Chronic pain is one of the most common complaints of cancer patients. There are many pharmacological and non-pharmacological treatment modalities used for the treatment of pain. Nonetheless, non-pharmacological interventions are preferred because of potential side effects in cases resistant to medical therapy that require a dose increase or potent drug use. In most real-life situations, the decision on which technique to choose is based on the clinical but subjective decisions of the practitioners. This study aimed to find out the best non-pharmacological treatment option for patients with chronic cancer pain by following a rational and reasonable approach.Since the evaluation of treatment options requires to make a comparison between a number of alternatives in the light of certain criteria, we utilize the order relation analysis (G1-method) which is a method for determining the weights based on the improved Analytic Hierarchy Process (AHP). The method uses the relative importances on prioritizing the four criteria and eight sub-criteria defined by the experts of three pain physicians, one oncologist, and one oncologic surgeon. Four alternatives are then compared according to the Technique for Order Preference by Similarity to Ideal Solution (TOPSIS) using the verbal subjective judgments of the practitioners.Obtained results indicate that the general medical condition of the patient and the stage of the cancer are the essential factors in the selection of the treatment method. It is followed by the extent of the pain and the level of evidence, respectively. According to the evaluations performed, spinal port and splanchnic nerve radiofrequency thermocoagulation treatments are the first and second priority methods for pain treatment, respectively, compared to lumbar epidural catheter and celiac plexus block.The results of this study emphasize the need to integrate critical criteria into the decision-making process objectively. This is the first study in which multi-criteria decision-making tools are used in the evaluation and selection of pain management methods in cancer patients. Chronic pain is defined as persistent pain, which lasts longer than three months, and usually requires long-term treatment. It is a global health problem and is present in the range of one-third to 50 % of the population . ChronicCancer patients are among the most frequently concerned focus groups having chronic pain. Especially, upper abdominal malignancies lead to chronic, intractable pain for patients. They may experience pain due to direct tumor effects  or from adverse events of treatments or pain associated with comorbidities . There aMulti-criteria decision making (MCDM) provides the appropriate selection between a number of alternatives, in the light of specific criteria. Using MCDM techniques, it is possible to determine and sort the preferred alternatives. As the decisions to be made in health systems are of vital importance, it is not a rational approach to leave them to the subjective judgments of individuals. In the literature, there are studies regarding the multi-criteria selection and evaluation of possible diagnosis and treatment options of various diseases. Among the ones published in the last five years; Wagner et al.  tried toIn this study, we discussed how to make a selection among various treatment options that can be used in the treatment of chronic pain. In patients with cancer, it is known that pain occurs in the majority of cases and that millions of people complain about pain due to cancer every day. Therefore, in this study, non-pharmacological intervention methods used in cancer patients are compared to each other with respect to a number of criteria.The aim of this study is to select the best treatment alternative among the following four non-pharmacological methods for the chronic pain observed in upper abdominal malignancy patients: administration of lumbar epidural catheter (Alternative 1), spinal port (Alt. 2), celiac plexus block (Alt. 3), and splanchnic nerve radiofrequency thermocoagulation (Alt. 4). The alternative treatment methods considered are determined by the help of the literature review together with the opinions of the pain medicine experts, who are three pain physicians, one oncologist, and one oncologic surgeon.Epidural catheters are placed into the epidural space to inject local anesthetics and narcotics in order to provide regional analgesia. With an epidural catheter, the pain of patients can be relieved within minutes, but this relief ends when the effect of the given medication is over. The major advantage of this approach is the easy implantation of the catheter without a need for an imaging device such as fluoroscopy or computed tomography. However, the main complication of this technique is the infection that may occur in the catheter’s entry site and the epidural space. This technique is available for up to several weeks with frequent cleaning and dressing of the incision site.Spinal port is a surgically implanted device which allows delivering medications to the intrathecal space. The port is placed under the skin on the anterior face of the chest, and the drug is delivered to the subarachnoid region with a catheter. The most significant advantage of the spinal port is that it is a closed system and thus can be used for years by reducing the risk of infection in most. The major disadvantages are the cost of the system and the need to be more precise in dose adjustment.Celiac plexus block with neurolytic agents such as phenol or alcohol is an established treatment modality in upper gastrointestinal malignancies. Computed tomography guidance is usually needed for this approach. The success of block is strongly correlated with the spread of neurolytic drug in the celiac area . The paiSplanchnic nerve radiofrequency thermocoagulation can be administered in patients who have distorted anatomy of celiac ganglion because of advanced malignancy . This teIn the first part of this study, we want to determine the specific criteria that affect the choice of the treatment method. Thus, the initial step of the method was to create the problem hierarchy. At this point, the structure consisting of the main criteria and sub-criteria was defined. While determining the criteria, the literature regarding the choice of treatment method was examined, and the opinions of the experts related to the subject were consulted. In the light of the researches and evaluations, it is concluded that the choice of possible treatment should be done by considering the convenience C1), pain (C2), risk (C3), duration (C4) and cost (C5) criteria. The hierarchical structure created for the problem is shown in Fig. , pain , stage of cancer (C12), and level of evidence of the procedure (C13). For the assessment of the general medical condition, the medical history of the patient should be questioned, and a good physical examination should be performed. By this way, contraindications and risk of complications can be predetermined. The general medical condition is graded up according to the American Society of Anesthesiologists (ASA) physical status classification system. In this classification, ASA I and II are accepted as well, ASA III and IV as medium, and ASA V and VI as poor. The second one is the stage of cancer, which is evaluated with the “tumor, node, metastasis” (TNM) system. TNM is based on three main parameters, which are the extent of the tumor, spread to nearby lymph nodes, and spread to distant parts of the body (metastasis). Tumors without metastasis and does not spread to lymph nodes are low stage. Tumors which are spread to lymph nodes, without metastasis are intermediate stage. Tumors which are spread to lymph nodes and have metastasis are considered to be high stage, and almost all of these patients are inoperable and have low survival times. The last sub-criterion of this group is the level of evidence of the interventions for the individual diagnosis, that is obtained from well-designed studies, especially randomized controlled trials. It is indicated by a numerical value and a letter, followed by a positive or negative sign. 1A+, 1B+ and 2B+ indicates the highest, 2A+, 2B ∓ and 2C+ medium, and 0, 2C- and 2B- poorest recommendation levels. Consequently, the level of evidence indicates the recommendation rate of the procedure in light of the results from previous studies .The second group of sub-criteria is defined under the heading of pain. The first one is the extent of the pain (C21), defining whether it is localized or extensive. The pain that only localized to the abdominal region is referred as well, having back pain in addition to abdominal pain as medium. Apart from these, it is accepted that pain, which includes distant areas such as widespread bone pain, shoulder pain, is ranked as poor. The second one is concerned with the character of pain (C22); which can be visceral, somatic, or neuropathic. Visceral pain is observed due to the tumor’s press on nerves, bones, or organs. Somatic pain occurs when cancer spreads to surrounding tissues or distant sites such as bone metastasis. Neuropathic pain is due to nerve damage caused by tumor pressing, radiotherapy, or chemotherapy. Having visceral pain is considered to be good, whereas visceral and somatic pain coexistence is considered as moderate, and visceral, somatic, and neuropathic pain observed at the same time is accepted as poor.The third criterion title is the risk and its subheadings are the risk of complication of the procedure (C31) and the radiation exposure (C32). Each procedure has an individual risk of side effects, and complications vary from low to high. The complication risks of the procedures are evaluated according to the previous studies and the experience of the practitioners. For example, in the celiac plexus block, there are serious complications such as aortic and kidney injuries, while the epidural catheter has a low risk of dural puncture. Related to these possible risks of each of the procedures, the “benefit per complication” rate should be well evaluated before the procedure. Procedures with less risk of complications or have easy to manage complications are preferred to be applied first. Furthermore, there is a specific level of radiation exposure observed for some of the treatment options. Although the effects of radiation exposure are not immediately observed, it should be considered as a risk for long term complications. There is more radiation exposure in computed tomography (CT) guided procedures than fluoroscopy guided ones. While the spinal port and epidural catheter procedures do not need radiological guidance, the celiac plexus block usually administered under CT guidance and