Ninety-nine patients (70%) declared themselves “healed” from jaw functional limitation with no residual painful symptoms, 31 (22%) improved their symptoms and jaw function, 11 (8%) reported no changes compared to T0 and no one worsened. As for all parameters analyzed, the comparison between the ones before and after treatment was statistically significant (p < 0.05). The RA.DI.CA. splint proved to be highly performing and promoting functional and symptomatologic recovery, also in the medium and long term, through the restoration of the functional disc-condyle relationship and the healing of joint tissues.The study aimed at assessing the effectiveness of the RA.DI.CA. splint in the management of temporomandibular joint disc displacement without reduction (ADDwoR) and jaw functional limitation. The authors developed a retrospective clinical study. A total of 2739 medical records were screened. One hundred and forty-one patients with chronic unilateral disc displacement without reduction and jaw limitation, treated with a multifunctional RA.DI.CA. splint, were enrolled. Temporomandibular pain, headache, familiar pain, neck pain, and emotional strain, maximum spontaneous mouth opening, and lateral excursions were evaluated at baseline (T0), after therapy (T1), and during the follow-up (T2). Descriptive statistical analysis was performed. Wilcoxon test assessed changes in symptomatology and functional aspects before and after treatment and between T1 and T2, with  The most common issues that the gnathologist has to face in the management of temporomandibular disorders (TMD) are temporomandibular joint (TMJ) and/or masticatory muscles pain, as well as the qualitative and quantitative anomalies of the mandibular movements, due to the dysfunction of the stomatognathic components . The altThe course of this kind of pathology has been widely investigated, remaining a debated issue among clinicians. Some researchers believe that ADDwoR has a spontaneous resolution, at least under the aspect of the functional recovery . Even ifOver the years, several therapeutic strategies have been proposed in scientific studies, classified in conservative and surgical treatments ,11,12,13The most debated conservative approach is the one using occlusal splints  and thisIn order to make therapeutic protocols as targeted as possible, the authors of the study have designed and patented a particular type of multifunctional splint, called RA.DI.CA. , highly specific for jaw functional limitations. The characteristics of the device and its therapeutical effectiveness were evaluated in initial comparative studies ,19,20.The authors have been using it for years, adapting the protocols and some parts of the splint to the individual characteristics of the patient . The choIn this retrospective clinical research, the authors aim at reporting the experience of the last decade in the use of RA.DI.CA splint in patients with ADDwoR and jaw limitation, and at monitoring the results of the application of this device, over the years, with a medium-long term follow-up.To address the research purpose, the authors developed and implemented a retrospective clinical research between January and December 2019. The study was approved by the Institutional Ethics Committee of Sapienza, University of Rome, Protocol no. 349.Medical records of patients, taken in between 2007 and 2017 at the Gnathology Service, Department of Oral and Maxillo-facial Sciences, Sapienza University of Rome, were screened.Patients who fulfilled the following criteria were enrolled in the study: (a) patients over 18 years old; (b) diagnosis of jaw functional limitation due to unilateral disc displacement without reduction for more than 6 months, verified in MRI (Magnetic Resonance Imaging), according to RDC/TMD Research Diagnostic Criteria for Temporomandibular Disorders) ,18,19 anThe exclusion criteria were: (a) incomplete medical records; (b) jaw limitation due to other factors such as connective tissue diseases (sclerodermia), traumas (mandibular or condylar fractures), deformities, tumors, TMJ ankylosis, muscular locking; (c) other concomitant conservative therapies such as physical rehabilitation.Out of 2739 medical records examined, 141 (5.14%) fulfilled the above inclusion and exclusion criteria.All the patients were visited according to the RDC/TMD ,21,22 unIn order to collect a sample which was sufficiently large and homogenous by pathology, only patients with jaw limitation due to disc displacement without reduction were enrolled in the study, because ADDwoR is the most common cause of jaw limitation, compared to other pathologies.Based on the analysis of the medical records, these categories of variables were considered.Sociodemographic factors: gender, age, marital status, and occupation.Occlusion: occlusal and skeletal class, dental formula, occlusal abnormalities, incisal guide, loss of teeth and parafunctions. These parameters were collected on the basis of the clinical examination and upon standard lateral radiograph and dental orthopantomography.Medical History: previous trauma, previous click, and beginning of symptoms.Types of pain: temporomandibular pain , headache, familiar pain, neck pain, and emotional strain, according to verbal numeric scale (VNS) before (T0) and after treatment—i.e., the end of the joint rehabilitation—(T1) and during the follow-up—i.e., patient monitoring after completion of therapy—(T2).Functional aspects: maximum mouth opening and lateral excursions, expressed in mm before (T0) and after treatment (T1) and during the follow-up (T2).Hours per day of splint application and duration of therapy.Number of days necessary to resolution of closed-lock and degree of resolution.Presence of click after the treatment and perception of any occlusal change.In order to prevent systematic errors (bias), the authors used standardized protocols for data collection, including training of study personnel and blinding of operators during the evaluation of post-treatment patients’ status. Patients were selected using rigorous criteria to avoid confounding and evaluated according to validated international diagnostic criteria.n = sample size; in the numerator, 0.05 is the expected prevalence and in the denominator, 0.05 is the level of required precision. The minimum sample size should have been of 73 subjects.Sample size was calculated using the following statistical formula at 95% confidence interval:As for the mandibular functional aspects, maximum mouth opening was dichotomized as: no limitation (≥35 mm) and limitation (<35 mm). Lateral excursive movements and protrusive movements were categorized as: no limitation (≥6 mm) and limitation (<6 mm). As for pain symptomatology, data were collected on the basis of the values conferred upon it in terms of VNS  and divided into the following categories: mild pain (0–29); moderate pain (30–60); severe pain (61–100).T1H: healed, no sign, no symptom.I: improved, absence of initial dysfunctional signs and symptoms with occasional presence of slight symptomatology and no symptoms worsened.S: stationary, no change, neither improvement or worsening, of the previous state.W: worsened, at least one symptom or one sign worsened and none improved. T2H: healed,complete disappearance of the symptomatology present at T1.I: improved, disappearance of at least one sign or symptom present at T1.S: stationary, no change, neither improvement or worsening, of the previous state.W: worsened, worsening of at least one symptom compared to T1. As for the aspects of joint functionality and symptomatology at the end of therapy (T1) and during the follow-up (T2), results of treatment were expressed through the following categories:https://jasp-stats.org/download/. Descriptive statistical analysis  was performed for each variable of the study, collected at the baseline (T0), at the end of therapy (T1), and during the follow-up (T2).All analyses were performed with JASP Version 0.8.0.1, downloadable at p < 0.05. Confidence intervals were set at 95%.Wilcoxon signed-rank test, which is a non-parametric statistical test for repeated measures on a single sample, was performed in order to assess changes in symptomatology and functional aspects before and after treatment and between T1 and T2. Z test was conducted, with a level of statistical significance 1),A heat-cured acrylic resin upper plate (2),A heat-cured acrylic resin lower plate (3),An anterior hinge (4),Two vestibular springs made with orthodontic wire (5),Two or more Adams clasps and/or two ball clasps (6).A vestibular steel arch  vestibular springs, connected in the canine-premolar site, in order to give an elastic resistance to the lower plate during the functional movements of mouth closure. The springs can be hard or soft according to the characteristics of the patient. The functional action is carried out through a “pushing” mechanism at the level of the posterior area of the lower dental arch, which induces a downward and forward movement of the mandibular condyle .Therefore, by means of its components, the illustrated device has, as its main therapeutic goal, the recovery of the functional relationship between articular disc and mandibular condyle and in more severe cases, where the recovery is not achievable, the rehabilitation of jaw function and the reduction of algic symptomatology ,5.The management protocol included progressive phases which modified the duration of daily application of the occlusal splint, up to a minimum use.It lasted not less than 6 weeks and no more than 24 months.In general, at the end of therapy with the RA.DI.CA. splint, the patient is evaluated again, in order to establish the need to replace this kind of splint with other ones, such as DI.TRA  or Michigan splint . In thisThe sample was composed by 121 females (86.5 %) and 19 males (13.5%), with a mean age of 37 years (range 25–60).Forty-one percent of patients (58 patients) had Class I dental occlusion, 38% (53 patients) had II Class dental occlusion, 9% (13 patients) had Class III dental occlusion, 12% (17 patients) reported a combination of the previous ones.Fifty-six percent of the sample (78 patients) reported direct and indirect traumas, such as whiplash, falls, accidents at the medical history .In the examined sample, 35% (49 patients) came to visit 6 months after the beginning of dysfunctional symptomatology, 35% (49 patients) 7 months to 1 year after, 30% (43 patients) over 3 years after.In 60 % (84 patients), disc displacement affected right TMJ, in 40% (57 patients) it affected left TMJ. As for the articular symptomatology, the following characteristics were found: pain in the affected joint, n = 92 (65%); pain in the non-affected joint, n = 15 (11%); bilateral pain, n = 34 (24%). No patient had mild temporomandibular pain, 37% of the sample (52 patients) had moderate pain, 63% of the sample (88 patients) had severe pain.As for comorbidities, headache in the temporal region, modified or provoked by oral function was present in 75% of sample (105 patients), of whom 53% (56 patients) had moderate headache and 47% (49 patients) had severe headache. Neck pain was detected in 65% of the sample (91patients), of whom 46% (42 patients) had moderate pain and 54% (49 patients) had severe pain.As for the functional aspects, the following findings were reported: all the patients reported mouth opening limitation (< 35mm) and limitation of lateral excursion (<6 mm) on the affected side. The deviation of the mandibular movement towards the affected side during mouth opening was detected in 100%.As for the results of treatment in terms of improvement of joint functionality and pain, the categories with the largest number of patients were “Healed” and “Improved”. Eleven patients (8%) did not report any improvement and no patient suffered a worsening of painful symptomatology and limitation .p < 0.05) in all the parameters analyzed  of pain symptomatology  and range of mouth opening (in mm), the comparison between the ones before and after treatment was statistically significant  reported no deviation in mandibular movement during the opening of the mouth and no limitation in lateral and protrusive excursions.As for the perception of occlusal changes, only 7 patients (5%) reported a negative occlusal change after three months of active therapy. However, at T1, no one reported negative occlusal changes.The shortest therapy had a duration of 3 months and the longest one of 23 months with a mean duration of 15 ± 5 months. The functional recovery was obtained in a shorter time compared to the decrease of algic symptomatology .The number of patients who agreed to undergo a post-therapy MRI was 42 (38.8%).