two groups: group one were patients who achieved a clinical reduction in pain without additional opioids. Group two were patients who achieved a clinically relevant reduction in pain with the supplemental use of opioids. A clinically relevant reduction of pain was reached when patient’s level of pain was lowered by ≥35% when the initial pain score was ≥6 (moderate pain) on the NRS. For patients with severe pain (NRS≥8) a decrease of ≥45% was regarded as clinically meaningful according to Soledad Cepeda and colleagues.16We used a one-way repeated measures analysis of variance to assess the change in NRS in time. A p<0.05 was considered statistically significant. Statistical analyses were performed using SPSS 18.0 software package for Windows .Forty-three patients were included in this study: 22 women, 21 men, with a mean age of 76 years. Nineteen patients had a femoral neck fracture and the other 24 patients had a pertrochanteric or subtrochanteric fracture. There were no patients with an ASA-score of 4 or 5. Thirty-three percent of patients showed an ASA-score of 3; 49% of patients showed an ASA score of 2. Only 12% of patients had a history of diabetes.Differences in pain were registered from 30 minutes to 480 minutes after the FICB, which are represented in The FICB technique was performed with minimal risk to patients. The levobupivacaine was given at a safe distance from the neurovascular bundle. During this study 17 different residents were responsible for 34 FICBs, while EPs were responsible for the remaining nine. Close observations of the patients’ vital signs and cognitive function increased the safety profile of the procedure by allowing early detection of systemic toxicity. No adverse events were reported. FICB was easy to perform and required minimal training. They found it easy to master the technique. EPs and residents performed the procedure successfully within less than five minutes of instruction.Nurses from the department of general surgery were enthusiastic because they believed they could take better care of patients after FICB placement. After this positive feedback we interviewed four nurses randomly. They were all very satisfied after block placement since they found an improvement in care when the patient received a FICB. Although we did not measure pain levels during movements such as transfers, most patients indicated experiencing no pain during transfers.FICB seems to be a safe and practical method for reducing pain in patients with a hip fracture. FICB has been reported to provide effective pain relief in hip-fracture patients when performed by anesthesiologists, without the use of a nerve-stimulator or ultrasound, and without causing major side-effects.13The aim of this study was to investigate the safety profile and success rate in a busy ED in the Netherlands with rotating physicians and time pressures, as an alternative or additive to conventional analgesia for hip-fracture patients. In this study, we achieved clinically relevant differences in pain in 76% of 34 documented patients at 120 minutes and in 88% of 25 documented patients at eight hours. Our results are comparable to those published in earlier studies, in which the block was performed by non-anesthesiologists with a success rate of 70–80%.Anesthesiologists routinely place nerve blocks for pain control in the pre- and post-operative period, but have traditionally used nerve stimulators to guide their placement. Most EPs do not routinely use nerve stimulators but are increasingly trained in ultrasonography. There is good evidence to show that peripheral nerve blocks performed with ultrasound guidance can be placed with great success. However, with a success rate of 76–88% we achieved very good results and ensured that our EPs and residents performed the loss of resistance technique correctly. This increases practicality in our busy ED as it avoids the need for ultrasound scanners. Most Dutch EPs have no access to an ultrasound machine in their EDs and it takes less time to perform a FICB without ultrasound.This study shows a clinically relevant reduction in NRS in 62% of patients after 30 minutes , which iOur recommendation is to give hip-fracture patients a FICB in the ED, but because levobupivacaine is a long-acting anesthetic, we have to bear in mind that additional short-acting opioids are possibly needed in the ED. Levobupivacaine seems to be more helpful in patients who have to wait four to eight hours for surgery. For ED patients, the use of lidocaine could be more helpful since onset of effect is usually within half an hour. Further research is needed and one of our recommendations is to investigate the use of lidocaine in FICB because this is a short-acting anesthetic and its effect will be more pronounced in the ED.This pilot study ended after nine months because of reasons indicated below. Furthermore, willingness from personnel to start with the intended randomized placebo controlled double-blind study was low, due to very promising results. FICB was implemented in the protocol of our department.The dropout rate was significant and mainly due to pre-defined exclusion criteria. During one shift, there was no EP available who could perform this technique. In the beginning of the study, doctors forgot to include patients in the study protocol. Unfortunately study forms were lost in six cases, probably during the transfer to another ward. For example, when patients went to the cardiology ward for cardiac problems and were thereafter brought to the department of general surgery, the forms weren’t traceable. In four cases it was too busy in the ED, so patients went upstairs before they were included in the study. And in one case, nurses from the department of general surgery forgot to fill in the form.Unfortunately not all measurements of pain scores were performed. A possible explanation could be that nurses of the department of general surgery forgot to fill in the pain scores because patients didn’t complain about pain after administration of the FICB, or because the nurses may have been too busy to fill in the forms. The use of an independent research nurse would be a good option to minimize patient drop out.We did control the amount of conventional pain treatment used before and after the FICB, but incidentally the patient was given morphine instead of fentanyl, which may have influenced the level of pain. To compensate this problem we measured pain at different time intervals, even after eight hours after block placement. The decrease in pain at four (and eight) hours after the FICB was likely due to the analgesia provided by the FICB, as this was beyond the scope of the effect of morphine.In a busy ED with rotating residents of varying levels of experience, fascia iliaca compartment block seems to be an efficient, safe and practical method for reducing pain in patients with a hip fracture. In two hours there was a clinically meaningful decrease in NRS in 76% where 65% of patients achieved this reduction without the use of opioids. Even after eight hours this reduction was achieved in 88% of patients from whom 72% didn’t needed opioids. No adverse events were reported. Because of small numbers and the lack of a control group, the investigator aims to collect more data to answer questions on safety and efficiency.