splanchnic radiofrequency is administered under fluoroscopic guidance.Duration is the fourth criterion, and the sub-groups are the duration (C41) and the persistency of the procedure (C42). The four procedures performed in the study are administered under sedation without general anesthesia. In upper abdominal cancer patients, procedures performed in the shortest possible time should be selected as these patients cannot tolerate long-term procedures due to the pain that is aggravated with the position. The estimated duration of the procedures varies from a few minutes to more than an hour. We accept the duration of less than 10 min as short, and more than 30 min as the long ranked. The persistency of the treatment is another important outcome of the treatment in terms of patient comfort, causing no need to repeat the procedure. Persistency of a procedure can be a few days to a couple of years. Less than one month is accepted as short, and longer than three months is accepted as long term persistence.The last criterion is cost, for which two sub-criteria are defined: the cost of the materials used (C51) and the cost of hospitalization (C52). Even though the management of pain and the clinical condition of the patients are the most important parameters, the financial aspect of the procedure is also important. According to the cost of materials used in the alternative treatments considered in our study, there is a huge difference between an epidural catheter and a spinal port. Thus, expensive systems are possibly preferred in patients who have long survival probabilities. In each procedure, different materials are used. We accepted less than fifty dollars as low, and higher than 500 dollars as high material cost. For last, factors affecting the duration of hospitalization are considered. Complications such as infection, bleeding, a patient’s ability to continue home treatment after the intervention, and the need for new procedures affect the length of hospital stay and increase the associated cost. The cost of hospitalization is related to the number of hospitalization days and the need for intensive care. In this study, outpatient procedures are accepted as short, hospitalization period up to 4 days as medium, more than 4 days or need of intensive care is considered as long length of stay.After defining the important criteria for the goal of selecting the best treatment alternative among the four non-pharmacological methods for the chronic pain observed in upper abdominal malignancy patients; we find out which one(s) among these criteria are more important over this decision, and determine which treatment method suits best to this specific group of patients. In this study, we propose a two-stage solution approach, in which we first determine the importance levels, namely the weights, of the sub-criteria that are important with respect to the selection and ranking problem that we focus on, and then we compare the alternatives with respect to the specific criteria and obtained weights, using the scorings of experts. While defining the solution procedure, the results presented by Wątróbski et al.  are usedWith these aims of study, in the first stage we use the relation analysis method (G1-method) which is a simple and practical method for determining the weights based on the improved AHP method. Following this stage, the alternatives are ranked using another MCDM approach, namely TOPSIS method.In the first stage of the procedure, we obtain the criteria weights using the scale value determined by the relative importance. The specific steps of the G1-method are as follows :Step 1: Determine the order relationship of the criteria.C(1), C(2), …, Cn − 1) ≻ C(2) ≻ … ≻ Cn − 1)( ≻ Cn)( ≻ Cj)( is greater (or not less) than Cj)( and Cj)( is defined by rj)(:wj)( are the weights of the criteria (j) and (j − 1) respectively. However, wj)( and wj − 1)Step 3: Calculate the subjective weights ωsj of each criterion by Eqs. ( by Eqs. –3)2\do2\doStepOnce the weights are obtained, it is time to rank the alternatives and determine the best possible one. According to the TOPSIS technique, the best alternative is the one that is nearest to the positive-ideal solution which is the one maximizing the benefit criteria while minimizing the cost criteria, and farthest from the negative-ideal solution which maximizes the cost criteria while minimizing the benefit criteria. The method consists of the following steps :Step 1: Establish a decision matrix D for the ranking. This matrix can be shown as follows:Ai denotes the alternatives i, i = 1, …, m; Fj represents jth alternative or criterion, j = 1, …, n, related to ith alternative; and fij is a crisp value indicating the performance rating of each alternative Ai with respect to each criterion Fj.Step 2: Calculate the normalized decision matrix R(=[rij]). The normalized value rij is calculated by the following formula:Step 3: Calculate the weighted normalized decision matrix by multiplying the normalized decision matrix by its associated weights. The weighted normalized value vij is calculated as:Step 4: Determine the positive-ideal and negative-ideal solutions, respectively:J is associated with the benefit criteria, and J′ is associated with the cost criteria.Step 5: Calculate the separation measures, using the m-dimensional Euclidean distance. The separation measure Similarly, the separation measure Step 6: Calculate the relative closeness to the ideal solution and rank the alternatives in descending order. The relative closeness of the alternative Ai with respect to positive-ideal solution V+ can be expressed as:In order to obtain the decision matrix in the first step, experts are asked to make a criterion-based assessment for each alternative. In this step, according to the scores determined by the experts, each alternative is scored based on each of the eleven sub-criteria. The scoring table proposed, together with the experts, is given in Table The procedure given in “Methods” section is applied to the problem of selecting the best non-pharmacological intervention method used in cancer patients.At the first step of the first stage, the criteria and the alternatives are defined, and the hierarchy of the criteria and alternatives is given in Fig. rj values by referencing to Table r2 value of 1.2. Obtained subjective priorities for the problem are given in Table Then, the importance levels for each of the eight sub-criteria are determined. The comparisons are made by the evaluations of the four experts; 3 pain physicians (PP), 1 oncologic surgeon (OS), and 1 oncologist (OC). The experts determine the order of the sub-criteria and the rationale assignment of For the alternatives to be evaluated, scoring is performed, and criterion-based score values are obtained for each of the four alternatives, which are given in Table It is one of the hardest decisions of physicians to give which treatment to which patient. The impact of personal judgments and preferences plays an important role at this point, where many independent criteria are effective in making such important decisions. These criteria often involve conflicting purposes. MCDM techniques stand out as a scientific approach commonly used at this point.Throughout this study, evaluations from the experts are used together with the related literature research. At this point, it would be appropriate to explain the logic followed in defining the criteria-based scoring for alternatives. The patient group in which we try to determine the most appropriate treatment choice is the advanced cancer patients. For this group of patients, we determine a treatment method which has a high level of evidence, low complication risks, and costs. Since the criteria discussed have contradictory objectives, the evaluation is performed using MCDM logic. The techniques used in this process are determined according to the descriptors defined in the literature, and the results are obtained by the help of the opinions of experts concerned with pain treatment in cancer patients.At the end of the study, spinal port treatment is found to be the most preferable treatment in upper abdominal cancer patients based on the opinions of experts participating in our study. It is a treatment modality which has been widely used in cancer patients to administer opioid intrathecally to provide a systemic effect. We know that intrathecal administration provides better analgesia with lower doses of opioids and local anesthetics . HoweverOur study also has some specific limitations. Decision-makers hesitated at some points in the evaluation of criteria and alternatives, and have difficulty in specifying exact values. At this point, the preference of using fuzzy or hesitant fuzzy term sets, which are frequently used in MCDM studies, may help decision-makers to be more comfortable in presenting their subjective judgments. Furthermore; in this study, a small number of experts working in a particular region could be consulted, and doctor-patient evaluations are not included. For the solution, in addition to these involvements, it is envisaged that a more accurate assessment can be made when a decision-making approach is used in which a larger number of experts is consulted and/or the preferences of the patients (or their relatives) are also involved. In the scope of this study we are mainly interested in the decision-making process, and the evaluation of the found treatments (compared to other possible treatments) is not focused on. However, any researcher can examine this issue, performing additional clinical studies. As it is mentioned before, this is a first study, hence the quality of the decision making process can be increased in follow-up studies in the hope that our manuscript is of enough interest.To the best of the authors’ knowledge, this is the first study focusing on the choice of treatment options for chronic pain. The problem addressed is a complex decision problem because each of the options discussed has its own advantages and disadvantages. In this study, we presented a G1 Method + TOPSIS based solution method for selecting the most suitable MCDM method for a specific problem. A number of effective criteria that are important in the treatment of chronic pain in cancer patients are defined by the help of the literature researches and the information obtained from the experts, and the problem is organized in a hierarchical framework consisting of five main criteria and eleven sub-criteria.Different decision-making methods can be used for future research, and the results can be compared with the results obtained in this paper. It is possible to apply the proposed model to other multi-criteria decision-making problems in medical or health care procedures.