-10 patients (23.8%) gained a complete condyle-disc ratio.-19 patients (45.2%) gained a partial condyle-disc ratio.-13 patients (30.9%) did not gain the condyle-disc ratio.The 42 patients who underwent the post-treatment MRI showed the following results:The average follow-up time was 5.6 years (range 2–10 years).p > 0.05). The treatment outcome, achieved at the end of the active therapy (T1), remained stable (no significant improvements or worsening).There was not a statistically significant difference between T1 and T2, as for records analyzed . In these circumstances, the goal of the treatment should be to recreate function by re-establishing the disc condyle relationship or, more often, by reducing restriction in movement, also in order to eliminate pain .Two of the best-known distraction splints are the Functional Appliance by Rocabado, designed for joint distraction ,35, and As for the anterior repositioning splints, the aim is to restore the physiological disc-condyle relationship. However, the stability of disc recapturing depends on the range of disc displacement and the stage of internal derangement in TMJ. In cases of persistent closed lock, protrusive occlusal splint does not lead to the recapturing of the disc, but it has only a pain-relieving effect ,38.The RA.DI.CA. device acts as an “intra-oral physiotherapy”. By the induction of a downward and forward movement of the mandibular condyle, an “increase” of the intra-articular virtual spaces is allowed, resulting in a reduction of the pressure load on the retrodiscal (bilaminar) structures and the increase of blood flow and tissue tropism ,5. In faIn patients with disc displacement without reduction and chronic dysfunction, the use of this device creates the conditions to recover spacial and, above all, functional relationship between condyle and disc. As confirmed by MRI also without recapturing the displaced disc, normal function could be obtained through the recovery of the functional relationship of the disc-condyle complex. The authors, aware that the recovery of the dislocated disc could not always be possible, also considering the initial conditions of the patient, have always focused on the recovery of joint mobility and functionality without pain. Despite this, post-treatment MRI also showed that in most patients who had undergone this evaluation, a complete or partial recovery of the dislocated disc was achieved ,42,43.In many patients with permanent disc displacement without reduction, restitutio ad integrum is not achievable, but nevertheless, the device has proved to be capable of performing functional and symptomatic recovery. Furthermore, this device allows an active and passive gymnastic with a gradual action, in order to recover not only the articular functionality but also the muscular one, made possible by the activation of the sliding of the myofibrils of actina and myosin in sarcomers, switched off by the contracture status ,5. The rOverall, the recovery of functionality is achieved through the biomechanical repositioning of the stomatognathic components with the resulting restoration of normal mandibular range of motion, and through the reduction of pain, due to the biological and histological healing of the structural components.As for surgical options, arthrocentesis and arthroplasty are among the suggested therapies in the scientific literature, with a high standard of effectiveness. Nevertheless, no significant differences between conservative and surgical treatment strategies were found  so, withPotential limitations of the study: bias after trial in data analysis were avoided by blinding the operators as for the type of splint used by the patients, during post-treatment and follow-up pain and functionality assessment.The benefits of RA.DI.CA splint therapy are: (a) the effectiveness in terms of recovery of function and symptoms, also in the medium-long term follow up; (b) a low rate of adverse events; (c) a good tolerability and comfort for the patient. The recovery of the functional-orthopedic aspect is what allows also the recovery of symptoms and the stability of the patient’s conditions over time.


The ESAS and PSQI questionnaires confirmed these positive results . Conclusions: This prospective investigation by an Italian expert group, has confirmed that careful management of BTcP induces a paramount improvement on the HRQoL. Because in cancer patients there is a high prevalence of BTcP and this severe acute pain has deleterious consequences, this information can have an important clinical significance.Objectives: To explore the effect of breakthrough cancer pain (BTcP) treatment on quality of sleep and other aspects of the health-related quality of life (HRQoL) in patients with cancer pain. Methods: In an observational, multicenter, cohort study, cancer patients from palliative care units, oncology departments, and pain clinics and affected by BTcP were included. Enrolled patients were assessed at the four visits: T0 (baseline), T7, T14, and T28. Stable chronic background pain  during the whole study period was mandatory. BTcP was treated through transmucosal fentanyl. Three questionnaires were used to measure the HRQoL: EORTC QLQ-C15-PAL, Pittsburgh Sleep Quality Index (PSQI), and the Edmonton Symptom Assessment System (ESAS). RESULTS: In 154 patients, the HRQoL showed a significant improvement for all physical and emotional characteristics in the EORTC QLQ-C15-PAL, except for nausea and vomiting (linear  Pain is one of the most frequent symptoms in cancer patients as it occurs in 20–30% of cases during the initial stages and in up to 75% of patients in advanced disease. The prevalence of cancer pain at any stage of the disease is over 50%. Concerning pain intensity, moderate to severe pain can affect up to 40% of all patients. Furthermore, this symptom strongly affects the patient’s health-related quality of life (HRQoL) and daily activities throughout the cancer disease . As a con = 4016), dissected the features of this painful phenomenon and demonstrated that in 86% of patients the occurrence of BTcP induced a marked interference with their daily activities [Assessment and management of cancer pain become particularly critical when the patient faces temporary exacerbations of pain despite adequate control with opioids. This phenomenon, termed as breakthrough cancer pain (BTcP), is a very frequent condition as approximately 70% of patients suffering from chronic pain of oncological nature report episodes of BTcP . TypicalThe present observational study—indicated as breakthrough cancer pain evaluation study (BEST-Study)—aimed at assessing the impact of BTcP management on HRQoL, sleep and daily activities in patients from different clinical settings and with adequately controlled background pain through strong opioids. This clinical study was conducting by following the Declaration of Helsinki’s ethical principles. Individuals with a diagnosis of any type of solid cancer and affected by chronic pain effectively controlled—numeric rating scale (NRS) ≤4—by around-the-clock (ATC) opioid maintenance therapy through ≥ 60 mg of oral morphine equivalent daily doses (OMEDD) on the day of enrollment, were included in this national multicenter prospective cohort study, from March 2015 to August 2017. Approval from the Institutional Medical Ethical Committee (protocol 32/14 OSS) of the Istituto Nazionale Tumori-Fondazione Pascale, Naples was obtained, and patients signed informed consent before enrolling in the study. The Strengthening Reporting of Observational Studies in Epidemiology (STROBE) guidelines were followed .Patients’ eligibilities were evaluated by an oncologist or pain specialist or palliative care specialist and in-hospital patients, outpatients, and those in home-care settings, were included. Each participating patient was observed for a maximum of 28 days. During the study, patients underwent to four consultations starting from baseline examination (T0) for enrolment and data collection. In particular, in this initial step demographic characteristics, settings, tumor type, background pain characterization (the type of pain and pain intensity), and performance status through the Eastern Cooperative Oncology Group (ECOG) 0–5 scale, were collected. Each participating patient was then evaluated after 7 days (T7), 14 days (T14), and 28 days from baseline (T28), .Data were collected from the patient’s medical records and summarized in e-CRF (electronic Case Report Form). The definition of BTcP was: a transitory pain exacerbation of moderate to severe intensity that occurs spontaneously or predictably , well diThe impact on BTcP treatment through transmucosal fentanyl on HRQoL, sleep quality and daily activities in patients with background pain adequately controlled by ATC opioids as maintenance therapy.The primary objective of the study was to define:The HR quality of life (QoL) was measured by the European Organization of Research and Treatment Quality of Life Questionnaire-Cancer 15 (EORTC QLQ-C15-PAL)  and the Baseline background pain characteristics;BTcP features including type , and the number of episodes. Differences according to visits  on number of BTcP episodes were evaluated;BTcP management in terms of median time to pain relief.The secondary objective was to evaluate the:Any serious adverse event related to background pain therapy and for BTcP management was reported.p-value indicates the statistical trend for the four measures, while the square p-value shows the statistical change from the last visit to the baseline (T28 vs. T0). Categorical variables were presented by frequencies and percentages. The general linear model (GLM) for repeated measures analysis was used. This statistical approach is mathematically identical to multiple regression analysis and it is particularly useful for the correlation of multiple qualitative and quantitative variables. According to this strategy, the mean-scores for HRQoL parameters in T0, T7, T14, and T28 were evaluated: the linear Results were only based on non-missing data , unless specified otherwise; in particular, the number of patients that completed each visit was taken into account: T0 = 154 pts; T7 = 136 pts; T14 = 124 pts and T28 = 100 pts. The Bonferroni’s method can be used to compare different groups at the baseline. It provides a pairwise comparison of the means, investigates on the relationship between variables, or examines one or more endpoints in clinical trials. To obtain effect size, partial eta-squared (η2p) was calculated. Estimates of effect size give a partial eta squared (η2p) value for each effect and each parameter considered. The partial eta-squared statistic describes the proportion of the total variability attributable to a factor . ® SPSS® Statistics, version 25 . All statistical tests were two-sided, and p values of less than 0.05 were considered significant.Statistical analyses were performed using IBMWe used a mathematical approach that could allow us to obtain the greatest amount of information despite the reduced sample size. In particular, since each score represented a continuous quantity, to make the variable discrete, we applied a statistical approach proposed by Osaba et al.  which alAn