To determine the relation between the degrees of chronic pain and drowsiness levels.The study was conducted with 115 patients, who answered the questionnaire as diagnostic criteria in the survey. After evaluation based on the protocol of chronic pain registry RDC/TMD- Axis II, the Epworth Sleepiness Scale was applied to assess drowsiness levels.Among the participating patients, there were more females (80%), and the type of pain more prevalent was chronic (70.4%). Concerning the grades of chronic pain, grade II predominated (38.3%), corresponding to high pain intensity and low disability. The ratio observed for levels of sleepiness was more prevalent for sleep debt average (38.3%).The grades of chronic pain and the levels of sleepiness did not correlate with each other or with the gender of patients. International Association for the Study of Pain is “an unpleasant sensory and emotional experience associated with current or potential damage, or described in terms of that damage”.Pain, according to the When named “chronic pain”, it is characterized as continuous or recurrent pain, with a minimum duration of three months, many times with uncertain etiology, which does not disappear with conventional therapeutic procedures, becoming the cause of prolonged disabilities and inabilities. According to the American Academy of Orofacial Pain (AAOP), orofacial pain has been evolving and it comprises headaches, neurovascular pain, masticatory musculoskeletal pain, temporomandibular joint disorders, sleep disorders, among others.When pain is related to the mouth and face structures per se, it is called “orofacial pain”. However, both the skull and neck structures can cause facial pains. The denomination “orofacial pain” became popular among dental surgeons and healthcare professionals involved in the treatment of this type of pain.The number of studies related to chronic orofacial pain has been increasing in literature. An instrument constantly employed to identify the complex interaction between the physical and psychological dimensions of chronic pain is known as research diagnostic criteria for temporomandibular disorders (RDC/TMD).,5 This is because, according to some researches, patients with chronic temporomandibular dysfunction present some impact of pain in their lives, such as sleep abnormalities, which can cause significant changes in the subject's physical, occupational, cognitive and social functioning, in addition to substantially compromising the quality of life.,7,8 This result is in accordance with the conclusions obtained by researchers who observed that patients with chronic pain suffer from poor quality of sleep. Other studies address the association between chronic pain and sleep, highlighting the importance of dental surgeons who play a relevant role in relief of orofacial pain and sleep-related problems.It is possible to use the RDC/TMD questionnaire and Epworth Sleepiness Scale (ESS) to evaluate chronic pain and the level of sleepiness of patients, respectively, as well as to relate them.,11 It comprises a subjective, fast and self-applicable evaluation, in addition to being accompanied by instructions for scoring the situations asked, such as the chance of napping while sitting, reading or watching television. It is a valid and reliable instrument to evaluate sleepiness, being equivalent to its original version when applied to subjects who speak Brazilian Portuguese.The Epworth Sleepiness Scale was designed by Murray Johns and validated to Portuguese by Bertolazi.To determine the relation between the grades of chronic pain and the levels of sleepiness among patients from a specialized treatment center.Universidade Tuiuti do Paraná, located in the city of Curitiba (PR), from March 2012 to March 2013. The study was approved by the Brazilian Platform under Opinion Number 241,463. The patients involved in this research signed an Informed Consent Form (ICF).Study conducted with patients from the Center for Diagnosis and Treatment of Temporomandibular Joint and Functional Dentofacial Abnormalities  of the The patients were randomly selected and the study included 115 patients – a significant percentage in relation to the total of patients who went to the clinic during the study. The patients answered all the questions from the RDC/TMD questionnaire, but the current study used only some of them. Subsequently, the data related to the protocol of chronic pain registry (RDC/TMD) – Axis II were evaluated, allow evaluating intensity of pain, relating it to disability it can cause by means of a classificatory chart.Afterwards, the Epworth Sleepiness Scale was applied to 115 patients. The results were used to classify them in regard to level of sleepiness.2 value with a significance level of α ≤ 0.05.Data treatment was conducted using the software Microsoft Excel. This research consisted on determining the linear distribution, obtaining the line equation and the RThis present study involved 115 patients, with mean age 41±16 years; the youngest patient was 12 years old, and the oldest patient was 77 years old.In regard to gender, there were more females (80%) .As to female and male genders, with and without chronic pain, it was observed that 70% presented chronic pain and 30% did not present it. The proportion of patients with and without chronic pain per gender is shown in Concerning the grades of chronic pain, grade II was predominant, which corresponded to high pain intensity and low disability, followed by grades with no chronic pain, I, III and IV. . It is iWhen genders were related to grades of chronic pain, it was observed that grade II was prevalent among females while male patients more often had no chronic pain .Considering the levels of sleepiness, average sleep debt was more prevalent .The data in The only absence of patients was observed for grade IV of chronic pain with level of sleepiness with no sleep debt .The results obtained for the correlation between genders and grades of chronic pain, genders and levels of sleepiness, grades of chronic pain and levels of sleepiness are shown in The results obtained from this study allowed us to observe that most of the patients who sought CDATM were female and, of those, the majority presented chronic pain. which showed high incidence (41.4%) of chronic pain in the population, predominantly in females, after evaluating 2,297 subjects aged ≥ 20 years, in Salvador (BA), between 1999 and 2000.This result is in accordance with literature,–16 also observed that the prevalence of chronic pain in the general population has been higher in women than in men. A study involving 4,100 subjects showed that this morbidity affected 39% of men and 45% of women.Other studiesThe evaluation of grades of chronic pain in 115 patients included in this current sample showed that 29.6%of them did not present chronic pain, 14.8% presented grade I of chronic pain, 38.3% grade II, 11.3% grade III and 6.0% grade IV. This result reinforces the high incidence of grade II chronic pain among the patients.–20 were conducted in order to determine the percentage of patients in each grade of chronic pain. In a study with patients from the Department of Head and Neck Surgery at the National Institute of Cancer, it was observed that 9 out of 30 patients presented grade I (30%), 9 patients presented grade II (30%), 4 patients presented grade III (13.33%) and 8 patients (26.67%) presented grade IV chronic pain.Similar studies However, Teixeira separated the patients into three groups: group A (muscular), group B (articular) and group C (mixed), according to the origin of TMD and, from the values obtained, observed higher incidence of grade II chronic pain in groups A (40%) and C (50.7%).Likewise this study, the literature has also demonstrated higher incidence of grade II chronic pain.The evaluation of sleepiness levels showed 17.4% of patients without sleep debt, 12.2% with less sleep than needed, 38.3% with average sleep debt, 17.4% with severe sleep debt and 14.7% with extremely severe sleep debt. For level of sleepiness with highest incidence, the average sleep debt, the proportion between females and males was 28.7 and 9.6%, respectively, thus showing that both genders contributed to the higher proportion seen in this level. the highest incidence was also observed in patients with average sleep debt when compared with the other levels of sleepiness. However, the literature also showed studies with results different from the ones observed here, showing, among the levels of sleepiness, a higher incidence of mild sleepiness, which corresponds to the level of less sleep than needed.According to the literature,The association between grades of chronic pain and genders showed different results; the highest incidence in females was for grade II chronic pain (33%) and, in males, for patients without chronic pain (9.6%).This result corroborates other results previously discussed about the higher incidence of chronic pain in female patients. However, when evaluating the levels of sleepiness, no differences between genders were observed, since both presented higher incidence of average sleep debt, with females and males representing 28.7% and 9.6%, respectively.Establishing the association between the grades of chronic pain and levels of sleepiness allowed us to observe that, in patients without chronic pain, patients with grades I and II chronic pain, average sleep debt was prevalent. For patients with grade III chronic pain, we observed the same percentage of average sleep debt and severe sleep debt and, in patients with grade IV chronic pain, extremely severe sleep debt was prevalent. It is important to emphasize that extremely severe sleep debt is related to high disability and limitation.2 value were equal or close to 1, because, according to the literature, the higher the correlation, the closer to 1 the R2 value is. Therefore, through the results of correlation it is possible to state that, from the grade of chronic pain of a patient, we cannot predict the level of sleepiness of that patient, and vice-versa.No correlation was verified between variables. There was no linear relation between patient genders and grades of chronic pain  or levels of sleepiness . This result showed that both females and males presented all levels of sleepiness and for the degrees of chronic pain only males did not present grade IV chronic pain, while the others were observed for both genders. This result would be different if RMost of the patients who sought CDATM were females and presented chronic pain. Of the grades of chronic pain, the highest incidence was observed for grade II (high pain intensity and low disability). In regard to the levels of sleepiness, patients with average sleep debt were prevalent. The degrees of chronic pain and the levels of sleepiness do not present an association among them or with the patient gender.