Successful response to repetitive transcranial magnetic stimulation (rTMS) of the motor cortex requires continued maintenance treatments. Transcranial Direct Current Stimulation (tDCS) may provide a more convenient alternative.This pilot study aimed to examine the feasibility of a randomized, double-blind, double-crossover pilot study for patients to self-administer tDCS motor cortex stimulation for 20 minutes/day over five consecutive days. Primary outcomes were as follows: usability of patient-administered tDCS, compliance with device, recruitment, and retention rates. Secondary outcomes were as follows: effect on overall pain levels and quality of life via Short Form-36 anxiety and depression via Hospital Anxiety and Depression Scale, and Mini-Mental State scores.P=0.43, Sham vs Cathodal  P=0.94, or Cathodal vs Anodal  P=0.053 treatments. Furthermore, no significant changes were demonstrated in anxiety, depression, or quality of life measurements. The data collected to estimate sample size for a definitive study suggested that the study’s sample size was already large enough to detect a change of 15% in pain levels at 90% power for the overall group of 21 patients.A total of 24 subjects with neuropathic pain, who had previously experienced rTMS motor cortex stimulation  were recruited at the Pain Research Institute, Fazakerley, UK. A total of 21 subjects completed the study. Recruitment rate was 100% but retention rate was only 87.5%. All patients reported satisfactory usability of the tDCS device. No significant difference was shown between Sham vs Anodal  This study did not show a beneficial effect of tDCS in this group of patients and does not support the need for a larger definitive study using the same experimental paradigm.ISRCTN56839387 Stimulation of the primary motor cortex M1) has been shown to be effective in the treatment of chronic neuropathic pain. has been7TMS involves placing a coil over the scalp through which an electric charge is passed, generating a magnetic field, which can induce an electric pulse in the brain sufficient to activate cortical neurons. When appropriate patterns or trains of pulses are used, it results in modulation of activity of cortical circuitry,23We wished to establish the efficacy of using a patent’s response to motor cortex rTMS as a screening method for tDCS designed for home-based use and to assess the feasibility and efficacy of using home-based tDCS therapy in two groups of neuropathic pain patients (responders vs nonresponders to rTMS).The plan was to design a definitive trial to test whether tDCS over the M1 cortex reduces pain scores in subjects known to have previously gained relief from high-frequency rTMS of primary motor cortex. Our hypothesis was that rTMS responders would derive greater benefit from anodal tDCS than nonresponders. Furthermore, we postulated that there would be no difference between responders and nonresponders in pain relief from cathodal or sham tDCS.As this study design includes the use of patient-delivered tDCS, a pilot study was necessary to examine the practicality of this approach.The aims of this pilot study were to test whether tDCS over M1 area could be manageably delivered by patients or carers at home, and to test recruitment and retention rates for this study design.The study design also collected outcome data on average weekly pain scores, quality of life via Short Form-36 (SF-36), anxiety and depression via Hospital Anxiety and Depression Scale (HADS), and Mini Mental State Examination (MMSE) to assess for cognitive changes. These assessments will form the primary and secondary outcomes of the full trial. These data will be used to inform sample size calculations for future study. Overall data will be used to identify challenges in the study conduct.All participants had previously taken part in a clinical trial examining effect of rTMS motor cortex stimulation in chronic pain.1) Age between 18 and 85 years old. 2) Diagnosis of unilateral neuropathic pain as defined by the International Association for the Study of Pain Special Interest Group on Neuropathic Pain.1) Pain of other origin, for example, musculoskeletal pain as this could interfere with the reporting of the neuropathic pain being targeted. 2) Metal implants/coils/electronic devices. 3) Drug or alcohol abuse. 4) Pregnancy. 5) Psychiatric or psychological disorders. 6) Epilepsy. 7) Inability to understand instructions or operate equipment. 8) High-dose opioids. 9) Uncontrolled medical conditions .The study was carried out at the Pain Research Institute, Clinical Sciences Center, Fazakerley, Liverpool, UK.This study was conducted in accordance with the Declaration of Helsinki. Ethics approval was obtained from the national ethics committee (NRES REC reference 12/EE/0315), and all subjects gave informed written consent to participate in the study.A randomized, double-blind, double-crossover design was used so that all subjects participated in both anodal and cathodal active treatments (tDCS) and sham treatment . The treatment sequence was randomized and counterbalanced and the subjects and the response assessor were blinded to it.Assessment of pain and other pain-related variables occurred at initial assessment, for 14 days starting at and including each 5-day period of intervention, and at 4-week followup (after a minimum 2-week period for washout). Stable medication use before and during the trial was required. The randomized crossover design is shown in We wished to optimize patient selection to those patients who had previously undergone mapping of the motor cortex using brain navigation TMS localization, and therefore, had a known degree of cortical reorganization, with optimal coordinates for each participant available to guide the placement of tDCS electrodes on the scalp.As subjects had previously been enrolled in a TMS study evaluating the impact of target location on pain relief, they had undergone MRI of the brain and mapping of the motor cortex.242, 5 × 5 cm). A current of 1.4 mA (30 second ramp on) was delivered, giving a current density of 0.056 mA/cm2, which is comparable to previous studies.tDCS used was similar to that described previouslyDuring active tDCS treatment, subjects received stimulation of the primary motor cortex (M1). For anodal stimulation, the anode electrode was placed over the previously identified “hotspot” during TMS mapping and the cathode electrode over the contralateral supraorbital area. For cathodal stimulation, the electrodes were reversed. Stimulation was applied to the opposite hemisphere to the side in which the dominant neuropathic pain was felt.At the initial visit, measurements were taken for individually fitted headband locators to facilitate electrode placement. Once fitted, subjects were shown how to position the headbands reproducibly and asked to demonstrate this to the investigator. Photographs and measurements were taken by the patients in case of the need for reference at home. Electrode placement was checked at the beginning of each treatment block.Patients were administered a constant current of 1.4 mA for 20 minutes daily for 5 days at the same time of the day. All subjects were asked to remain non-active during this time and engage in either light reading/watching television or listening to the radio.Patients were asked to record the ease of use of their tDCS device setup and report if they had any difficulties with electrode placement or device use. Each device kept an internal record of the number of times the device was used and an exact record of the date, time of day, and duration the device was used for. It also recorded the current and average resistance during each stimulation. This allowed the investigator to track the use of the device.Individual stimulators were interrogated after each 5-day period of use to check correct stimulation delivery. The device records the number of stimulations delivered, the time and date of stimulation, and the stimulation parameters, including current strength, duration of stimulation, and resistance of circuit in ohms. It also recorded if any error occurred during stimulation, eg, if stimulation was aborted. This allowed full assessment of device compliance with each patient and treatment block.For sham stimulation, the electrodes were placed in the same positions as that for anodal M1 stimulation; however, a constant current of 1.4 mA was delivered only for 5 seconds (30-second ramp on). This sham delivery is pre-programmed into the device and automatically stops at the correct time period. The settings on the device visible to the patient are indistinguishable from active treatment settings. A countdown timer on the display panel will continue to count down over 20 minutes and the patient then removes the device. During active tDCS treatment, subjects typically report tingling sensations under the electrodes, which rapidly fade.30Subjects were randomized in two ways. First, each stimulation device was assigned a random treatment order. Second, each subject was assigned to a random device number. Both these tasks were completed by a researcher (unrelated to the study) by picking the folded paper containing the treatment order/subject order from an urn. This order was written down as a master key and divided into two study keys. A research assistant (not otherwise related to the study) set the stimulation parameters as indicated by the first study key, and was aware of the treatment order each device was programmed for but was unaware which subject received each device.The investigator was aware which device to give to each subject by following the second study key but was unaware of the treatment order programmed in that device. The master randomization key was kept in a sealed envelope.Subjects were not directly informed that a sham stimulation was being used. Rather they were told that three different types of stimulation treatments would follow each other, some of which may or may not feel different.Only at the end of the study were subjects informed that a sham stimulation was one of the treatments. At this time, they were asked verbally if they were able to guess the order of stimulation. Their guess was checked against the randomization key.The ease of use of the tDCS setup for patient administration was assessed by a patient experience questionnaire. This included four questions: 1. Did you feel the device was easy to use? 2. Did you have any problems using the device? 