adjusted logistic regression analysis was performed to assess the association between the best response of HRQoL questionnaires  and some covariates. Odds ratios (ORs) and 95% confidence intervals (95% CI) were estimated. p-value = 0.1), and dyspnea . Moreover, there was a significant improvement in the global health status at the end of the study (p = 0.002)  .p = 0.002, and p < 0.0001 respectively) , and in all domains of the HRQoL including psychological outcomes (ESAS), after 28 days of observation (ctively) . ConcernConsistent results were found when QoL best response was calculated A. The imp= 0.01). Finally, data from the PSQI questionnaire indicated that the older age (>70) is significantly associated with worse sleep quality (OR = 8.46 95% CI 2.46–29.11). Subsequently, the improved were compared with worse response to assess variables that contributed to explain this difference for the three questionnaires adopted . Some covariates were also studied. p = 0.2) (p < 0.001). The reduction was also significant for the clusters 8-14 and 15-21 events. In particular, 15-21 episodes at baseline were reported for about 15% of patient to decrease to 7% at T28 (p < 0.001) (p < 0.0001 ). Furthermore, the number of patients who responded to treatment in 20–30 minutes also dropped significantly from about 29.2% to 15% (p < 0.0001). On the contrary, the response increased in ultra-short (<5 min) and short  times. In addition, in these ranges, the variations were significant (p < 0.0001) (p = 0.2) A. At T0,< 0.001) B. Concer 0.0001) C.The major limitation of the study seems to be the poor consistency of the sample size. For instance, the small size simple and the lack of a complete multivariate analysis, associated with the rapid-onset opioids (ROO) pharmacokinetics features  made it difficult to establish how the therapeutic variable was related—in a cause-effect relationship—with the type of response. However, thanks to the statistical approach adopted which combined the multivariate analysis with the careful interpretation of the changes in the HRQoL scores, we were able to measure the change in the four observation times for each patient enrolled, estimating, in turn, the trend. In other words, an ’outcome’ variable was established making the analysis independent from the sample size. In addition, adjusted multivariate analysis was also applied to the three questionnaires. Another limitation is the lack of data on the type of treatment of background pain . As a characterization of therapy was not the aim of the study, we considered all patients with OMEDD of ≥ 60 mg and well-controlled pain to be enrolled. Finally, the lack of the control group due to the study design did not allow for a precise analysis of different dose response patterns. We hope that the data from this observational investigation can be used to design controlled studies.This study explored the effect of BTcP treatment on several aspects of the HRQoL in patients with cancer pain. The HRQoL was investigated through a battery of tools capable of evaluating the largest number of domains. General data were investigated by the EORTC QLQ-C15-PAL, the PSQI questionnaire served to evaluate sleep quality, and the ESAS one helped to explore general domains and psychological aspects of cancer pain including anxiety and depression.In regards to BTcP management, we have chosen to treat BTcP through rapid-onset opioids (ROOs), drugs specifically indicated for this purpose. ROOs, indeed, have a pharmacodynamics that mirror the sudden start and brief duration of the pain event . HoweverAlthough the HRQoL investigated through the EORTC QLQ-C15-PAL instrument showed a significant amelioration in the global health status at the end of the study and a significant improvement for all physical and emotional descriptors of the questionnaire, except for nausea and vomiting, and dyspnea. Concerning dyspnea, it is a symptom of advanced disease, whereas nausea and vomiting are mainly related to opioid therapy but can be also related to the cancer disease itself, and anticancer therapies. Having observed an improvement for constipation and not for nausea and vomiting, perhaps may indicate that during opioid therapy more attention is paid to constipation than to other adverse effects that only apparently have a lower impact on HRQoL. p < 0.0001) at the end of the study. Nevertheless, the adjusted logistic regression analysis demonstrated that the elderly patients (>70 years) had a risk 8.5 fold higher than those observed in patients less than 60 years of age. These findings are not surprising as a recent cross-sectional multicenter study has highlighted that around 80% of cancer patients experienced poor sleep quality, and this issue mainly concerns older patients [Concerning quality of sleep, compared to the baseline we observed a significant improvement (patients . The clip < 0.0001). However, the regression analysis failed to find a correlation between these positive results and age-related factors, gender, and type of underlying pain. Whatever the underlying correlation, we can assume that the treatment of cancer pain induces an important improvement of multiple patient’s psychological aspects [The ESAS questionnaire also showed a significant improvement between the end and the beginning of the study ( aspects . p < 0.01). Several pieces of evidence suggested that different pain thresholds may exist between men and women. Physiologic factors such as ovarian hormone and increased serotonergic activity, and psychological dynamics  have been called into question to explain this phenomenon which, in turn, must be better explained [Further significant data came from the regression analysis. Female gender, for example, was associated with an improvement in global health status (xplained . Howeverxplained . Again, xplained . ProbablOf note, the main finding that is found in all questionnaires is the paramount role of pain therapists as there was significant improvement in the setting of patients treated by these clinicians. Pain therapists are perhaps more likely to perform pain management through tailored therapies and by coordinating multidisciplinary strategies . The impWith regards to background pain, the best results have been achieved in patients with mixed pain, although only in the EORTC questionnaire. The data can be explained with probable greater attention towards forms of pain that represent a challenge for those who must treat chronic pain.The analysis of BTcP and its trend during the investigation period showed interesting data. Our study suggested that adequate BTcP management can probably reverberate on the characteristics of BTcP by reducing the number of episodes. Of note, there was also an improved response to therapy. The phenomenon, however, requires further investigation as multiple factors such as type and course of cancer disease, clinical setting, and background pain therapy can influence the incidence and characteristics of BTcP. Furthermore, this unpredictable severe acute pain represents a heterogeneous condition and includes spontaneous forms and those induced by voluntary, or involuntary movements. Therefore, especially incident pain benefits from better therapy. In a longitudinal study, carried out on in-hospital patients, the incidence changed over time, falling from 87% to 32% after six months from the first detection. The greatest decrease in BTcP occurrence concerned the incident subtype . MoreoveBTcP treatment remains a great challenge in medicine. It requires, indeed, individualized treatment through the involvement of a multidisciplinary team. Despite the limitations, results from this multicenter, observational cohort study conducted by an Italian expert group, has confirmed that accurate management of BTcP from the baseline may improve several aspects of the HRQoL. Because of in cancer patients there is a high prevalence of BTcP and this severe acute pain has deleterious clinical consequences, this information can have an important clinical significance. In this population, more attention should be given to the treatment of sleep disturbances and the management of nausea and vomiting. Further studies are needed to verify the fascinating hypothesis that adequate BTcP treatment can probably reduce the number of episodes, also improving its response to therapy, and in turn, the HRQoL of these fragile individuals.


Background and study aims: Acute health service requires focused palliative care (PC). This study was performed to provide guidance for the establishment of a palliative care consultation service (PCCS). Patients and methods: This study was conceived as a retrospective single-center study for observing, analyzing and evaluating the initial setup of a PCCS from 1 May 2015 to 31 May 2018. Patients from Muenster University Hospital with advanced life-limiting diseases, identified to require PC, were included. Results: PCCS was requested from various departments, for between 20 and 80 patients per month, corresponding to a total of 2359 for the study period. Requests were highest in internal medicine (27.3%), gynecology (18.1%) and radiotherapy (17.6%). Time to referral was significantly shorter in departments with special PCCS ward rounds . The most frequently reported symptoms were fatigue, pain and loss of appetite. Pain was frequently localized in the stomach (20.4%), back (17.1%), or in the head and neck area (14.9%). After the first PCCS consultation, 254 patients (90%) reported sufficient pain relief after 48 h. An introduction/modification of painkiller medication, which was recommended for 142 inpatients, was implemented in 57.0% of cases by the respective departments. Overall, the direct realization of PCCS recommendations reached only 50% on average. Conclusions: Besides an analysis of the ability to address the symptoms of the referred patients by the PCCS, this study highlights the importance of the interaction between PCCS and other departments. It further elucidates the role and possibilities of this service both in regular ward rounds and individual staff contacts. Palliative care (PC) supports patients with life-limiting disease and their relatives by improving quality of life. “Pain and other problems, physical, psychosocial, and spiritual”, are parts of the assessment and treatment . The mosStrikingly, Becker et al. reported that 9.1% of all patients older than 65 years would require PC . This inSeveral different estimates have been made regarding the demand for PC beds in Europe . ConsideA palliative care consultation service (PCCS) supports physicians and nurses in both in- and outpatient departments by providing medical recommendations for the respective patients. It must be noted, though, that it is incumbent upon the physicians and nurses in charge to make the final decision about a patient’s treatment .The advantage of a PCCS is the ability to consult a large number of patients within a short period in the hospital. Particularly, an outpatient setting allows for easy and early access to patients .Use of a PCCS also improves pain and symptom control, while reducing anxiety and hospital admissions . FurtherThus, a PCCS is needed for every hospital in addition to a PC ward, and every hospital should have access to a PCCS if required . FurtherCancer patients facing progressed stages of their disease should be consulted by a member of the PCCS . PCCS istrust in the treating physician, avoidance of unwanted life support, effective communication, continuity of care and life completion” [Palliative care also has a wider dimension: PC treatment involves patients, nurses, doctors and relatives who all have different perceptions concerning their “own truth” of the situation . In thispletion” . This study aimed to provide guidance regarding how to structure, establish, and set up a PCCS in an acute hospital setting. We investigated the type and severity of symptoms presented to the PCCS, and