Injection of fibrin glue mixed with blood into the epidural space to reliably and effectively treat medically refractory orthostatic headache caused by spinal cerebrospinal fluid (CSF) leaks and subsequent intracranial hypotension has recently been described. The study described in this article utilizes an analogous technique to gauge the therapeutic reproducibility of this novel technique.Eight patients with medically refractory headache resulting from intracranial hypotension caused by spinal CSF leaks received epidural injections of combined fibrin glue, autologous blood, and Isovue contrast at the L1—2 vertebral level using intermittent fluoroscopic guidance. Pre-procedure, 1-week post-procedure, and 3-month post-procedure headache pain scores were collected and used for comparison.Three out of 8 patients reported relief at 1 week, although 1 of these 3 patients had returned to their baseline pain intensity at 3 months. Four patients reported no change at 1 week, though 2 of these patients had reduction of their chronic headache pain at 3 months. A single patient reported increased pain 1 week after the procedure, which persisted at 12 weeks. Overall, 4 out of the 8 patients had decreased pain scores at 3-month follow-up.We did not achieve a similar frequency of headache resolution as reported in prior original studies. However, a subset of patients did appear to receive substantial benefit from the combined fibrin glue-blood patching procedure. This technique may prove to be useful in medically refractory cases, including those patients who continue to have symptoms despite the prior administration of conventional epidural blood patches. Headache associated with spontaneous intracranial hypotension (SIH) is often although not always orthostatic (provoked or aggravated in upright position and decreased or relieved in recumbency). The diagnosis is made based on the synthesis of patient history, clinical findings, cerebrospinal fluid (CSF) examination, and imaging studies. These headaches, which are now well defined in the scientific literature, can be frontal, occipital, frontooccipital or holocephalic in anatomic location  has emerged as the treatment of the choice for patients who fail initial conservative management. The mechanism of action for blood patching is twofold, with both immediate and delayed effects. The immediate effect results from tamponade of the dural sac , leading to translocation of axial CSF to the intracranial compartment and subsequent increased CSF pressure. Delayed effects are attributed to actual sealing of the leakage site, which allows the intrathecal space to be reconstituted with normal volume as CSF is naturally regenerated and recirculated. Previous studies have pointed to success rates ranging from 36 to 85 % after a single epidural blood patch for SIH headaches , pre-procedure and 1 week post-procedure headache pain scores were collected and available to review via electronic medical records. The patients were contacted via telephone at 3-month post-procedure and headache pain scores were recorded at that time. Patients were also questioned about duration of pain relief and functional improvement after receiving the fibrin glue blood patch. To further assess patient satisfaction, they were also asked if they would recommend this procedure to others or if they would be willing to undergo a repeat procedure. Mean and median NRS score were graphed to compare changes  did report some pain relief at 7 days. At 3-month follow-up, only 1 patient (12.5 %) had complete resolution of her headache, while an additional 3 (37.5 %) had prolonged partial resolution of their symptoms. Unfortunately, 1 patient (12.5 %) had prolonged increased pain after the procedure that persisted at 3-month follow-up. While our results were not as encouraging as those of prior reports, they do indicate that the combined blood and fibrin glue patch may prove beneficial in a subset of medically refractory patients who have failed conservative treatments and conventional EBPs.The small sample size is a limitation of our study. A study involving a larger number of patients is underway. Of significant note, we were not able to reproduce the exact procedural protocol of prior original studies (Franzini et al. We noted some benefit for some patients from the injection of both fibrin glue and autologous blood into the epidural space. We are hesitant to advocate the regular use of this technique for all patients with SIH headaches because of the expense, efficacy, and possibility of side effects of this technique in the setting of only modest expected efficacy. However, this procedure may prove to be useful in refractory cases. A pre-procedure discussion of the risks and benefits is warranted.