3. Did you have to contact a member of the research team for advice about using the machine while at home? 4. Did you have to abandon using the device for any reason?As patients may have felt the device was easy to use but still have used it incorrectly, compliance with the device was assessed. This was done by a combination of device interrogation to discern the timing, number, and duration of stimulations delivered during use and if any errors had occurred. Also, at return appointments, patients were asked to demonstrate the positioning of the electrode placements to ensure that they were complying with the correct anatomical positioning.A record was kept of the number of patients recruited and the date they joined the study. Also, the number, timing, and reasons for any patient withdrawals from the study were documented.Effect on overall pain was assessed on an 11-point (0–10) NRS questionnaire. Patients were asked to complete these at home each night based on the average pain scores over the previous 24 hours. Pain diaries were returned at the next patient visit.Subjects completed the following questionnaires at baseline and at the end of each treatment period: SF-36 to assess quality of life, HADS to assess anxiety and depression, and MMSE to assess for cognitive changes. Patients were also asked to complete a questionnaire regarding any difficulties encountered in using the device during the trial.For this pilot study, the sample size was based on an opportune sample of 24 patients who had previously undergone rTMS and expressed willingness to take part in the study. No formal power calculations were carried out prior to the study. Results from this study have been used to calculate a definitive sample size from the recorded effect size and SDs of the observed data. This is reported in the discussion at the end of this paper.Simple descriptive statistics were used to describe the primary outcomes and adverse events.To investigate the effect of the three modes of stimulation on the secondary outcomes of interest, a linear mixed effects model was used. The mode of tDCS, treatment period, responder group, and time were all regarded as fixed effects, and the patient (nested in sequence) as the random effect. Three time points were used when measuring daily pain intensity; days 1, 5, and 14, which corresponded to the beginning and end of treatment, and the end of the observation period, respectively. The mean of the 7-day baseline pain diary was used as baseline for the first mode of treatment. As a baseline pain diary was not completed before each tDCS treatment period, the pain score recorded on the first day of the observation period was taken as the baseline measurement for the second and third treatment. A one-way ANOVA test was implemented on these measurements to ensure that they did not differ significantly between treatments. As the secondary outcomes – HADS and SF-36 – were only measured once for each treatment, a time component was not included as a fixed effect when analyzing them.For sensitivity analysis, baseline and clinical measurements were added one by one to the model and those that altered the results significantly were included. A treatment by period interaction was investigated to see whether there was a difference in pain according to the sequencing of treatments.The association between tDCS and rTMS responders was investigated using Fisher’s exact test. A tDCS responder was classified as a pain reduction from baseline of at least 15%.Stata Statistical Software: Release 13. College Station, TX, USA: StataCorp LP).All analyses were performed using Stata version 13  with unilateral neuropathic pain were recruited for this study between October 2012 and August 2014. Of those recruited, 13 (54%) were prior responders to rTMS treatment. The mean duration of pain was 8.04±4.9 years .The target number of patients was recruited within the allotted time period. Although the study required several attendances at the research unit and also required multiple treatment sessions, only three patients (12.5%) dropped out, with a retention rate of 87.5%.One subject was excluded from the analysis as the patient failed to complete/return any pain diaries within the time frame of the study; the subject completed the randomized treatment. Two patients withdrew from the study; one withdrew after the first sham trial due to an exacerbation of pain and one withdrew after one sham trial and one failed cathodal trial, reporting difficulty in accommodating treatment sessions with daily schedule. One subject returned an incomplete pain diary for the sham trial and one subject returned an incomplete diary for the cathodal trial and failed to return one for the anodal trial.All patients reported the device was easy to use with a general appreciation of the convenience of home-based stimulation. This reflects the simplicity of this particular model of tDCS device with a simple on/off switch and start button. Positioning of headbands was not considered a problem. All subjects said that the positioning marking on the headbands was easy to follow and positioning was easy to replicate. Two subjects with single limb paralysis even reported being able to position the headbands one handedly, although they usually received help from a relative for speed. One subject reported that the headband would slip during use, which required readjustment. One subject who did not return any pain diaries during the study did not report any problems using the device. Another subject felt that although the device itself was easy to use, the time required for treatment sessions, that is, 20 minutes for stimulation and ~10 minutes setup time was difficult to fit in with daily activities.The main issue affecting compliance was that if there was unsatisfactory contact between the electrode and skin, then the current circuit was broken and the device would abort the stimulation. This was usually easily rectified by re-wetting of the electrode sponge; however, the patient would need to start a different stimulation session. In practice, when this happened, an extra stimulation was delivered if the patient noticed but if it went unnoticed, an aborted stimulation was recorded on the device log.Seven patients (29%) reported that they had to contact the research team for advice regarding this issue. All issues were resolved via a telephone conversation. Two patients (8%) did not notice a signal failed stimulation; this was subsequently identified on interrogation of the device log. No subjects had to totally abandon using the device.The actual number of stimulations self-administered by subjects per trial is shown in A total of 16 (62%) subjects reported tingling of the forehead/scalp and 12 (50%) reported redness after treatment, both during active and sham stimulations. Two (8%) reported tiredness. One subject reported a sharp increase in pain after sham stimulation and withdrew from the study. Five (20%) subjects reported headache following treatment, which lasted for ~2 hours and occurred in both active and sham stimulations. Two (8%) patients reported an exacerbation of parathesia experienced in the affected area at 4-week follow-up.P=0.9941).Numerical pain rating scores for each treatment over time are summarized in P=0.43), Sham vs Cathodal , or Cathodal vs Anodal . No significant difference was seen between mean pain scores on day 1, 5, or 14 for any treatments; day 5 vs day 1 , day 14 vs day 1 , and day 14 vs day 5 . No carryover effects were present.A linear mixed model was fitted to the data and the treatment-by-day and treatment-by-period interactions were investigated. There was no significant difference in overall pain between treatments ; Sham vsMean values of anxiety and depression scores are shown in P=0.014) and also showed a greater reduction with increased number of stimulations . However, the effect from the number of stimulations could be spurious as 85% of the trials recorded five simulations. There was an imbalance in mean levels of anxiety within the sequences. The average anxiety for sequence Cathodal–Anodal–Sham was much higher than that for the other sequences at baseline and throughout, while the mean for sequence Sham–Anodal–Cathodal was lower than the rest.Effects on anxiety and depression scores are summarized in No differences were seen in depression between treatment modalities.P=0.013).Analysis of effect on two summary domains of patient-reported health outcomes in the SF-36 questionnaire Physical Component Summary (PCS) and Mental Component Summary (MCS) showed that tDCS treatment had no effect on PCS or MCS. An increase in the number of stimulations was associated with an increased MCS  at 14 days. The upper 95% CI limit for this SD was 0.99; therefore, we can use this as a conservative estimate of the SD. We set the minimum clinically important difference as a reduction of 15% of our observed mean pain score of 6.4 after 14 days of sham treatment). A sample size of 13 patients would give 90% power to detect a difference of 1 point between two treatments with α=0.05.The overall sample size of this study was 24 subjects recruited and 21 followed through to the end of the study. This would suggest that this study is already large enough to detect a 15% change in pain scores in the overall trial but that sample size for the proportional analysis based on responder vs nonresponder subgroups has not been reached.As our pilot study was already larger than the calculated sample size for a definitive study, and our CI estimates indicate that all differences were significantly lower than the minimum clinically important difference of 1 point, the results of this pilot study do not support the need for a larger definitive study using the same stimulation parameters and the same electrode configuration.Efforts have been directed toward better defining the precision of current application in tDCS, and advances in high-definition tDCS montage configurations may provide a more focal stimulation to the M1 cortex. Likewise, utilization of alternative parameters, such as transcranial alternating current stimulation or online remote confirmation of electrode placement, may enhance the design of future experiments. It does show that patients can quickly be acquainted with using these devices and home-based trials are both feasible and realistically achievable.