analyzed the overall characteristics of patients referred to our PCCS, as well as the realization of our recommendations by the referring department. Furthermore, we hypothesized the existence of distinct patterns of symptoms in different patient cohorts, so that differences in the presence of symptoms of referred patients from different departments could be comparatively analyzed. In addition, we hypothesized that departments with regular PCCS ward rounds would refer patients faster to the PCCS as compared to departments without established PCCS ward rounds.More specifically, each medical department could involve our PCCS if there was a need for PC treatment. Requests were answered within 24 h. Our PCCS team focused its attention on the anamnesis of the existence and severity of symptoms and conditions of the referred patients, and subsequently made recommendations aiming at the control or relief of these symptoms; however, the final decision regarding further medical treatment was made by the referring department and, thus, the PCCS took on an advisory role.This study was designed as a retrospective, single-center study at the Muenster University Hospital, where a PCCS was established in May 2015. For the following study, we analyzed the first years of building up a PCCS from 1 May 2015 to 31 May 2018. In the subgroup analysis, we include data from the first 13 months after establishing the PCCS.Patients with advanced life-limiting and progressive disease were referred to the PCCS by ward physicians when, together with their team, a need for PC was identified. A specialized palliative care (SPC) physician or nurse performed the initial PC assessment, including a detailed symptom burden assessment  .Focusing on the individual needs, the patients were processed according to the algorithm shown in ® .All data were electronically available using the hospital information system Orbis-OpenMed1 activity restriction, but the ability to work; 2 the inability to work, but the ability for self-supply; 3 a restricted self-supply with 50% of the time confined to bed or chair; 4 complete dependence on care; 5 means death [The Eastern Cooperative Oncology Group (ECOG) score was used to assess patient performance regarding activities of daily living . ECOG cons death . Symptom burden was assessed in 6 categories: stable (asymptomatic), slightly reduced, reduced, greatly reduced, unbearable, and no data. These were summarized and color-coded in a heatmap in the following manner: green (stable), yellow (slightly reduced and reduced), red (greatly reduced and unbearable) and white (no data). The theme introduced in PC by Dame Cicely Saunders, “Low technology, high personality”, describes the importance of the team members in PC. Our core team consists of two physicians, two nurses, two physiotherapists, a half-time weekly psycho-oncologist, a half-time weekly social worker, and a music therapist. Dieticians, pain therapists and chaplains support the core team. Continuous variables are summarized by the mean and standard deviation. Categorical variables are presented as absolute and relative frequencies. p-value of < 0.05 was considered to indicate statistical significance.Time to referral was defined as the time from hospital admission to first contact with the PCCS. To test if the time to referral differed between departments with vs. without a PCCS ward round, the Mann–Whitney U test was used. A two-sided Symptom burden presented at first PCCS consultation was visualized on a scale of stable , slightly reduced , reduced , greatly reduced  and unbearable , and presented as a symptom heatmap sorted by patient and symptoms.2 test. A comparison of the realization of recommendations between males and females for the respective symptom was analyzed using the χhttp://www.R-project.org/).The statistical analysis of the data was performed using the SPSS software  and SAS software . The symptom heatmap was generated using the ggplot2 package [We analyzed a total of 2359 patients in the period from May 1, 2015 to May 31, 2018. Of all patients, 1946 (82.5%) were inpatients and 413 (17.5%) outpatients. All were seen by the PCCS, and within 12 months, the number of patients increased from 20 to 60–80 per month at the end of the study period. The number of patients per year is shown in p < 0.001).We defined the time from hospital admission to first contact with the PCCS as the time to referral. The median time to referral in the observation period was 10 ± 19 days, with a minimum of 0 and a maximum of 332 days. In departments with special PCCS ward rounds, the median time to referral was significantly shorter compared to the departments without ward rounds  requested PCCS support for their treatment. The PCCS established initial regular weekly ward rounds at the department of radiotherapy and gynecology; later, rounds were also included for the department of hematology/oncology. All departments with inpatient care , gynecology (18.1%) and radiotherapy (17.6%). The data for the other departments are presented in n = 1635). The following subgroup analysis displays the data for 578 patients, covering the period from 1 May 2015 to 31 May 2016; however, the parameter “pain relief within 48 h after PCCS consultation” was introduced later, and includes the following period: 1 July 2016 to 31 May 2018  and healthcare proxy, can be found in Further, 88% of our patients had cancer and 12% had other diseases (429 patients with cancer vs. 61 with other diseases). The fields with the most common diagnoses in our subgroup analysis were gastrointestinal (12.9%), gynecological (8.4%), head and neck (8.3%) and genitourinary cancer (7.4%). n = 350), metastatic disease was observed in 80.3%, and peritoneal carcinosis in 11.7%. Interestingly, the majority of the evaluated patients were found to be ECOG 3, which means a restricted self-supply with 50% of the time confined to bed or chair , nausea (30.4%), edemata (28.7%), vomiting (20.8%) and wounds (19.2%) were presented. Most of our patients could not be assessed regarding neurologic symptoms (56.9%) or bleeding risk (56.2%). Moreover, we used the visual analog scale (VAS), from 0 (no pain) to 10 (strongest imaginable pain), to assess patient pain levels. As a result, 278 (56.7%) of our patients suffered pain, with 28.0% of them in low (1–3), 42.0% in middle (4–7), and 23.9% in high (8–10) pain . n = 278), the pain was mostly located in the stomach (20.4%), back (17.1%), or in the head and neck area (14.9%) (Of our patients who suffered pain ( (14.9%) A. In our analysis, 414 (84.5%) of our patients took one or more painkillers, and of these patients, 102 (24.6%) were in step I (non-opioid) of the WHO pain ladder, 26 (6.3%) were in step II (weak opioid ± non-opioid), and 286 (69.1%) were in step III (strong opioid ± non-opioid). For 142 inpatients , the PCCS recommended a drug conversion for painkillers, and for 328 patients (66.9%), no change was recommended. Further, for 81 patients (57.0%), the PCCS recommendations were performed directly (within 48 h of recommendation). When analyzed according to sex, females (59.1%) experienced slightly more frequent, though non-significant, receipt of recommended pain care compared to males (55.3%).There were four possibilities for optimizing the pain medication: (1) the pain medication could be increased by taking a step in the WHO pain ladder ; (2) the opioid could be changed ; (3) a WHO pain ladder step could be completed, such as through adding a non-steroidal anti-inflammatory drug (NSAID) to the regimen ; or (4) the dose could be escalated .If a new opioid was added or there was a conversion in the opioid medication, we documented the recommended opioid via the PCCS. We obtained data from 74 patients, and the main opioids were hydromorphone , morphine , tilidine , oxycodone  and fentanyl . n = 1635), and whether they met this criterion. There were 372 patients who reported pain, out of which 282 suffered moderate to severe pain. Of the latter group, 254 (90%) patients described reduced pain levels, and 28 (10%) described the same or worse pain levels 48 h after consultation. Pain relief 48 h after consultation is a hallmark of PC quality . Hence, We scheduled our inpatients’ premedication with respect to other symptoms. We detected that many of our patients took drugs for nausea (56.5%), excretion problems (45.5%), depression (36.5%), edemata (30.8%) and insomnia (28.8%). In addition, some patients took medication for neurological symptoms (16.3%) or dyspnea (11.6%). After our PC assessment, we recommended drug conversion because of excretion problems (19.8%), nausea (15.3%), insomnia (15.9%), dyspnea (6.5%) or depression (6.5%). In some cases, changes in drugs for the treatment of neurological issues (1.4%) were suggested.p < 0.01) , nausea (45.3%), insomnia (32.1%), dyspnea (46.9%), depression (59.4%) and neurological symptoms (57.1%). Moreover, we found that for male patients (41.2%), the recommended insomnia treatment was significantly more often realized when compared to female patients  .We offered further care services besides our medical care. Many of our patients needed physiotherapy (81.2%), consultation for social issues (70%) and counseling about AHCD, healthcare proxies and/or further (outpatient) PC (55.9%). Furthermore, many patients received psychotherapy (43.3%) and spiritual care (36.9%). Other services that were offered included nutritional guidance (26.1%), dietary counseling (23.1%), music therapy (12.9%) and wound/stoma care (2.7%). In the period from May 1, 2015 to May 31, 2018, the number of patients referred to the PCCS increased continuously. This trend has also been previously reported by other groups setting up a PCCS ,22,23. Furthermore, at the University Hospital in Munich, it was shown that only 30.3% of terminally ill cancer patients had been in contact with the PCCS before they died; in 54% of cases, the consultation was requested in the last week of the patient’s life . This leAnother study reported the views of two different groups: the first group consisted of physicians with previous PCCS contact, and the second of those without any experience with PCCS . Both grMany oncologists tended to request SPC in cases of advanced disease, when the control of symptoms could no longer be managed . This fiMoreover, to set up a PCCS, it is important to know which patients to expect, and to be aware of the required core competencies of the designated PCCS team. In a study by Dhillon et al. at the M.D. Anderson Cancer Center of the University of Texas, the most common diagnoses were of thoracic/head and neck, gastrointestinal, genitourinary and gynecologic cancer . Those aAdditionally, many of our patients suffered from fatigue (82.7%), depression (68.6%), loss of appetite (64.7%), constipation (62.7%), pain (56.7%) and insomnia (54.9%). It is an important core competence to know how to treat these common symptoms. Within our service, the head physician is a gastroenterologist and could easily address gastrointestinal symptoms. Strong cooperation with our department of psycho-oncology, physical therapy and anesthesiology was established from the beginning. In the data provided by Delgado-Guay et al., reduced wellbeing (93%), fatigue (92%), pain (91%), loss of appetite (84%), insomnia (76%) and anxiety (70%) were common symptoms . To concIn our study, admissions to internal medicine, gynecology and radiotherapy departments accounted for the highest numbers of referred patients. The regular ward rounds were performed once a week in those departments. This underlines the importance of the regular ward rounds for establishing an awareness of PC. Internal marketing was recognized as an important factor for raising the awareness of departments with regard to getting in contact with PC services . The thrWe were able to show that 90% of our patients reported pain reduction 48 h after the first PCCS consultation. These patient-dependent evaluations are important for analysis of the quality of care in PC situations . CieminsAt the beginning of the PCCS, however, we could see that our recommendations for drug conversion were not always directly realized. There might be different reasons for this gap between recommendation and realization, e.g., the electronic recommendation was not seen by the physician in charge of the patient, or he/she has a different view concerning the symptoms or the need for PC. We recommend adopting an active approach, in which the implementation of the recommendation is evaluated the following day. In conclusion, palliative care aims at a better quality of life and control of symptoms for patients with life-limiting diseases. To implement a PCCS, you need to establish a multidisciplinary team ,39,40. w