Background. Persistent pain as a consequence of surgical treatment has been reported for several common surgical procedures and represents a clinical problem of great magnitude. Material and Methods. We describe the case of a 47-year-old female who presented a retractile scar that adhered to deep planes at the upper right of the vestibule due to surgical removal of maxillary exostosis, which determined important pain symptoms extending till the right shoulder during both chewing and rest. We subsequently treated her with autologous fat grafting according to Coleman's technique. Results. Clinical assessments were performed at 5 and 14 days, 1, 3, and 6 months, and 1 year after surgical procedure. We observed a progressive release of scar retraction together with an important improvement of pain symptoms. Conclusion. The case described widens the possible application of autologous fat grafting on a new anatomical site as buccal vestibule and in one specific clinical setting confirming its promising biological effects. Exostoses are nodular protuberances of mature bone whose precise designation depends on anatomic location.Buccal exostoses occur along the buccal aspect of the maxilla or mandible, usually in the premolar and molar areas. Palatal exostoses are found on the palatal aspect of the maxilla, and the most common location is the tuberosity area. These entities could become symptomatic when they reach such a volume to interfere with feeding and speaking or to alter facial mimic and contour.The histologic features of exostoses are described as hyperplastic bone, consisting of mature cortical and trabecular bone . Their eWhen being symptomatic, exostosis allows the possibility of surgical removal that could be related to different drawbacks.Postsurgical scar retraction should be mentioned together with pain sensation during chewing, which can compromise dramatically the quality of life of patients.Up to now no support therapy has been described to treat these weakening symptoms in this group of patients.Autologous fat grafting is a relatively new technique which has been recently adopted to treat various pathologic conditions in reconstructive surgery, such as scars and burn keloid –7, and pMoving from these evidences, we decided to adopt autologous fat grafting for the treatment of postsurgical scar retraction and pain sensation related to exostoses surgical removal, in order to verify its possible beneficial effects in this new approach.A female patient, aged 47 years, came to Department of Plastic Surgery at Humanitas Research Hospital in February 2013. She was referred to the department for surgical removal of maxillary exostosis in 1999 and related to the surgery a scar adhered to deep planes at the upper right of the vestibule which determined important pain symptoms extending till the right shoulder both during chewing and at rest, interfering with feeding and speaking.Moreover the patient revealed chronic assumption of analgesic medication (Ibuprofen 600 mg) to control pain sensation. She did not assume any other medications.Clinical history revealed a diagnosis of Sjogren syndrome and corrective surgery of cleft palate in 1996; no other pathologic conditions were present.Clinical examination showed a postsurgical scar area of about 2 cm in length, retracted and adherent to deeper planes just at the upper right of the vestibule, which causes pain at digital pressure.After collection of both clinical history and examination we proposed to our patient surgical scar tissue correction with autologous fat grafting.Our patient was informed about surgical procedure in particular regarding fat grafting unpredictable reabsorption rate and clinical results in this particular case. Both informed consent form and preoperative images were collected .After routine preoperative examination and clinical assessment, the patient underwent liposuction under sedation and local anesthesia. The adipose tissue was harvested from the right flank, which is an easy accessible and abundant reservoir of adipose tissue.Following Coleman's procedure , the obtFollowing surgery pressure dressing was applied over donor site for 5 days and antibiotic therapy was recommended for 5 days (cefixime 400 mg 1 pill per day).Clinical assessment was performed after surgical procedure at 5 and 14 days, 1, 3, and 6 months, and 1 year.During the clinical meeting we observed progressive release of scar retraction and quality improvement measured with POSAS scale , togetheAfter 3 months from surgical operation we performed an MRI of the facial skeleton and we appreciated a soft tissue volume increase in the area of previous fat grafting . No locaExostoses have been described as nodular protuberances of mature intraoral bone.Palatal exostoses revealed a prevalence of 30% while buccal exostoses presented a prevalence rate of 0.9 per 1000 persons .These clinical entities could become invalidating for patients especially when they reach such a volume to interfere with feeding and speaking or to alter facial mimic and contour.In these advanced cases surgical treatment is needed to remove bony prominences and to restore oral function and contour. Nonetheless also surgical removal could be related to different drawbacks. In fact postsurgical scar retraction could determine chronic pain in oral region, in particular during chewing, with an overall reduction of patients' quality of life.No support therapy has been described until now for these weakening symptoms in this group of patients who, most of the time, are analgesic medications dependent.Persistent pain as a consequence of surgical treatment has been reported for several common surgical procedures and represents a clinical problem of great magnitude.Our team adopts autologous fat grafting in the treatment of multiple pathological status beyond all scar treatment and pain syndromes.We start treating postmastectomy pain syndrome obtaining significant decreases of neuropathic pain , 9.Supported by our promising results we approached with positive results also chronic headaches of cervical origin, both chronic cervicogenic and occipital neuralgia .Moving from these evidences we consider autologous fat grafting as an innovative solution for pain syndromes related to scar retraction although the exact mechanism of action is still unclear.Laboratory findings have demonstrated the presence of mesenchymal multipotent stem cells in the adipocyte cell fraction of fat graft .We hypothesize that autologous fat graft due to the regenerative role of the stromal fraction of adipose tissue grafted could promote a reorganization of fibrotic tissue together with soft tissue regeneration, leading to scar release and reducing nerve excitatory pattern with consequent positive clinical results on pain control.In addition to that, surgery-associated tissue injury leads to an inflammatory reaction accompanied by increased production of proinflammatory cytokines, which can induce peripheral and central sensitization with a failed nociception system, leading to pain augmentation.Mesenchymal stem cells and adipose-derived stem cells could efficiently reduce T-cell activation inhibiting the proliferation of CD4 and CD8 T lymphocytes . It coulThe case reported showed a positive final outcome. Buccal vestibule scar retraction showed a release after one procedure of autologous fat grafting and our patient referred to clinical remission of pain which did not need any analgesic treatment with a total follow-up of one year.The case described widens the possible application of autologous fat grafting on a new anatomical site as buccal vestibule and in one specific clinical setting confirming its promising biological effects.In fact our experience could open a new route of regenerative surgery addressing a mucosal tissue as buccal one.