Background: Adjuvant chemotherapy for breast cancer (ACBC) has been associated with fatigue, pain, depressive symptoms, and disturbed sleep. And, previous studies in non-cancer patients showed that melatonin could improve the descending pain modulatory system (DPMS). We tested the hypothesis that melatonin use before and during the first cycle of ACBC is better than placebo at improving the DPMS function assessed by changes in the 0–10 Numerical Pain Scale (NPS) during the conditioned pain modulating task (CPM-task) (primary outcome). The effects of melatonin were evaluated in the following secondary endpoints: heat pain threshold (HPT), heat pain tolerance (HPTo), and neuroplasticity state assessed by serum brain-derived neurotrophic factor (BDNF), tropomyosin kinase receptor B, and S100B-protein and whether melatonin’s effects on pain and neuroplasticity state are due more so to its impact on sleep quality.Methods: Thirty-six women, ages 18 to 75 years old, scheduled for their first cycle of ACBC were randomized to receive 20mg of oral melatonin (n = 18) or placebo (n = 18). The effect of treatment on the outcomes was analyzed by delta (Δ)-values (from pre to treatment end).Results: Multivariate analyses of covariance revealed that melatonin improved the function of the DPMS. The Δ-mean (SD) on the NPS (0–10) during the CPM-task in the placebo group was −1.91 [−1.81 (1.67) vs. −0.1 (1.61)], and in the melatonin group was −3.5 [−0.94 (1.61) vs. −2.29 (1.61)], and the mean difference (md) between treatment groups was 1.59 ; TrKB md = 0.61  and S00B-protein md = −8.27. However, melatonin’s effect on pain and the neuroplastic state are not due to its effect on sleep quality.Conclusions: These results suggest that oral melatonin, together with the first ACBC counteracts the dysfunction in the inhibitory DPMS and improves pain perception measures. Also, it shows that changes in the neuroplasticity state mediate the impact of melatonin on pain.Clinical Trial Registration:www.ClinicalTrials.gov, identifier NCT03205033. Chemotherapy treatment for breast cancer has been associated with fatigue, pain, depressive symptoms, and disturbed sleep . Even inIn vitro studies revealed that melatonin resists microglial cytotoxicity by suppressing apoptosis and inhibiting the activity of NF-κB  activity, a transcription factor found within neurons and glial cells . NF-κB rof NF-κB . Also, sof NF-κB .BDNF has been positively correlated with the potency of the DPMS . Also, iOverall, this set of evidence suggests that the benefits of neuroprotective effects of melatonin can counteract the neurotoxic effects induced by adjuvant chemotherapy for breast cancer (ACBC) on neuroplastic mechanisms involved in the pathophysiology of pain associated with chemotherapy. Thus, we tested the hypothesis that supplementing patients with melatonin before and during the first cycle of ACBC is better than placebo. We tested the hypothesis that melatonin use before and during the first cycle of ACBC is better than placebo to improve the DPMS function assessed by changes on the 0–10 Numerical Pain Scale (NPS) during the conditioned pain modulating (CPM) task (primary outcome). Melatonin’s effects were evaluated in the following secondary endpoints: heat pain threshold (HPT), heat pain tolerance (HPTo), and the neuroplasticity state assessed by serum BDNF, TrkB, S100B-protein, and whether melatonin’s effects on pain and the neuroplasticity are due more so to its impact on sleep quality.http://www.clinicaltrials.gov/  before inclusion of the first patient. We obtained oral and written informed consent from all patients before participating in this study. The identified data related to interventions and primary outcomes will be available upon request to interested to Caumo W (Wcaumo@hcpa.edu.br) with no time restriction. Flow of this study is presented in This randomized, double-blinded, placebo-controlled trial was approved by the Institutional Review Board of Hospital de Clínicas of Porto Alegre , and it was registered on Inclusion criteria: females scheduled for their first cycle of ACBC one month following lumpectomy or mastectomy. Exclusion criteria: patients with previous chemotherapy, patients planned for neoadjuvant chemotherapy, or those with prior or other concurrent malignancies. Also excluded were patients with a history of melatonin allergy, sleep apnea, diabetes, autoimmune disease , decompensated liver cirrhosis, severe kidney disease, epilepsy, cerebrovascular stroke, body mass index above 35 kg/m2, pregnant or breastfeeding, and a predictable likelihood of poor compliance.Patients were selected from the Mastology and Oncology Service at HCPA, a public tertiary teaching Medical School. Females aged 18 to 75 years with the capacity to read and write were selected. f2 = 0.35) to compare melatonin and placebo by multivariate analyses of covariance (MANCOVA), with two predictors in a 1:1 ratio, the estimate indicated a sample size of 32 for a power of 80% and an α of 0.05. Considering possible dropouts, we increased the sample by 12%, and the final sample size comprised of 36 patients (18 per group).We estimated the sample size based on previous studies that assessed melatonin’s effect on the DPMS measured by the change on the NPS during the CPM-task . AccordiWe used a randomly selected block sizes of 8 and 6. Thirty-six women were allocated to receive melatonin or placebo, an allocation of 1:1. Before the recruitment phase, randomization was computer generated by two investigators uninvolved in the patients’ assessments. Envelopes containing the allocated treatment were prepared, sealed, and numbered sequentially. The envelope was opened following the sequence of numbers registered in the envelope after the participant consented to participate in the trial. Following the conclusion of treatment, we assessed the effectiveness of the blinding protocol by asking patients to guess which treatment they each received .Patients were instructed to take 20 mg of oral melatonin or placebo daily approximately 1 h before bedtime. Melatonin capsules were produced using crystalline melatonin with a certificate of purity  by a compounding pharmacy. The tablets of melatonin and placebo were physically identical. Assessments to confirm adherence to treatment included: i) Pill counting during the study period. ii) Patient diaries were kept in order to record if they failed to use the medication. iii) Patients were encouraged to remain on melatonin throughout the ten days of treatment.All assessments were conducted by two independently trained research personnel to apply psychophysical pain measurements. The timeline of assessments is presented in The treatment effect on primary and secondary outcomes were evaluated by the Δ-value, defined by measurements at treatment end minus values at baseline. Changes in the NPS during the CPM-task assessed the function of the DPMS (primary outcome). The secondary outcomes were the changes produced by treatment in the following measures: HPT, HPTo, BDNF, TrkB, S-100B-protein.QST was the method utilized in the assessment of HPTs using the method of limits with a computer Peltier-based device thermode (30 × 30 mm) (× 30 mm)  that wasHPTo is the temperature induced by the QST to induce the maximum pain tolerated, with a ceiling of 52°C.DPMS was evaluated by the changes on the NPS ranging from 0 (no pain) to 10 (worst pain imaginable). The CPM was induced by a heterotopic noxious stimulus administered concurrently with a QST enough to produce a pain score of 6/10. The conditioned pain modulation (CPM) test was provoked by immersions of the nondominant hand into cold water (00C) for 1 min. During the CPM-task, subjects were asked to rate the pain induced by a pre-defined thermal stimulus to produce a score of 6/10 on the NPS, then 30 seconds later the heterotopic stimulus with cold-water hand immersion was performed. The CPM was defined as the difference between the average pain rating on the NPS before and after cold water immersion.Neuroplasticity state biomarkers were evaluated using serum levels of BDNF, TrkB, and S100B collected in plastic tubes and centrifuged for 10 min at 4,500 rpm at 4°C in a −80°C freezer for further BDNF and TrkB assays. Serum-mediator concentrations were determined using BDNF , TrkB , S100B , and enzyme-linked immunosorbent assay kits in accordance with the manufacturer’s instructions.Beck Depression Inventory is a questionnaire composed of 21 multiple-choice questions with four