The study was registered at https://www.ClinicalTrials.gov (ID: NCT03723317). CCI exhibited the best diagnostic performance for 90 days in the training  and Validation Sets  when compared to the BAR, D-MELD, MELD, and EAD scores. The cut-off value of 47.3 (third quartile) showed a diagnostic odds ratio of 48.3 and 7.0 in the two sets, respectively. As for 1-year graft loss, CCI showed good performances in the training  and validation sets . The threshold of 47.3 showed a diagnostic odds ratio of 21.0 and 5.4 in the two sets, respectively. All the other tested scores always showed AUCs < 0.70 in both the sets. CCI showed a good stratification ability in terms of graft loss rates in both the sets (log-rank p < 0.001). In the patients exceeding the CCI ninth decile, 1-year graft survival rates were only 0.7% and 23.1% in training and validation sets, respectively. CCI shows a very good diagnostic power for 90-day and 1-year graft loss in different sets of patients, indicating better accuracy with respect to other pre- and post-LT scores.In the last years, several scoring systems based on pre- and post-transplant parameters have been developed to predict early post-LT graft function. However, some of them showed poor diagnostic abilities. This study aims to evaluate the role of the comprehensive complication index (CCI) as a useful scoring system for accurately predicting 90-day and 1-year graft loss after liver transplantation. A training set (Clinical Trial Notification: NCT03723317. In the last years, several scoring systems have been developed with the intent to predict early clinical course after liver transplantation (LT). The model for end-stage liver disease (MELD) is recognized as the most accurate liver allograft allocation model, and it prioritizes patients according to the severity of their disease , 2. HoweRecently, the comprehensive complication index (CCI) has been developed to assess the actual complication rate after surgery . Some reThis study aims to compare the abilities of CCI vs. other commonly adopted pre- and post-transplant scoring systems in diagnosing 90-day and 1-year post-transplant liver graft loss. The diagnostic capabilities were investigated in a training set and validated in a validation set.Training set was generated retrospectively analyzing 1262 patients undergoing a first LT during the period January 1, 2005–December 31, 2016. Four European collaborative LT Centres were involved in creating the Training Set, namely the Polytechnic University of Marche, Ancona , Université Catholique de Louvain, Brussels (Belgium), Sapienza University, Rome , and University of Padua . Exclusion criteria for patient selection were: (a) living donation, (b) combined transplant, (c) domino transplant, and (d), pediatric (< 18 years) transplant.https://www.ClinicalTrials.gov (ID: NCT03723317).Validation Set was created retrospectively analyzing the data of 520 patients transplanted during the same timeframe in the Karolinska Institute of Stockholm (Sweden). The same exclusion criteria were adopted. The study was registered at https://www.assessurgery.com/).Organ procurement was defined as “local” when done in the same region in which the LT was performed. All complications were graded according to the Clavien–Dindo Classification . A web-cx)]/2.The CCI was calculated using the following original algorithm: CCI = [√(wC1 + wC2 … + wCThe CCI is based on the complication grading by Clavien–Dindo Classification and implements every occurred weighted complication (wC) after an intervention. Clavien–Dindo grade I corresponds to 8.7, grade II to 20.9, grade IIIa to 26.2, grade IIIb to 33.7, grade IVa to 42.4, grade IVb to 46.2, and grade V to 100. All the complications collected were summed, even if the same patient received several times multiple administrations of the same medical  or interventional  treatment. The overall morbidity is reflected on a scale from 0 (no complication) to 100 (death).Retransplantation during the first hospitalization was calculated as IVa (liver failure) plus IIIb (reoperation) complication. Multiorgan failure (MOF) was defined as the presence of at least two organ failures and ranked as grade IVb complication. Primary non-function (PNF) was identified as a liver failure observed for non-technical reasons within seven days after surgery and ranked as IVa complication.EAD was defined according to the Olthoff criteria , and claU test was used for comparisons between groups in case of continuous variables, and Fisher’s exact test was adopted in case of categorical variables.Continuous variables were reported as medians and interquartile ranges (IQR). Categorical variables were reported as numbers and percentages. Missing data always involved < 10% per variable and were handled using the maximum likelihood estimation method. Mann–Whitney p value < 0.20 were introduced into a multivariable model. A multivariable Cox regression model was constructed adopting the backward conditional method [A univariate Cox regression analysis was performed in the training set for the identification of the risk factors for graft loss. All the variables with a l method . Beta-cop value < 0.05 was considered statistically significant in all analyses. Statistical reports and plots were performed using the SPSS statistical package version 24.0 .C-statistics was used for comparing the diagnostic ability of different scores in terms of 90-day and 1-year graft loss in both the training and validation set. Specifically, CCI was compared with MELD, D-MELD, BAR, and EAD. Areas under the curve (AUC), standard errors, and 95% CI were reported. The following CCI cut-off values were investigated in the training set: first quartile, median, third quartile, and ninth decile. Sensitivity, specificity, and diagnostic odds ratio (DOR) were reported for each cut-off value. The higher the DOR value, the greater its discriminative power. The same CCI threshold values obtained in the training set were validated in the Validation Set. Graft survival rates were estimated with the Kaplan–Meier method; the log-rank test was used for evaluating survival differences. A The training and validation sets were composed of 1262 and 520 LT recipients. All grafts were procured from donors after brain death.In the training set, the median follow-up was 3.7 years (IQR 1.1–7.6), with 1108 (87.8%) and 991 (78.5%) cases exceeding 90 days and 1 year, respectively.During the entire study period, 371 (29.4%) patients died: of whom 154 (12.8%) and 66 (5.2%) within 90 days and during the time interval of 91–365 days, respectively.Four hundred and nine (32.4%) grafts were lost: 186 (14.7%) and 70 (5.5%) within 90 days and 91–365 days, respectively. Seventy-eight (6.2%) retransplantations were performed: 54 (4.5%) and 12 (1.0%) within 90 days and 91–365 days, respectively.In the validation set, the median follow-up was 4.8 years (IQR 3.0–7.2), with 504 (97.9%) and 485 (93.3%) cases exceeding 90 days and 1 year, respectively.During the entire study period, 104 (20.0%) patients died: 15 (2.9%) within 90 days and 18 (3.5%) during the time interval of 91–365 days from LT.One hundred and fourteen (21.9%) grafts were lost: 17 (3.3%) within 90 days and 20 (3.8%) during 91–365 days. Twelve (2.3%) retransplantations were performed: one (0.2%) within 90 days and three (0.6%) during 91–365 days.The characteristics of the sets are displayed in Table n = 785; 62.2%). In approximately half of the cases, the procurement was performed in a local hospital. Median cold and warm ischemia times were 7.2 h and 45 min. Median BAR score was 5; 77 (6.1%) and six (0.5%) recipients had a score exceeding 15 and 20, respectively.In the training set, median lab-MELD was 15 points, with 161 (12.8%) patients showing a MELD ≥ 30. Median waiting time and age at LT were 4 months and 56 years, respectively. HCC was the main indication for LT in 527 (41.8%) patients. The main cause of the liver disease was HCV-related cirrhosis (35.7%). Median donor age was 57 years, with 328 (26.0%) and 77 (6.1%) donors exceeding 70 and 80 years. The leading brain-death cause was cerebrovascular accident  recipients presenting a MELD ≥ 30. Median waiting time and age at LT were 2 months and 54 years, respectively. HCC was the leading indication for LT in 131 (25.2%) patients. HCV-related cirrhosis was reported in 148 (28.5%) cases. Pathologies uncommonly reported in the Training Set were, on the opposite, commonly reported in the validation set: biliary pathologies like primary biliary cholangitis and primary sclerosing cholangitis were reported in 124/520 (23.8%) cases, followed by 37 (7.1%) cases of familiar amyloid polyneuropathy, and 25 (4.8%) cases of autoimmune hepatitis.n = 346; 66.5%). In ~ 75% of cases, the procurement was performed in a local hospital. Median cold and warm ischemia times were 8.3 h and 40 min. Median BAR score was 11; 30 (5.8%) recipients had a score exceeding 15, while no case exceed 20.Median donor age was 57 years, with 91 (17.5%) and eight (1.5%) donors exceeding 70 and 80 years. The leading cause of brain death was a cerebrovascular accident  or abdominal drainage . Two hundred and seventy-one (21.5%) patients required a “IIIb procedure”. The most common procedure was reoperation for bleeding , followed by explorative laparotomy . Retransplantation during the same hospital stay of the first transplant was necessary for 45 (3.6%) recipients. MOF was observed in 45 (3.6%) recipients. EAD and PNF were reported in 508 (40.3%) and 37 (2.9%) cases. Mild renal dysfunction and RRT were detected in 90 (7.1%) and 91 (7.2%) patients. Vascular and biliary complications were reported in 80 (6.3%) and 110 (8.7%) subjects. Median CCI value was 29.3 (IQR: 12.2–47.6): CCI values < 20, 20–39, 40–49, 50–99, and 100 were observed in 366 (29.0%), 483 (38.3%), 121 (9.6%), 144 (11.4%), and 148 (11.7%) patients.The postoperative courses of the two sets are displayed in Table n = 55; 10.6%) or abdominal drainage . Two hundred and one (19.4%) patients required a “IIIb procedure”. The most common was reoperation for bleeding , followed by explorative laparotomy . Early retransplantation was necessary in only three (0.6%) cases. MOF was diagnosed in 12 (2.3%) recipients. EAD and PNF were observed in 87 (16.7%) and three (0.6%) cases. Mild renal dysfunction and RRT were reported in 19 (3.7%) and 39 (7.5%) patients. Vascular and biliary complications were reported in two (0.4%) and 11 (2.1%) subjects. Median CCI value was 24.2 (IQR: 8.7–44.4): CCI values < 20, 20–39, 40–49, 50–99, and 100 were observed in 148 (28.5%), 220 (42.3%), 57 (11.0%), 86 (16.5%), and nine (1.7) patients.In the validation set, median intensive care stay and overall length of hospital stay were one and 14 days. According to the highest Clavien–Dindo grade observed, 148 (28.5%) and 152 (29.2%) patients had a grade I and II, 77 (14.8%) and 75 (14.4%) had grades IIIa and IIIb, 46 (8.8%) and 13 (2.5%) had grades IVa and IVb, and, lastly, nine (1.7%) had a grade V complication. A total of 134 (25.8%) patients required a “IIIa procedure”. The most common procedures were thoracic , BAR score  and CCI   