Axial Spondyloarthritis (AxSpA) and chronic low back pain are rheumatic diseases that impact patients’ health-related quality of life (HRQoL). In other chronic conditions, HRQoL was positively associated with dispositional optimism, a personality trait. The objective was to explore the relationship between optimism and HRQoL in these two diseases.A cross-sectional study was performed in 2 tertiary care hospitals and 2 private practices in France. Patients had definite AxSpA or chronic low back pain according to the rheumatologist. A generic HRQoL questionnaire  with physical and mental composite scores (PCS and MCS respectively) and an optimism questionnaire  were collected. Analyses included non-parametric correlations and multiple regression analyses to study the effect of optimism on PCS and MCS.p <0.01) and these relations persisted in multivariate analyses .In all, 288 (199 AxSpA and 89 low back pain) patients were included: mean age, 47.3 ± 11.9 years, 48.6 % were males. Pain levels (0–10) were 4.5 ± 2.4 and 4.3 ± 2.4 in AxSpA and LOW BACK PAIN patients, respectively. HRQoL was similarly altered in both diseases, for both physical and mental composite scores . Optimism was moderate and similar in both populations. Optimism was positively correlated to MCS in both diseases  contains supplementary material, which is available to authorized users. Axial Spondyloarthritis (AxSpA) is a chronic inflammatory rheumatic disease affecting primarily the axial skeleton and sacroiliac joints. AxSpA is a painful and potentially disabling condition, typically diagnosed in early adulthood and its usual characteristics are pain, stiffness due to inflammation and impaired physical function . Non-speThe dispositional and global expectations individuals hold about success or failure are described by the constructs of optimism and pessimism. Dispositional optimism is defined as a stable, trait-like personality characteristic consisting of a general positive mood or attitude about the future with a tendency to expect favorable outcomes in life situations . In oppoIn different medical settings, optimistic people have been shown to have higher QoL compared to people with low optimism levels or pessimistic people –17. ThisExploring the relationship between optimism and HRQoL in AxSpA and chronic low back pain could have interesting practical implications. Indeed, as research has linked optimism to lower pain sensitivity and better adjustment to chronic pain , it coulThus, the objectives of the present study were to explore the levels of HRQoL and optimism in AxSpA and low back pain, and the relationship between optimism and HRQoL in these two populations.This study was a multi-centre cross-sectional study from the rheumatology departments of the Pitié-Salpetrière hospital in Paris and the René Dubos hospital in Pontoise as well as from two outpatient clinics from private practice rheumatologists in Paris, France. This study was approved by the Pitié-Salpetrière Ethic committee.All AxSpA patients according to the internationally recognised Assessment of Spondyloarthritis (ASAS) criteria  seen in Demographic characteristics including age, gender, body mass index, education level, family structure , and work status  were collected. The medical files were accessed for each patient to confirm the diagnosis , and forOptimism was assessed by the French version of the Life Orientation Test-Revised (LOT-R) , 33. TheHRQoL was measured by the French version of the Short Form Health Survey SF-12, a self-administered, generic health related quality of life (HRQoL) instrument assessing function and well-being via multi-item scales measuring 8 domains: physical function, role physical, role emotional, vitality, mental health, social functioning, general health and bodily pain . The SF1For all patients, anxiety and depression were assessed by the Hospital Anxiety and Depression Scale (HADS)  and Visup value <0.05 was considered significant.To evaluate the relationship between optimism and HRQoL in the two populations, Pearson correlations were performed. Multivariable linear regression analyses were performed to explain HRQoL (PCS or MCS) by optimism, taking into account: demographic variables, marital and work status, global assessment VAS, duration of symptoms, anxiety, depression, and BASFI and BASDAI for AxSpA patients. Only patients with available LOT-R and SF12 were included in the analysis (no imputation of missing data). The R statistical software version 3.0.2 was used; a Initially, 462 patients (321 AxSpA and 131 low back pain) were contacted; 307 (64 %) answered; and 288 (62 %) patients had analysable data: 199 (69 %) with AxSpA and 89 (31 %) with low back pain.N = 198, 68.8 %), had a higher education level  and were currently employed  , their radiographs or magnetic resonance imaging often showed sacroiliitis, the hallmark of this disease  and their disease was moderately active and severe: BASDAI 3.8 (2.0), BASFI 28.3 (25.7).The mean age of the 288 patients was 47.3 years (standard deviation (SD) 11.9, range 19–85), 140 (48.6 %) were men, and the majority were married (No significant differences were found between levels of HRQoL and levels of optimism between the two populations Table .p <0.01) whereas it was not correlated to the physical component . For low back pain patients however, optimism was positively correlated to both component of HRQoL with a stronger correlation for the mental component .For AxSpA patients, optimism was positively correlated to the mental component of HRQoL only . However, optimism was not related to PCS; rather, the elements associated with PCS were global assessment visual analogue scale and body mass index in both populations; and work status, BASDAI and BASFI in AxSpA  allows an assessment of HRQoL compared to the general population .These findings are in line with previous studies using the longer version of the SF-12, the SF-36 . In 2 SpThe present study indicated HRQoL was similar in both diseases. This is an interesting finding, given the different physiopathological nature of these diseases. It indicates the physical impact of these diseases may be close, perhaps due to similar functional limitations because of the spinal involvement. Regarding mental health, we anticipated that low back pain patients would have a lower mental HRQoL than AxSpA patients due to the lack of treatments and the difficulty in reducing symptoms but this was not the case.In this study, optimism could be considered for indicative purposes to be in the moderate range. Interestingly, optimism levels were similar in the 2 diseases studied and this may suggest that people suffering from either AxSpA or low back pain are rather less optimistic than a healthy population. Indeed, a study assessing optimism among 504 high school students reports a mean LOT-R of 16.5 whereas in this study, the mean LOT-R of the whole sample was 13.8 . Even thOptimism was related to mental HRQoL both in univariate and multivariate analyses in the present study. The link between moderate optimism and low quality of life might be explained by the role of coping strategies used by the patients. Indeed, it could be that less optimistic people use more dysfunctional coping strategies when confronting stressful events than optimistic people –53.The present findings were consistent with the previously published studies on optimism in the field of rheumatic diseases and chronic conditions –24. The In the present study, optimism had a very small effect on the physical HRQoL. These results indicate that optimism may not influence the interpretation of physical scores, widely used in the evaluation of AxSpA and low back pain.The present study evidenced non-psychological drivers of PCS including global assessment for both AxSpA and low back pain patients, and BASFI for AxSpA patients only. These results confirm the validity of the study.Applying the bio-psychosocial model to chronic diseases implies taking into account not only disease activity and severity, but also psychological aspects including optimism. We have shown optimism is a driver of psychological, but not physical, HRQoL in the 2 chronic diseases. However, further studies are needed to understand the pathway linking optimism to HRQoL and the potential factors playing a role in this relationship such as coping techniques.