options each (0–3). The total BDI score ranges from 0–63; higher scores indicate a higher degree of depressive symptoms . The PSQI is a self-reporting questionnaire that comprises 19-items to assess the quality of sleep and identifies sleep disorders  before and after treatment.t-tests for continuous variables and utilization of the Mann-Whitney non-parametric test. To control the inter-individual variability, existing imbalances between groups, and baseline differences of the DPMS function assessed using the NPS, HPT, HPTo, BDNF, TrkB, and S100B protein, we used the mean differences [delta(Δ)-values (at treatment end minus baseline)] to identifying the real changes in psychophysical and laboratories tests in each patient , were based on independent sample  patient . It reco patient . Also, a patient . So, it 25–75) were observed to be at 10  vs. 9 , P = 0.35, in the melatonin and placebo group, respectively. We observed that melatonin treatment reduced the severity of adverse effects as the median and interquartile (Q25–75) was 7  vs. 12.5 , P = 0.01, in the melatonin and placebo group, respectively.The characteristics of the participants are presented in t = -4.14, df = 33.57; P < 0.001]. The mean on the NPS during the CPM-task at T0, T1 and the Δ-value is presented in The efficiency of the DPMS assessed by the change on the NPS during the CPM-task increased 43.5% from T0 to T1 in the melatonin group, whereas it decreased 93% in the placebo group  with the adjustment for multiple comparisons is presented in l = 0.56 Table 3AThe Δ-values of means (Δ-means) of each group (mean at treatment end minus mean before treatment) and the mean difference between the melatonin vs. placebo group, with their respective confidence interval  compared using MANCOVA and adjusted for multiple comparisons showed that the melatonin reduced the serum levels of the neuroplasticity markers. Melatonin’s effect reduced the (Δ)-means of the serum neuroplasticity marker in placebo vs. melatonin The Δ-BDNF was 1.87 (7.17) vs. −20.44 (17.17), respectively, and the md = 22.31 [(95% CI = 13.40 to 31.22)]; TrKB md = 0.61  and S00B-protein md = −8.27. However, it was observed that melatonin compared to placebo increased both the HPT  and HPTo , respectively.These findings confirm the benefits of melatonin compared to placebo prior to and during the first cycle of ACBC by counteracting the neurotoxic effects on the inhibitory function of the DPMS evaluated by the change on the NPS during the CPM-task. Melatonin also increased the HPT and HPTo, while reducing the serum levels of the neuronal and astrocyte neuroplastic markers . The analysis showed that the effect of melatonin on the DPMS and the neuroplasticity state was not related to its impact on sleep quality.The novelty of this study was to reveal that melatonin may counteract processes related to ACBC that produces dysfunction in the inhibitory DPMS and in the neuroplastic state. These findings corroborate our previous results of melatonin’s effect on the DPMS in fibromyalgia patients  and provAlthough extensive literature supports the relationship between poor sleep quality and chronic pain, this relationship has been comprehended as a vicious cycle . AccordiThis study indicates that melatonin’s effect improved of the DPMS function, as well as reduced serum levels of BDNF. These results are in line with evidence from previous studies on chronic pain using melatonin, as serum BDNF was found to be reduced in patients with endometriosis , while iOther additional mechanisms to explain the neuroprotective impacts of melatonin’s ability to counteract the neurotoxicity of ACBC include anti-apoptotic, anti-inﬂammatory, and antioxidant effects . Indeed,via BDNF or glial cell-derived neurotrophic factor activation  demonstrated that blinding was guaranteed, since the rate of patients of the melatonin group believed to have received placebo, or vice-versa, was very similar. Further, our objective surrogate biomarkers and psychological measurements are less susceptible to bias. Hence the unblinding issue is unlikely to have affected our conclusions. Third, a positive effect of melatonin was to reduce the adverse effects due to ACBC. Likewise, 20 milligrams of melatonin or lower as an adjuvant to cancer care with and without chemotherapy reduced asthenia, leucopenia, nausea and vomiting, hypotension, and thrombocytopenia . HoweverIn conclusion, these results suggest that oral melatonin together with first ACBC counteracts the dysfunction in the inhibitory DPMS and improves pain perception measures. Also, it shows that changes in the neuroplasticity state mediate the impact of melatonin on pain.The datasets generated for this study are available on request to the corresponding author.wcaumo@hcpa.edu.br) with no time restriction.This randomized, double-blinded, placebo-controlled trial was approved by the Institutional Review Board of Hospital de Clínicas of Porto Alegre . We obtained oral and written informed consent from all patients before participating in this study. The identified data related to interventions and primary outcomes will be available upon request to interested to WC  Committee for the Development of Higher Education Personnel (CAPES PNPD [Grant to 2015)]. (ii) National Council for Scientific and Technological Development [(CNPq (Research grant: IT 302345/2011-6 and WC 30 1256/ 201 3-6)]. (iii) Hospital de Clínicas de Porto Alegre (HCPA) Research Fund (FIPE: 14-0701). (iv) Foundation for Research of the State of Rio Grande do Sul (FAPERGS). (v) Studies and Projects Financing Agency (FINEP: 1245/13).The present research was funded The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


However, the tables should have shown data for n = 42 chronic pain patients and n = 42 matched healthy controls. The corrected In the original article, there was a mistake in Additionally, there was a mistake in the legend for *education refers to 0 = no degree, 1 = lower secondary education, 2 = secondary school, 3 = A-levels, 4 = university degree; **on an 11-point Numerical Rating Scale  on the day of testing.“SD: Standard deviation; ADS-K: General Depression Scale - Short form; †The total amount of participants reporting different pain syndromes. In brackets, only the corresponding main pain category of each participant is listed.”Lastly, in the original article, there was an error. The number sense performance of patients with vs. without opioid medication, was compared using the same incorrect sample size as mentioned above.Results, Experimental Tests and Questionnaires, Clinical pain assessment, and number sense.A correction has been made to the n = 13; M = 4.7, SD = 1.7, t(40) = −0.542, p = 0.591] and position marking  compared to patients without opioid medication .”“Finally, the role of opioid medication on number sense performance was evaluated, suggesting that patients with opioid medication performed equally well on both number naming [The authors apologize for these errors and state that they do not change the scientific conclusions of the article in any way. The original article has been updated.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Chronic pancreatitis is a progressive and persistent inflammatory disease resulting in pancreatic insufficiency leading to diabetes and steatorrhea. Abdominal pain is the most debilitating feature and is often refractory to treatment. Medical management with adequate analgesia and replacement of pancreatic enzyme supplements is the first line in management of chronic pancreatitis. Surgery is reserved for those who fail medical management. The choice of surgical procedure and timing of surgery is a topic of debate.The objective of this study was to analyze surgical safety along with short- and long- term outcomes of Frey’s procedure for patients suffering from chronic pancreatitis.This was a retrospective review of cases of chronic pancreatitis who underwent Frey’s procedure from 2016 January to 2019 February at Tribhuvan University Teaching Hospital. Demographics, intraoperative findings, perioperative outcomes, and short- and long-time outcomes were analyzed.Total of 26 patients  underwent Frey’s procedure in the study period. Alcohol was etiology in six patients while the majority (76.9%) were nonalcoholic. Half of the patients had tropical pancreatitis. Intractable pain was present in all cases along with pseudocyst in three and pseudoaneurysm in one case. The mean preoperative Izbicki scores were 53.4 ± 17.6. Six patients