and Validation Sets  when compared to the BAR, D-MELD, MELD, and EAD scores. All the other scores always showed inferior AUCs, only ranging 0.58–0.60 and 0.47–0.57, respectively.CCI exhibited the best diagnostic performances in both Training  yielded a sensitivity of 98.4 and a specificity of 27.7 (DOR = 23.6). The threshold value corresponding to the median point (29.6) had a sensitivity of 96.8 and a specificity of 56.1 (DOR = 38.7). The value of 47.3, corresponding to the third quartile, exhibited a sensitivity of 88.8 and a specificity of 85.9, giving a high DOR value of 48.3. Lastly, the threshold value put at 84.9 (ninth decile) showed a sensitivity = 66.3 and a specificity = 98.7 (DOR = 149.4)  yielded a sensitivity of 82.4 and a specificity of 32.1 (DOR = 2.2). The cut-off set at 29.6 (median) had a sensitivity of 76.5 and a specificity of 52.1 (DOR = 3.5). The cut-off put at 47.3 (third quartile) exhibited a sensitivity of 64.7 and a specificity of 79.3, giving a DOR value of 7.0. Lastly, the threshold value put at 84.9 (ninth decile) presented a sensitivity = 41.3 and a specificity = 98.6 (DOR = 49.3)  and validation sets . All the other scores always showed inferior AUCs, only ranging 0.56–0.59 and 0.45–0.63, respectively.CCI exhibited the best diagnostic performances in both training  yielded a sensitivity of 94.9 and a specificity of 28.6 DOR = 7.5). The threshold value corresponding to the median point (29.6) had a sensitivity of 89.1 and a specificity of 57.8 (DOR = 11.2). The value of 47.3, corresponding to the third quartile, exhibited a sensitivity of 75.0 and a specificity of 87.5, giving a high DOR value of 21.0. Lastly, the threshold value put at 84.9 (ninth decile) showed a sensitivity = 53.5 and a specificity = 99.9 (DOR = 1149.4)  yielded a sensitivity of 86.5 and a specificity of 33.1 (DOR = 3.2). The cut-off set at 29.6 (median) had a sensitivity of 78.4 and a specificity of 53.4 (DOR = 4.2). The cut-off put at 47.3 (third quartile) exhibited a sensitivity of 56.8 and a specificity of 80.5, giving a DOR value of 5.4. Lastly, the threshold value put at 84.9 (ninth decile) presented a sensitivity = 27.0 and a specificity = 99.2 (DOR = 45.9) (Table p < 0.001) and validation sets . Similarly, CCI was also the best diagnostic tool for predicting 1-year graft loss, with the best diagnostic performances in both training  and validation sets .The diagnostic ability of the five different scoring systems was also evaluated in a sub-analysis in which only transplants performed using organs from aged (≥ 70 years) donors were considered Table . As for In the training set, we obtained an excellent stratification of graft survival rates using the investigated CCI thresholds.p < 0.001)   score represents a paradigmatic example: despite its good predictive ability, the score is based on 18 different pre-transplant variables, making it difficult to calculate . ConversHowever, all these scores based on pre-transplant data typically yielded inferior results compared to scoring systems based on variables available in the immediate post-transplant period. Among the post-transplant scores, the Olthoff-EAD is the most commonly adopted , 23.The great and largely unsolved challenge in LT remains how to correctly allocate a limited resource such as organs from deceased donors, which can be addressed only with preoperative variables. Therefore, a score composed by post-transplant parameters cannot be used with the intent to optimize the allocation process. However, such a score should maintain its potential usefulness as a diagnostic tool for early  clinical course prediction.In the present series, we observed that the CCI model presented high relevance for LT survival prognostication in both the Sets we investigated. Moreover, CCI outperformed both the pre- and post-transplant scores in diagnostic ability.CCI was initially created to report complication rates more accurately. The CCI aimed to inform about the severity of cumulative postoperative complications precisely . RecentlSeveral studies investigated the prognostic impact of CCI in the setting of different types of cancer. A US study showed that CCI was a strong survival predictor in patients undergoing hepatic resection for colorectal metastases independently from the RAS mutational status. Patients with high CCI (≥ 26.2) had worse recurrence-free and cancer-specific survivals with respect to low-CCI patients .A study from Japan correlated postoperative complications with worse survivals in gastric cancer patients. Patients with a CCI ≥ 32.15 had significantly lower 5-year overall and disease-specific survivals than those observed in the CCI low group. Moreover, a multivariate analysis identified the CCI as an independent prognostic indicator . AnotherCCI was also correlated with several parameters of poor outcome after surgery, further explaining its potential role as a predictor of poor early outcomes. A study from Spain correlated CCI with the frailty status in elderly patients treated with surgery, suggesting a correlation among frailness, post-surgical complications, and poor outcomes . AnotherUp to now, only one Dutch study has revealed a prognostic role of CCI in the specific setting of liver transplantation. Specifically, when transplants performed with organs from deceased-cardiac donors (DCD) or deceased-brain donors (DBD) were compared, 6-month postoperative median CCI was significantly higher in case of DCD grafts (53.4 vs 47.2). Moreover, more DCD recipients underwent re-transplantation for ischemic-type biliary lesions in this period (4% vs 1%), therefore suggesting a correlation between CCI and the development of biliary complications .In the present experience, the CCI reported the best diagnostic ability respect to all the other tested scores in terms of graft loss risk, with AUCs of 0.94 and 0.77 in the training and validation sets for the diagnosis of 90-day graft loss. As for 1-year graft loss, CCI showed similar good performances in the training (AUC = 0.88) and validation sets (AUC = 0.75).The strength of the CCI was particularly evident in light of the poor performances observed by the other tested pre- and post-transplant scores. Interestingly, no one of them ever showed an AUC > 0.70 in both the 90-day and 1-year graft loss risk estimation.We also tested several CCI cut-offs. Interestingly, the value corresponding to the third quartile (47.3) was substantially similar to the threshold identified by Muller et al. on 7492 patients transplanted in 17 different centers .We clearly understand that the diagnostic utility of CCI should appear marginal, mainly in consideration of the potentially long time required for its calculation. Typically, scores based on post-transplant data are collected within seven to ten days from LT , 23. WhiAnother aspect to consider is the fact that, once a LT patient has developed a complication, the ability to improve the patient outcomes should be markedly limited if compared with the possibility to pre-operatively prevent this specific complication. We understand this shortcoming of the model, obviously limiting the impact on the CCI in conditioning important aspects like an early re-transplantation. However, we think the role of the CCI merits consideration, mainly in light of the possibility to identify patients that are more “fragile” at the discharge time.As an example, the sub-analysis focused on the transplants performed using aged grafts showed that the CCI even improved its diagnostic ability to predict early graft loss, therefore underlying the potential utility of this score in identifying transplanted patients at time of discharge requiring particular attentions during the follow-up.As previously reported, the CCI should play a role in the prognosis of tumoral patients , 25, 26.Another important element is the potential correlation between CCI and biliary complications. Only one study specifically reported this connection, therefore requiring more detailed studies with the intent to clarify the potential intercorrelation between poor initial clinical course and biliary complications . HoweverWe think such an opportunity is not of marginal relevance. As an example, 176/1262 (13.9%) and 102/520 (19.6%) patients in the training and validation sets overpassing the identified threshold of 47.3 were alive at discharging time. In the training set, 67/102 (38.1%) of these patients had biliary complications, and 40 (22.7%) required a re-transplantation during their follow-up. We are confident that these patients should potentially benefit from a modification of the post-discharge management policy, due to the peculiar condition derived from a complex post-transplant course.One can argue that a potential bias of the study is represented by the arbitrary decision to calculate the CCI only at the time of the first post-LT hospitalization, excluding the possible complications observed by the patient after discharge. As an example, in the study by Muller et al., the CCI value was calculated at 12 months after transplantation . On the p = 0.001), potentially explainable with worse histological aspects of the used graft. Unfortunately, due to the retrospective nature of the study, we were not able to explore this aspect. Last, we cannot exclude the presence of comorbidities like refractory ascites and portal hypertension in the recipients potentially justifying the observed results. Also in this case, we were not able to retrospectively evaluate in detail these aspects.The intent of the study was not to compare the training and the validation sets. However, in light of the observed results, we noted that the Validation Set reported better CCI and 90-day results despite a higher median MELD value. We can do some suppositions for explaining this paradoxical result. First, MELD alone is not necessarily able to capture the overall recipient technical difficulties, mainly in case of “exception” pathologies like HCC and biliary cholangiopathies. In approximately half of the Training and Validation Set cases, we exactly observed these types of pathologies, respectively. Second, the high number of HCC cases in the training set should explain the higher rate of vascular thromboses/stenoses as a consequence of several intra-arterial treatments caused by bridging/downstaging strategies , 30. ThiWe are aware that the study may have some limitations. First, the study is retrospective and pluricentric. The main concern connected with the retrospective nature of the study is the risk of missed post-LT complications, mainly for the grade I–II cases. A systematic retrospective collection of all the pharmacological needs of LT patients should be challenging. However, we can say that, although potentially underestimated, the diagnostic effect of CCI was particularly relevant in our series. Consequently, we can only assert that the CCI role should be even stronger in a prospectively collected database.Another limit of the study is connected with the fact that some complications have been classified for CCI scoring on a non-empirical basis, due to a lack of literature investigating on this aspect. Obviously, such a condition is of relevance because the heterogeneity in the CCI grading of specific complications may influence the performance characteristics of the score.As for the multicentricity of the training set, we should emphasize that the large sample size of this population should minimize possible biases related to data analysis. Moreover, the validation set was based only on a monocentric experience, however confirming an overall broad prognostic ability of CCI also in this context.In conclusion, the CCI shows a very good diagnostic ability for 90-day and 1-year graft loss in both a multicentric training and a monocentric validation set. Its diagnostic power is superior to other commonly adopted pre- and post-LT scores. Further analyses are required to prove its validity even in the long term.