Most patients who present with cancer have advanced disease and often suffer moderate to severe pain. Opioid therapy can be safe and effective for use in cancer patients with pain, but there are rightful concerns about inappropriate opioid use even in the cancer population. Since cancer patients live longer than ever before in history (and survivors may have long exposure times to opioid therapy), opioid misuse among cancer patients is an important topic worthy of deeper investigation. Cancer patients with pain must be evaluated for risk factors for potential opioid misuse and aberrant drug-taking behaviors assessed. A variety of validated screening tools should be used. Of particular importance is the fact that pain in cancer patients changes frequently, whether it is related to their underlying disease (progression or remission), pain related to treatment , and concomitant pain unrelated to cancer . Fortunately, clinicians can use universal precautions to help reduce the risk of opioid misuse while still assuring that cancer patients get the pain therapy they need. Another important new “tool” in this regard is the emergence of abuse-deterrent opioid formulations. The Cali Cancer Registry (CCR) is the best-known population-based source for descriptive epidemiology of cancer in Colombia specifically and in South America at large; dating back to 1962, it is the oldest cancer registry in Latin America . The maiPain is a common symptom of cancer, typically worsening with disease progression. Cancer survivors may likewise suffer from chronic pain syndromes associated with the cancer treatments, such as chemotherapy-induced neuropathic pain , tobacco use, mental health disorders (such as depression and anxiety disorders), and psychological traumas  may legitimately have moderate to severe pain associated with their malignancy. For terminally ill patients with severe pain, addictive disorders were once considered non-issues; the patient near death was given medications to stop the pain without concern about potential addiction. With patients surviving cancer for longer and longer periods of time, these issues are no longer minor. Moreover, unchecked substance abuse may exacerbate suffering in the palliative patient, complicate the management of other cancer-related symptoms, and have a distressing effect on the patient's family  demands for stronger or more analgesics, “lost” prescriptions , demands to see the physician without an appointment, and insisting on specific pain relievers by product name and dosage  in the composite CAGE-AID instrument. Participants are asked to respond yes or no to four questions that give the survey its acronym: (1) are they trying to use less (“cutting down”), (2) are they annoyed that people criticize their substance use (“annoyance”), (3) do they feel guilty about their substance use (“guilty”), and (4) do they need to use the substance first thing in the morning to get going (“eye-opener”). The test can be used for alcohol alone, as originally intended, or for other substances (CAGE-AID). The rule of thumb is that one yes warrants further evaluation of the patient, and two or more yes answers strongly suggests substance abuse. The CAGE survey is easy to use and is familiar to most clinicians, but it may be of limited utility and accuracy in patients with psychiatric disorders  was designed to evaluate patients prescribed opioid analgesics to manage persistent pain  evaluates 10 psychosocial risk factors for opioid abuse, including history of substance abuse, sexual abuse, and mental health disorders. ORT scores classify patients as being at low, moderate, or high risk for opioid misuse. Notably, ORT was specifically designed and validated for use in cancer patients , a subset the longer form of the original SOAPP 14-item questionnaire, is a 5-item questionnaire to be filled out by the patient. Patients who score 4 or more are considered to be at high risk for opioid abuse. SOAPP-SF has a sensitivity of 0.86 and specificity of 0.67 with a 33% chance of a false positive  is a short survey completed by the patient which evaluates analgesia, activities of daily living, and adverse events. A checklist on the form is to be completed by the physician evaluating the patient's potential aberrant drug-related behaviors .Ongoing or a recent history of substance abuse and certain mental health disorders are known risk factors for opioid misuse and abuse, but the specific prevalence of these conditions in the cancer population has not been thoroughly elucidated. Indeed, the cancer population has changed considerably in recent decades with more and more patients undergoing longer treatments and surviving longer with the disease, in remission, or cured. It has been estimated that about 20% to 50% of cancer patients have some psychiatric disorder, most frequently depression  is a simple, inexpensive, and familiar way to screen patients for inappropriate drug use ; the patient may be diverting the drugs and selling them rather than taking them; or, the patient may be noncompliant and not taking the drugs on “good days.” Any of these situations must be addressed. However, unexpected UDT results can also occur due to laboratory errors or screens that are not sensitive enough to detect the particular opioid in question. Unexpected or suspicious UDT results should be viewed first-and-foremost as an opportunity to discuss opioid-taking behaviors with the patient.A treatment agreement is a written document that spells out in plain language the goals, risks, and benefits of opioid therapy for a given patient. These agreements may be of great or limited utility, depending on how they are presented and administered  of specific opioid analgesic products are commercially available or in development. These formulations are specifically designed using innovative technologies to resist or deter abuse . The RFID is a tiny device (chip) which contains essential data in the form of an electronic product code and a serial number unique to each product. RFID technology allows opioids to be tracked throughout the supply chain.While large-scale longitudinal studies may be required to demonstrate the effectiveness of such ADF products in reducing opioid abuse, when ADF OxyContin was released, the average diversion rate decreased 60%  in advance. Pain levels must be assessed often. Patients taking opioids should be informed about potential side effects and these effects should be managed proactively. Since opioid-associated side effects can be treatment limiting, it is crucial to long-term therapeutic goals to manage them effectively.Fifth, clinicians must be vigilant about abuse, even in patients who did not seem to be at risk when opioid therapy commenced. Risk factors change over time (Pergolizzi et al., Finally, pain specialists treating pain in cancer patients should be conscientious in documenting their findings, evaluations, and other aspects of care. Cancer patients can be long-term patients with constantly changing needs and this requires diligence in documentation. Best practices should be conscientiously applied to mitigate the potential for abuse, but the clinician and all stakeholders must be aware that as long as opioids are used, there is a degree of risk.All authors participated in gathering and interpreting the information; all authors reviewed the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