had diabetes and two patients had steatorrhea. Major complications were seen in 11.5% of cases while mortality was in one patient. The median duration of the hospital stay was seven days. Over a median follow up of 17 months , there were significantly lower pain scores postoperatively and 92% were pain-free. Only one new case of diabetes developed postoperatively.Our early experiences suggests that Frey’s procedure can be a safe option for patients with chronic pancreatitis, with acceptable perioperative morbidity with adequate pain relief without worsening of pancreatic endocrine and exocrine function. Chronic pancreatitis (CP) is defined as an inflammatory disease of the pancreas characterized by persistent and often progressive fibrosis and irreversible morphological changes, leading to epigastric pain and/or exocrine and endocrine insufficiency , 2. ClasThe management of CP requires multidisciplinary approach involving pain management specialists, gastroenterologist, radiologist, surgeons, dietitian and psychiatrists. Gastroenterologists usually opt for endoscopic treatment before considering surgical treatment as it is less invasive and without major complications. Endoscopic treatment is warranted in patients with CP who have intraductal stones in the region of the pancreatic head, main pancreatic duct (MPD) stricture, and symptomatic pseudocyst .As endoscopic treatment requires frequent hospital admissions, inadequate pain relief, increasing the risk opioids dependence and most importantly rural located populations, surgical option was preferred more often as compared to repeated endoscopic therapy. Nepal has a great geographical diversity and health system in outside of capital (Kathmandu) is yet to develop properly. It is crucial to understand that patients from rural areas won’t come for repeat endoscopy and therefore surgery was chosen at first hand.Surgical treatment in CP includes either resection or drainage or hybrid procedures. The degree and extent of MPD dilatation along with gland morphology will guide in choosing the optimal operative procedure. A metanalysis showed Frey’s procedure had shorter operative duration along with less overall perioperative complications as compared to pancreatoduodenectomy (PD) and the Beger procedure , 4. AlsoThe main objective of this study was to evaluate the safety and outcome of the Frey’s procedure for patients with CP at Tribhuvan University Teaching Hospital (TUTH), a Nepalese tertiary referral center.n = 4), Beger with Bern modification (n = 1) and PD (n = 7).This was a retrospective review of prospectively collected data of surgically treated cases of CP who underwent Frey’s procedure from January 2016 to February 2019 at the department of surgical gastroenterology, Tribhuvan University Teaching Hospital (TUTH), Kathmandu, Nepal. All patients who underwent Frey’s procedure and had minimum of 3 months of follow-up available were included in this study. Exclusion criteria were procedure other than Frey’s procedure, lost to follow-up and inadequate data. Total of 38 cases of CP was operated in the above-mentioned duration out of which 26 underwent Frey procedure. Besides Frey, other surgical procedures were Partington- Rochelle procedure  combined with drainage of the MPD using longitudinal pancreatojejunostomy [CP was diagnosed based on history and imaging. Abdominal contrast-enhanced computed tomography (CECT) was routinely performed in all cases for diagnosis and characterization of the disease process. Magnetic resonance cholangiopancreatography (MRCP) was performed to further delineate ductal anatomy if CECT was inadequate. As the availability of endoscopic ultrasound (EUS) is new to our institute as well as country, EUS was not as part of routine investigation. Histopathological diagnosis of CP was confirmed postoperatively except in one case who underwent EUS and biopsy before preceding to surgery. Endoscopic resonance cholangiopancreatography (ERCP) and stenting were performed in that same case. Postoperative analgesia was given by epidural or parenteral route or both followed by oral analgesia usually from the third postoperative day. Third-generation cephalosporin was routinely used as prophylactic at time of induction, which later on continued for 3 days in the postoperative period. Further continuation of antibiotics depends on patient clinical status or features of sepsis or preexisting cholangitis. Deep vein thrombosis prophylaxis used in selected high-risk cases. All patients were encouraged for intensive spirometry in the postoperative period. Drain usually taken out after day three after the drain fluid amylase value along with clinical judgment and drain amount. Patients were discharged after assumption of oral diet, after removal of drain and being fully mobilized.Clinical characteristics and short – and long – term results were evaluated. Preoperative variables include demographics, etiology, duration of symptoms, the intensity of pain, analgesic requirements, presence of diabetes mellitus or steatorrhea, presence of pseudocyst, biliary obstruction (jaundice), duodenal obstruction, pseudoaneurysm, prior treatment. Similarly, intraoperative findings like the presence of bulky head, ductal stones, calcifications, and any complications were confirmed as of prior imaging. Also, operative findings like MPD diameter, intraoperative blood loss and operative time noted.The pain had been evaluated by Visual analog scale (VAS), analgesia group and Izbicki score. VAS had been defined as a scale of 0 to 100, where 0 indicated no pain and 100 indicated severe, unbearable, continuous pain. Analgesia group had been defined as class 1, acetaminophen or Nonsteroidal anti-inflammatory drugs (NSAIDS); class 2, acetaminophen and weak opioid combinations (like tramadol); and class 3, strong opiates  as per the World Health Organization analgesic ladder , 12. It Perioperative events had been defined as per Clavien Dindo classification system of surgical complications . Major cAll patient had been followed up for a minimum of 3 months. Long term follow-up for a minimum of 12 months was available in 21 patients. None of the patients was lost to follow up. Though follow up interval is not uniform as many patients belong to rural distant areas and they intended to follow up depending on suitability, information regarding postoperative status was possible on phone calls. Pain intensity along with analgesic requirement was evaluated again with VAS score and Izibcki score on each follow-up along with the development of new-onset DM or steatorrhea. Any readmission or intervention needed in the postoperative period were also noted and occurrence of any postoperative events was managed as per institutional practice.Statistical Package for the Social Sciences (SPSS) version 24.0 software . Quantitative data were expressed as mean ± standard deviation or median (whenever applicable) and range. Statistical difference between preoperative and postoperative pain scores was examined using the paired t-test. The Chi-square test or Fisher’s exact test were used to compare categorical variables, as appropriate. P values of < 0.05 were considered statistically significant.Statistical analyses were performed using Over the defined period, a total of 26 cases of CP underwent Frey’s procedure out of a total of 38 CP cases at TUTH.n = 14, 53.9%; female, n = 12, 46.2%; mean age, 27.9 ± 8.1 years, range 17–52 years). Females were predominant in tropical CP group as compared to male in non-tropical CP. Except the gender difference, there was no significant difference in between the groups  in regards to age, preoperative BMI, preoperative VAS score, preoperative Izbicki pain score, preoperative diabetes and preoperative indigestion. Though, the median duration of symptoms was shorter in tropical group as compared to non-tropical group, it was not statistically significant difference. Three patients (11.5%) were smoker while six patients (23.1%) were regular alcohol consumer. Etiology of CP were alcoholic  and nonalcoholic . Out of nonalcoholic, the majority were classified as tropical CP , recurrent biliary in one case while remaining were idiopathic . All patients had preoperative CECT while MRCP was performed only in five cases. EUS and ERCP were performed in only one patient who had undergone endoscopic stenting for pain relief.Table n = 8, 30.8%) and class III . The type of analgesia was based on the maximum level of analgesia used at any point of life after