Introduction Lower back pain is an extensive problem globally, and quite prevalent in Pakistan as well. In most cases of lower back pain, the cause is lumbar disc herniation. To treat this pain, there are various treatment options available. In this study, we aim to find the efficacy and safety of pregabalin in lower back pain due to lumbar disc herniation.Methods We conducted an open-label prospective trial in a public tertiary care hospital in Karachi, Pakistan, for a duration of five months, i.e. from July 2019 to December 2019. A total of 105 patients were randomized into two groups: pregabalin group and placebo group, and they were required to respond to visual analog scale (VAS) on day 0 and week 12 of the study.ResultsThe results showed a significant reduction in pain over time in both the groups: pregabalin  and placebo . However, the difference in pain reduction between pregabalin and placebo was not significant . The most commonly reported side effects were somnolence and dizziness.Conclusion Based on the results of this study, we conclude that adding pregabalin to non-steroidal anti-inflammatory drugs (NSAIDs) and physiotherapy had no significant effect on pain reduction. Further large-scale studies are needed to evaluate the role of gabapentoids in lower back pain due to lumbar disc herniation. Lower back pain (LBP) is an extensive condition, with around 80% of the global population reporting such cases at least once in their lifetime . In mostAccording to the National Institute for Health and Care Excellence (NICE) guidelines, most instances of back pain improve within a few weeks without any need of more potent analgesics like anticonvulsants . There aWe conducted an open-label prospective trial in a public tertiary care hospital in Karachi, Pakistan. The study duration was from July 2019 to December 2019.During the study period, we included all patients of LDH, complaining of LBP. Both males and females were included in the study with ages between 18 and 70 years. Pregnant and lactating mothers were excluded from the study. The diagnosis of LDH was made radiologically by MRI. The severity of pain was evaluated using the visual analog scale (VAS). A score of 0 was equivalent to no pain and a score of 10 was recorded as the worst pain. Patients were required to respond to VAS on two instances, i.e. day 0 and week 12 of the study. Patients were asked to visit the clinic every four weeks to maintain follow-up where their general assessment was done, but the VAS score was not recorded. Age, gender, and VAS score were recorded in a self-structured questionnaire.At the beginning of the study, we enrolled a total of 105 participants after taking informed consent. These participants were randomized into two groups: the pregabalin group (n = 52) and the placebo group (n = 53). The pregabalin group was prescribed 75 mg of pregabalin once a day with a non-steroidal anti-inflammatory drug (NSAID). In contrast, the placebo group was given only a NSAID. Participants of both groups were advised to undertake physiotherapy as well.By the 4th week, no patient was lost to follow-up in either of the groups. However, by the 12th week follow-up, six participants were lost to follow-up in the pregabalin group and eight participants in the placebo group. Hence, at the end of the 12th week, the sample size reduced to 91. Out of these, 46 patients belonged to the pregabalin group and 45 patients belonged to the placebo group. Data were processed and analyzed using SPSS for Windows, version 22.0 . Mean and standard deviation (SD) were calculated for continuous variables and frequencies, and percentages were calculated for categorical variables. For analysis of the mean scores of VAS, only those patients who completed the study (n = 91) were included, and for adverse events, all 105 patients were included. Mean was compared using the t-test. Adverse events were compared using the chi-square test. A p-value of less than 0.05 indicates that the difference between the pregabalin group and the placebo group is significant enough to discard the null hypothesis.Among the 91 patients who completed the study, 41 were men (45%) and 50 were women (54.9%). Their mean age was 51 ± 8 years (range: 39-70 years).Mean pain intensity recorded on VAS was compared for both pregabalin and placebo groups on day 0, and week 12. There was a significant reduction in pain over time within each group; however, the difference in pain reduction between the two groups was not significant , followed by dizziness (17.3%) , there was no significant difference in pain reduction between the pregabalin group and the placebo group. A meta-analysis and systemic review from 2018 echoes similar findings. They evaluated nine placebo-controlled randomized trials, similar to ours, for chronic LBP and lumbar radicular pain, and found high-quality evidence showing that gabapentinoids had no effect on pain and disability compared to placebo . AnotherThe most common adverse event in the pregabalin group was somnolence, followed by dizziness and fatigue. Weight gain and edema were also numerically higher, but not statistically significant in the pregabalin group compared to the placebo group. Similar central nervous system adverse events were reported elsewhere as well. Dizziness was reported in 31% of cases with pregabalin, compared to 9% in the placebo group. Somnolence was experienced by 22% of patients treated with pregabalin compared to 7% of those receiving placebo . Other pThere are various studies available in local literature that investigate the role of pregabalin in a post-surgical setting; however, to the best of our knowledge, this is the first study in our local setting that compares pregabalin vs placebo in LBP due to LDH. Nevertheless, this study has its limitations as well. It was a single-center study with small sample size; hence, care should be taken while inferring its data to a broader set of population.In the UK, the prescription of anticonvulsants for back and neck pain, including radicular pain, by general practitioners, has increased by 535% in the last 10 years . There iIn this study, pregabalin was found to be ineffective in significantly reducing LBP due to LDH, compared to placebo. Many other similar studies do not support the use of anticonvulsants for chronic LBP or lumbar radicular pain either. Consequently, we can state that pregabalin has notable adverse events, and clinicians should carefully consider the risks and benefits before prescribing it for patients with LBP.


Chronic neck pain (CNP) is a major concern for pain therapists. Many drugs including antidepressants such as amitriptyline have been used in the management of CNP. This study compared the efficacy and safety of 2 different doses of amitriptyline (5 mg and 10 mg at bedtime) in patients with CNP. A total of 80 patients of both sexes with idiopathic CNP, ranging in age from 18 to 75 years, were divided into 2 groups that received 5 or 10 mg oral amitriptyline at bedtime for 120 days. The primary outcome measure was neck pain disability index (NPDI). Neck pain intensity, Athens Insomnia Scale score, Hospital Anxiety and Depression Scale (HADS), side effects of the drug, and patient satisfaction were secondary outcome measures. NPDI decreased by 71.9% ± 13.4% in the 10 mg group compared to 47.3% ± 17.3% in the 5 mg group, representing a statistically significant difference . Additionally, the 10 mg group showed greater mean reductions in pain score and HADS scores , as well as improvement in sleep disturbance compared to the 5 mg group. A higher dose (10 mg) of amitriptyline at bedtime significantly reduced neck pain intensity, sleep disturbance, and anxiety and depression compared to a lower dose (5 mg) in patients with idiopathic and nontraumatic CNP after 120 days of treatment, with no significant difference between groups in the rate of side effects. Although idiopathic chronic neck pain (CNP) is a common and debilitating condition, its management is not always optimal. CNP is a musculoskeletal disorder characterized by continuous or recurrent pain lasting at least 3 months  that affCNP has been shown to be associated with increased sympathetic activity ; abnormaNonsteroidal anti-inflammatory drugs, acetaminophen, and muscle relaxants have been shown to be effective in the management of acute neck pain; however, they rarely provide adequate pain relief in CNP. Thus, there are currently no effective treatments for CNP . ChronicAlthough evidence-based strategies are used for the clinical management of CNP, a standardized treatment protocol is lacking , 15. TriAmitriptyline was previously shown to be the most effective antidepressant for the treatment of CTTH  and was This prospective, randomized, double-blind comparative study was carried out in order to compare the efficacy and tolerability of low doses of amitriptyline (5 and 10 mg) in patients with idiopathic CNP.PACTR202003721200086).The study protocol was approved by the Institutional Ethics Committee of El Fayoum University Hospitals. A total of 80 patients of both sexes with idiopathic CNP, ranging in age from 18 to 75 years, were recruited at 2 centers: the Pain Outpatient Clinic at Al-Fayoum University Hospitals and a private pain clinic in El-Fayoum City, Egypt. The study has been registered in the Pan African Clinical Trial Registry  were obtained for all patients during their first visit and were evaluated by the same 2 radiologists. Patients with CNP for more than 15 days per month and lasting at least 3 months, without a history of trauma or other neurologic disorders, with normal neurologic function (as assessment by a neurologist), and without any abnormalities on imaging except for a loss of cervical lordosis were included.Patients who had any other neurologic conditions; had abnormal imaging findings; had a history of cervical disc disease, migraine headaches, trauma, or major depressive disorder; abused analgesics or experienced side effects of tricyclic or tetracyclic antidepressants; had existing psychiatric illnesses or a history of glaucoma, arrhythmia, or severe constipation; or were taking medications for CNP  in the preceding month; as well as pregnant women and patients with prostatic symptoms were excluded. Neck pain was defined as pain in the posterior aspect of the neck and anatomical projection to the trapezius muscle, sometimes involving the head without any arm pain. A flow diagram of the patient selection process is shown in n = 40 patients per group). The patients were given 120 pills of 5 or 10 mg amitriptyline in a box, to be taken at bedtime. To ensure double-blinding, neither the patients nor the attending physician was aware of group assignment. No extra medications were allowed during the 4-month trial.The study was designed as a double-blind, prospective, comparative, randomized clinical trial. Patients who met the inclusion and exclusion criteria were provided with a protocol information document and consent form stating