The primary outcome measures are assessment and analysis of pain, discomfort, and sedation level before, during, and after the central venous catheter insertion at five time points. The median (IQR) pain score is worst for normal saline group at local anaesthetic injection [6 (4–6.7)] which was significantly attenuated by addition of fentanyl [3 (2–4)] and dexmedetomidine [4 (3–5)] in the immediate postprocedural period (P = 0.001). However, the procedure related discomfort was significantly lower in dexmedetomidine group compared to fentanyl group in the first 10 min of procedure after local anaesthetic Injection (P = 0.001). Fentanyl is more analgesically efficient for central venous catheter insertion along with local anaesthetic injection. However, dexmedetomidine has the potential to be superior to fentanyl and placebo in terms of providing comfort to the patients during the procedure.We aimed to show that a single preprocedural dose of either dexmedetomidine or fentanyl reduces procedural pain and discomfort and provides clinically acceptable sedation. In this prospective, double-blind study, sixty patients scheduled for elective surgery and requiring planned central venous catheter insertion were randomized to receive dexmedetomidine (1  Hospitals that are hard pressed to operate more number of cases per day usually carry out procedures like epidural catheter insertion or central venous catheter insertion (CVCI) in the holding area outside the operation theatre (OT) for the second case, while the first case of the day is still inside the operation theatre. Though this strategy reduces the surgical readiness time for the second case , the conA multicenter American study observed that 51.5% of patients had an increase in pain intensity immediately after the procedure (CVCI) over the baseline preprocedural pain . Two sinThe purpose of this prospective, randomized, double-blind clinical trial is to evaluate objectively the effects of addition a single dose of either fentanyl or dexmedetomidine to conventional subcutaneous LA infiltration analgesia on perceived pain and discomfort during CVCI.CTRI/2014/02/004397). The study was conducted in a randomized, double-blinded, placebo-controlled manner and conformed to the CONSORT guidelines. The study protocol conforms to the provisions of the Declaration of Helsinki in 1995 (as revised in Seoul 2008).The study protocol was approved by the Institute's Ethics Committee (IEC number: 350) on 30th January 2014 and written informed consent was obtained from each participant. The study protocol was registered with Clinical Trials Registry-India  as a part of normal care were enrolled in the study after obtaining due consent. Patients were included in the study if they were with 18–65 years, awake, alert, and oriented and their medical condition was stable enough to allow them to understand and use a verbal numeric rating pain scale (VNRPS) and systemic analgesics had not been administered for at least four hours before the procedure. All the patients received their routine premedication like alprazolam  night before surgery and on the day of surgery. Patients were excluded from the study if they were on any medication meant for controlling heart rate (HR) and blood pressure, had a known adverse reaction to the study drugs, had past history of undergoing any surgery with or without anaesthesia in the preceding one year, and were not willing to participate in the study.μg/kg, fentanyl 1 μg/kg, or 0.9% saline (placebo group), all made to a total volume of 10 mL. All the solutions were labeled “study drug” and coded to maintain the double-blind nature of the study. The study drugs were infused to the patients as per their group allocation over 10 min using a syringe infusion pump.All the study participants were called to the holding area adjacent to OT 90 min before the scheduled surgery and were allocated randomly to one of the three groups using a computer-generated random number table and a sealed opaque envelope technique. An anesthetist, who was not one of the observers, prepared syringes containing either dexmedetomidine 1 The procedure for CVCI commenced at the end of infusion of the study drugs. Each patient was positioned supine with a rolled up towel placed between the scapulae to extend the head and the patient was given 10–15° Trendelenburg position with the neck turned to the opposite side. A standard subcutaneous infiltration of 5 mL of 2% lignocaine was made after confirming the anatomical landmark of the target jugular vein. A physician blinded to the study drug injected 3 mL of the LA solution over 10 to 15 seconds through a 25-gauge needle at the apex of the triangle formed by the lateral and medial head of sternocleidomastoid muscle using anterior approach  SBP < 90 mmHg was treated with boluses of IV ephedrine 6 mg. Hypertension was defined as a persistent or recurrent rise in SBP by >20% and was treated with boluses of IV labetalol (5 mg increments). Bradycardia was defined as an absolute decrease in HR < 55 beats/min. Persistent (more than 30 seconds) or recurrent bradycardia was treated with IV atropine 0.6 mg. Tachycardia was defined as a persistent rise in HR by >30% above baseline and was treated with additional sedation and analgesia. The physician performing the CVCI procedure is responsible for data collection and analysis.Heart rate (HR), systolic blood pressure (SBP), respiratory rate (RR), and peripheral oxygen saturation  on 100 mm VAS during subcutaneous injection of LA in healthy volunteers . A reduc post hoc test. Categorical data were analyzed using proportion chi-square test. A value of P < 0.05 was considered to be statistically significant. Pain, discomfort, and sedation scores were compared among the groups using Kruskal-Wallis test. Follow-up tests were conducted to evaluate pairwise differences among the three groups, controlling for Type I error across tests by using the Bonferroni approach (P < 0.016).Statistical analyses were performed using software IBM Corp (2011), IBM SPSS statistics for windows, version 20.0 . Approximate normality of the distribution was assessed using Shapiro-Wilk test before applying a particular statistical test. Patients' characteristics and baseline continuous variables were compared using one-way ANOVA followed by BonferroniSixty patients were randomized, with all but one completing the study. One patient from fentanyl group was withdrawn due to failure in identifying a patent jugular vein and the physician opted for cannulating the subclavian vein , both the study drugs attenuated the pain response and reached statistical significance in comparison to placebo . In contrast to dexmedetomidine, fentanyl appeared to be more analgesically efficient in reducing the pain intensity numerically to CVCI after LA injection (LAI) but it has not reached statistical significance . The median VNRPS thereafter (at PP10 and PP60) were comparable among three groups  and hypotension (P = 0.046) than fentanyl and placebo groups. During study period, the absolute heart rate decreased below 55 in five, two, and nil patients from dexmedetomidine, fentanyl, and placebo groups, respectively. Two patients from dexmedetomidine group experienced bradycardia requiring treatment with atropine (0.6 mg bolus intravenous). Hypotension was evident in more number of patients from dexmedetomidine group (3/20) in contrast to fentanyl (0/19) and placebo (0/20) groups but did not require any treatment. One patient from fentanyl group experienced episodes of SpO2 < 92% and nausea compared to none from dexmedetomidine and placebo groups. However, the difference did not reach statistical significance. No patient vomited or required antiemetic medication  compared to placebo at LA injection and for the subsequent procedural steps. We did not find any significant difference in median sedation score between fentanyl and placebo groups. However, dexmedetomidine group patients were significantly more sedated compared to placebo and fentanyl groups at the end of the procedure (PP3). At the end of study period (PP60) all the patients were responding to verbally spoken words (OAA/S score of 4 or 5). No patient from any group manifested uncontrolled movement strong enough to hinder performance of the procedure .Overall, fentanyl and dexmedetomidine groups were not statistically different with median pain score at any time points, though fentanyl group patients trended towards less pain in the postprocedural period . However, dexmedetomidine group patients had a distinctly better discomfort score in the