that they would receive either 5 or 10 mg of amitriptyline. Enrolled patients were allocated (by computer-generation block randomization) to either the 5 or 10 mg amitriptyline groups , which reflects disability secondary to pain . The NPDSecondary outcome measures were also evaluated before and at the end of the 4-month treatment period. Neck pain intensity was measured using the visual analog scale (VAS), with 0 indicating no pain and 10 indicating the worst pain imaginable. Insomnia was assessed using the Athens Insomnia Scale (AIS), which is a self-administered test with symptom-related questions . AnxietySide effects of the 2 doses of amitriptyline were measured and recorded. At the end of the 4-month trial, the patient's subjective satisfaction was measured on a scale from 0 to 10, with 0 indicating complete dissatisfaction and 10 indicating complete satisfaction. Patients missing more than 5 out of the 120 days of treatment were excluded from the analysis.n1= (σ12 + σ22/K) (z1 − α/2 + z1−β)2/Δ2. We therefore recruited 40 patients per group, increasing the sample size by 12% to compensate for potential dropouts.The sample size for this trial was calculated using a power of 80% and 5% level of error. The mean percent improvement in the primary outcome measure (NPDI) with 5 mg amitriptyline was 42% ± 15% in a previous study [t-test, which was also used to analyze secondary outcomes. The difference in the rate of side effects in each group was evaluated with the chi-squared test. The correlation between patient satisfaction and other outcomes was assessed with Pearson's correlation coefficient. Statistical significance was set at P < 0.05. Data were analyzed with SPSS v24 software .Demographic and baseline characteristics of the patients were summarized as means and standard deviations for numeric data and as frequency distributions for categorical data. Data for the 2 treatment groups were analyzed for any imbalances after randomization. The primary analysis included comparisons of the main outcome measure (improvement in NPDI after 4 months of treatment) between groups using the independent samples A total of 80 patients were enrolled in the study, with 40 patients each receiving 5 and 10 mg amitriptyline for 4 months. Ten patients were excluded from the final assessment because of intolerance to side effects or loss to follow-up. Baseline patient characteristics and demographic data were comparable between the 2 groups . At baseAIS, Athens Insomnia Scale; BMI, body mass index; HAD-A, Hospital Anxiety and Depression Scale-anxiety subscale; HAD-D, Hospital Anxiety and Depression Scale-depression subscale; NPDI, neck pain disability index.P < 0.001). The mean reduction in pain scores was 5.7 ± 1.4 in the 10 mg group and 3.8 ± 1.2 in the 5 mg group, representing a statistically significant difference. Similarly, VAS decreased to a greater extent in the 10 mg group than in the 5 mg group (71.4% ± 13.7% vs 50.3% ± 15.9%) (The changes in outcome measures following treatment with amitriptyline are shown in ± 15.9%) .AIS, Athens Insomnia Scale; HAD-A, Hospital Anxiety and Depression Scale-anxiety subscale; HAD-D, Hospital Anxiety and Depression Scale-depression subscale; NPDI, neck pain disability index; VAS, visual analog scale.P < 0.05 for both). There was no difference in patient satisfaction between the 2 groups at the end of the treatment period.The higher dose of amitriptyline yielded a greater improvement in sleep, as measured by the AIS (72.1% ± 12% for 10 mg group vs 57.7% ± 10.2% for 5 mg group) . TreatmeThere were no significant differences in the rate of complications between the 2 groups . NPDI anAntidepressants have been shown to be effective for pain management; for example, the selective serotonin reuptake inhibitor (SSRI) paroxetine has been used to treat fibromyalgia , while tIn clinical practice, it is important to establish the minimum effective dose of a drug to reduce side effects. To this end, in the present study we compared the efficacy of 2 different doses of amitriptyline for the treatment of idiopathic and nontraumatic CNP. The results showed that the higher of the 2 doses (10 mg) relieved pain and improved emotional disorder (anxiety and depression) to a greater extent than the lower dose (5 mg) without increasing the occurrence of side effects.d-aspartate receptor, thereby inhibiting the firing of second-order neurons [The mechanism of action of amitriptyline in CNP is not known, as this drug exerts multiple effects on the nervous system and the pathophysiology of CNP is unclear. Animal studies have shown that amitriptyline may antagonize the N-methyl- neurons . Additio neurons . A previ neurons , and a r neurons .We used the NPDI as the primary outcome measure, as most of our patients were workers who were functionally incapacitated in their work as a result of CNP. NPDI improved to a greater extent with 10 mg amitriptyline than with the 5 mg dose. In a previous study, 5 mg amitriptyline decreased NPDI by 42.22% ± 15.5% in patients with CNP [The mean decreases in VAS and pain score and improvement in AIS were greater with 10 mg amitriptyline as compared to the 5 mg dose. The mean percent reduction in VAS in the 5 mg group in our study (50.3% ± 15.9%) was also similar to the previously reported value , which lAnxiety and depression in our CNP patients, as evaluated by HAD-A and -D, respectively, were improved to a greater extent by 10 mg as compared to 5 mg amitriptyline. However, despite these and other positive effects associated with the higher drug dose, there was no difference in the level of satisfaction between the 2 groups for reasons that remain unclear. We observed positive correlations between VAS and HAD-A and -D scores in patients treated with 10 mg amitriptyline, although the correlations were weak and moderate, respectively. In the study by Maarrawi et al., there was no correlation between the primary outcome measure for CNP (VAS) and anxiety and depression scores .A higher dose of amitriptyline (10 mg) was more effective than a lower dose (5 mg) in alleviating neck pain, disability, sleep problems, and anxiety and depression symptoms in patients with idiopathic and nontraumatic CNP, without increasing the rate of adverse effects. Based on these findings, we recommend 10 mg amitriptyline for the clinical management of CNP.


A common denominator in the clinical phenomenology, initially described already as early as in the 2th century CE (see Nurmikko and Eldridge2) is the paroxysmal pain component, usually only a few seconds in duration, not infrequently accompanied by a “tic”  on the affected side. In addition, some patients report an “atypical” concomitant continuous or near-continuous ongoing pain on which the paroxysms are superimposed. These sufferers always have an initial history of paroxysmal pain only. The majority of patients also report trigger zones, extra- or intraorally, where mild tactile stimuli may induce a painful tic. Not infrequently a period of refractoriness will be evident so that new triggers fail to induce a pain paroxysm for a short period of time. If, for example, chewing, intraoral stimuli or swallowing trigger an attack, the refractory period can be used to literally shove food down the gastrointestinal tract, before sensitivity returns.Trigeminal neuralgia (TN), a classical neuropathic pain state, is a time-honored diagnosis and a well characterized condition with a variety of possible etiological backgrounds. It has recently been classified and described in detail by the International Headache Society (35). Based on these considerations we conclude that from a scientific as well as an ethical standpoint, animal experiments in pain research should be subjected to rigorous experimental design. Keeping this in mind, it is conspicuously disturbing to note that according to Pub Med, between 2016 and 2019 at least 21 articles have been published where the authors claim that they are using an animal model of TN (e.g. see previous works611). Among those are articles published in Molecular Pain.Explorations in animal models are used for the understanding of disease mechanisms potentially translatable into development of new therapies for patients. In neurobiology, the degree to which these models are successful in mimicking the disease that is investigated varies, and is frequently not satisfactory (e.g. see literature12), a condition significantly different from TN not only from the clinical phenomenology perspective,13 but also regarding evidence-based treatment.14These reports, performed on a rodent model that is supposed to reflect TN in humans, are to us a long overdue wakeup call that must not pass unnoticed. The model used is a mechanical injury to the infraorbital nerve, the major branch of the n.V:2, which is said to induce the specific painful symptoms and signs of TN in all animals included. It is far from clear to the reader why TN is brought forward in these studies, since the same injury in other work is postulated to induce a painful trigeminal neuropathy . This hyperexcitability would be a sequel of nerve injury and demyelination, coming from e.g. compression of the trigeminal nerve root by a blood vessel close to the brainstem. Accordingly, the situation is improved in some, but not all, patients with this etiology who undergo surgical intervention to decompress a nerve root. Some patients with various etiologies of TN also benefit from glycerol injection, thermocoagulation or balloon compression of the trigeminal ganglion, alternatively from gamma irradiation in the trigeminal root entry zone.17The molecular mechanisms behind TN are still unknown, and the quest for it constitutes a major challenge for neurobiology and neurology. Some 25 years ago, Devor and colleagues based on electrophysiological data and clinical observations suggested that the mechanism behind TN characteristics in some specific etiologies such as triggering, amplification and discontinuation of pain attacks is related to altered (increased) excitability of trigeminal ganglion neurons  were not reported. Thus, it was not a model of TN, although this was stated even in the title of the paper.Experimental damage to the infraorbital nerve as a model for TN is indeed questionable. When this nerve was injured in the rat using cobra venom, it was claimed that significant changes in exploratory, resting, face-grooming, and head-shake behaviors appeared after surgery.17 or from neurosurgical strategies such as those mentioned above. The remaining sufferers need serious innovative attempts in neuroscience and neurology to receive help.In conclusion, we urge researchers in the field, and certainly referees of data that is submitted for review, not to take TN lightly. As far as we know, there is no animal model that even remotely meet the criteria for a TN model. TN is a devastating disease for those patients who do not get relief from evidence-based interventions, such as administration of carbamazepine/oxcarbazepine,