postprocedural period (PP3 and PP10).Traditionally pain has been described as a combination of unpleasant sensory and emotional component. In our study, the sensory and emotional components of pain that might have been resulted from CVCI were measured with VNRPS and VNRDS, respectively.The primary findings of the study are that subcutaneous LA infiltration induces maximum pain in the placebo group and preprocedural fentanyl and dexmedetomidine reduced this pain response. However, in terms of patients' comfort dexmedetomidine appears to be more efficient than fentanyl in the immediate postprocedural period.Two American studies have described pain and discomfort as two separate perceptions experienced by patients during CVCI , 10. TheFentanyl has been studied extensively for pain management and its efficacy is well documented for management of acute pain , 12. HowShort acting opioid has been favored for brief painful procedures. An Indian study concluded that both fentanyl and sufentanil boluses 10 min before chest tube removal reduce the mean pain intensity score significantly compared to placebo control at 5 and 20 min in the recovery room . SimilarP = 0.001 and 0.003). However, fentanyl appeared to be more analgesically efficient than dexmedetomidine in reducing the pain intensity at all time points  but it has not reached statistical significance. In contrast, there is a sharp statistical difference in discomfort level as assessed by VNRDS between fentanyl and dexmedetomidine groups indicating superiority of dexmedetomidine over fentanyl in the immediate postprocedural period (PP33 and PP10). This difference in action between fentanyl and dexmedetomidine can be partly explained by multidimensional model of procedural pain [The sole use of dexmedetomidine as a sedative analgesic is not consistently successful for many moderately painful invasive procedures. A multicenter American study suggested that the surge in pain arising out of CVCI in a conscious patient may lead to central sensitization and could be a potential cause for persistent pain which continues for some time after a noxious event and advocated use of preemptive analgesia to avoid central sensitization . In the ral pain . Fentanyμg/kg) reported higher incidence (15%) of oxygen desaturation [μg/kg infusion and reduced the risk of clinically significant respiratory depression requiring intervention like head tilt-chin lift maneuver, naloxone administration, and resuscitation with bag-mask ventilation, without compromising the analgesic efficacy. Only one patient from fentanyl group in our study desaturated (SpO2 < 92%) and needed a simple sequential verbal stimulation to maintain peripheral oxygen saturation above 98%.All patients from dexmedetomidine group had peripheral oxygen saturation of more than or equal to 99% by pulse oximeter in room air. However, more number of patients from dexmedetomidine group also attained an unwanted sedation level (lower OAA/S sedation score) during the study period which may sometime hinder the patient cooperation needed by the physician while inserting central venous catheter. This finding also confers the advantage of dexmedetomidine in providing adequate sedation with clinically insignificant respiratory effects, including apnea, hypoxemia, or airway obstruction during ICU procedures. However, a higher incidence of bradycardia and hypotension associated with dexmedetomidine is a worrisome predicament. A previous study using a higher dose of fentanyl (2 turation . We haveThe major limitation of the current study cohort is a possible risk of inclusion bias with limited external validity as the decision to place a central venous catheter was at the discretion of attending anesthesiologist. Many patients who will need a CVCI may not belong to American Society of Anesthesiologists physical status grade 1/2 with age around 40 years; even then we feel this study might serve as a pilot for further research in more critically ill patients. The second limitation is a precision bias owing to small sample size. All the study participants were premedicated with a dose of anxiolytic on the night before surgery and also on the morning of surgery which might have influenced the motivational components of pain and the effect size due to possible potentiating effect of the study drugs, but since all included subjects were given the same premedication, this may not really represent a major limitation. The third limitation is the fact that unavailability of an ultrasound for CVCI and lack of the ultrasonographic assistance could have been a confounding factor as it could have reduced the procedure time and number of attempts for CVCI, both of which might correlate to patient's sense of discomfort and pain. However, we are unaware of any study comparing the pain and discomfort associated with ultrasound guided CVCI versus conventional technique of CVCI.μg/kg is a better alternative to provide additional analgesia for CVCI. Further studies are required to see whether reduced preprocedural dexmedetomidine infusion will bring a beneficial cardiovascular and respiratory effect without compromising analgesia and patient's comfort level.In conclusion, both fentanyl and dexmedetomidine provide comparable analgesia for CVCI along with LA field infiltration. Dexmedetomidine is superior to fentanyl and placebo in terms of providing comfort to the patients during the procedure but is associated with a tendency to excessive sedation and unwanted cardiovascular events. With minimal adverse respiratory and cardiovascular events and a comparable analgesic efficacy, fentanyl 1


TN usually leads to paroxysms of short lasting but very severe pain. Between the attacks the patient is usually asymptomatic, but a constant dull background pain may persist. Carbamazepine is currently the drug of first choice in the treatment of TN. It is efficient in 70-80% of patients but often associated with severe adverse effects such as drowsiness, confusion, nausea and ataxia, which may require discontinuation of medication. Surgical interventions may not be suitable for all patients and waiting for the procedure can be agonizing. Therefore different non-invasive treatment options are indispensable.To investigate the efficacy of transcranial direct current stimulation (tDCS) of the primary motor cortex on pain and trigeminal nociceptive processing in subjects with classical trigeminal neuralgia (TN).Seventeen subjects with TN were recruited in the study. Patients stimulated daily for 20 minutes over two weeks using anodal (1mA) or sham tDCS in a randomized cross-over design. Primary outcome variable was pain intensity on a verbal rating scale (VRS). VRS and attack frequency were assessed daily for one month before and after tDCS using an individual patient diary. The impact on trigeminal pain processing was assessed with pain-related evoked potentials (PREP) and the nociceptive blink reflex (nBR) following electrical stimulation on both sides of the forehead (V1) before and after tDCS. All patients gave written informed consent prior to study inclusion. The study was approved by the Ethics committee of University of Duisburg-Essen medical faculty.Anodal tDCS reduced pain intensity more effectively than sham stimulation after two weeks of treatment. The attack frequency reduction was not significant. PREP showed an increased N2 latency and decreased peak-to-peak amplitude after anodal tDCS. No severe adverse events were reported. Patients with concomitant chronic background pain do not seem to benefit from tDCS as described previously for medical therapy and surgical intervention.Daily anodal tDCS over two weeks ameliorates trigeminal pain in TN. It may become a valuable treatment option for patients unresponsive to conventional medical treatment or on wait for surgical procedures. International, multicenter, randomized controlled trials are needed with higher patient numbers before a definite recommendation can be proposed.No conflict of interest.