being diagnosed as CP. Average preoperative VAS pain score was 70 ± 15.5 (30–90) while the average preoperative Izbicki score 53.4 ± 17.6 (17.5–85). Diabetes mellitus was present in six cases (23.1%) while features of indigestion were evident in two cases (7.7%). No patients had jaundice, features of biliary obstruction or duodenal obstruction in our series.Similarly, Table All relevant intraoperative details are shown in Table Similarly, perioperative outcomes are shown in Table Table p-value < 0.01). Also, there was no significant worsening of endocrine (DM) or exocrine (steatorrhea) function.Comparison of pain score and the function of the pancreas is described in Table Owing to the geographical difficulties, and financial constrain, providing one time treatment which is long lasting along with acceptable perioperative morbidities, surgery is definitely the cornerstone of management of CP in counties like Nepal. It is well known that Frey procedure can be very helpful in patients with CP where the benefit of one time treatment outweighs the perioperative complications along with the uncertainty regarding multiple need of endoscopic therapy along with financial burden. The results of our study suggests that Frey’s procedure is safe and causes relief of symptoms in patients with CP. Ninety-two percent of patients were pain-free with significantly lower pain scores postoperatively while major complications developed in 11.5% cases without worsening of exocrine and endocrine functions. So Frey’s procedure can be considered a choice of treatment of CP in countries like Nepal.Alcohol is the most common etiology of CP worldwide. However, there is a form of idiopathic early-onset CP prevalent in tropical countries like India and the southern part of Nepal popularly known as tropical pancreatitis. Tropical Pancreatitis (TP) is a juvenile form of chronic calcific, nonalcoholic pancreatitis . It is sRegarding pain score, both VAS and Izbicki had higher mean values in tropical pancreatitis in comparison to non-tropical and hence tropical pancreatitis got operated earlier than non-tropical. Mechanism of pain is poorly understood but traditionally is caused by pancreatic ductal hypertension and pancreatic parenchyma hypertension. Newer theories include activation of intrapancreatic nociceptors, hypertrophy, and inflammation of intrapancreatic nerves and abnormal pain processing in the central nervous system . Long-stThe current standard of management of painful CP is multidisciplinary step-up approach as published in HaPanEU guideline in 2017 . Step upMajor complications were seen in 11.5% and one patient (3.8%) had mortality in our series and is compared with various published reports of morbidity (7.5–22.0%) and mortality (0–3.2%) , 21. NonThe intensity of pain as assessed by VAS score and Izibcki score had decreased significantly following Frey’s. In our study only two patients require readmission due to exacerbation of pain and were managed with intravenous analgesics and rest of patients were comfortable without the need of opioids analgesia in the postoperative period over a median follow up of 17 months. Results of pain relief are 92% compared to other reports , 22. FreESCAPE  trial conducted by the Dutch Pancreatitis Study Group will give a clear answer to the optimal timing of surgery in CP . This raFrey involves local resection of the head of the pancreas so it prevents the inadequate decompression of the pancreatic ducts in the head of the pancreas unlike the Partington–Rochelle pancreatojejunostomy. About 90% long term pain relief has been reported after the Frey’s procedure , 22. AlsRajendra VKP reported the effectiveness of Frey’s procedure in tropical pancreatitis from India in reducing pain along with significant improvement in health-related quality of life . Long teSo Frey’s procedure could be the standard operation for CP patients with dense calcification or stones in the head of that pancreas and dilation of the MPD and can be performed for almost all patients with CP and dilation of the MPD without suspicious of malignancy. The Frey’s procedure is safe and pancreatic endocrine function is preserved. However, a proper selection of patients is the most integral part of achieving good results.This study has some limitations. First being retrospective in nature and this review was only of the patients operated. So other patients under medical management and endoscopic treatment were not evaluated. Also, outcomes have not been compared between Frey’s and other procedures. Though follow-up was available in all cases, fix interval of follow-up were not possible. Also, long term follow-up involving a larger sample size is needed to conclude the best surgical procedure. Median follow up of 5 years will help to assess the long term outcome of Frey’s procedure in making it the choice of treatment.Our early experiences suggests that Frey’s procedure can be a safe option for patients with CP, with acceptable perioperative morbidity with adequate pain relief without worsening of pancreatic endocrine and exocrine function. However, further prospective controlled studies with long-term follow-up are needed to make definitive conclusion.


The World Health Organization’s (WHO) guidelines for cancer pain management were intentionally made simple in order to be widely implemented by all physicians treating cancer patients. Referrals to pain specialists are advised if pain does not improve within a short time. The present study examined whether or not a reasonable use of the WHO guideline was made by non-pain specialists prior to referral of patients with cancer-related pain to a pain clinic.Cancer patients referred to a pain specialist completed several questionnaires including demographics, medical history, and cancer-related pain; the short-form McGill Pain Questionnaire (SF-MPQ); and the Short Form Health Survey SF-12. Data from referral letters and medical records were obtained. Treatments recommended by pain specialists were recorded and categorized as “unjustified” if they were within the WHO ladder framework, or “justified” if they included additional treatments.Seventy-three patients  aged 55 years  participated in the study. Their pain lasted for a mean of 6 (1–192) months. Mean pain intensity scores on a 0–10 numerical rating scale were 7 (2–10) at rest and 8 (3–10) upon movement. Most patients complied with their referring physician’s recommendations and consumed opioids. Adverse events were frequent. No significant correlation was found between the WHO analgesic medication step used and mean pain levels reported. There were 63 patient referrals (85%) categorized as “unjustified,” whereas only 11 patients (15%) required “justified” interventions.These findings imply that analgesic treatment within the WHO framework was not reasonably utilized by non-pain specialists before referring patients to pain clinics. The treatment of cancer-related pain is a primary goal for healthcare professionals. Pain affects two-thirds of patients with advanced cancer, reaching intensities of moderate-to-severe in more than half of them.5A principal concept of the WHO guideline, the “three steps analgesic ladder,” refers to the pharmacological management of cancer-related pain . It emph8Regardless of the growing understanding of cancer pain mechanisms and treatment, and despite increasing efforts to disseminate the WHO guideline worldwide, only little progress has been made during the past three decades in terms of reducing the prevalence and severity of cancer-related pain.10International as well as several national guidelines on cancer-related pain have been published and disseminated in Israel.The study was approved by the Ethics Committee at Rambam Health Care Campus in Haifa, Israel .Both hospitalized patients and out-patients with cancer who were referred to a pain specialist for cancer-related pain management were recruited for the study. Inclusion criteria for the study consisted of being aged 18 and above; having a referral for cancer-related pain or cancer treatment-related pain; having the ability to understand the study aims; and giving written informed consent to participate in the study. Patients were excluded if their pain diagnosis was not related to cancer or cancer treatment, as determined by a pain specialist.Patients were asked to complete a questionnaire upon arrival to their consultation with a pain specialist at the Institute of Pain Medicine at Rambam Health Care Campus. The questionnaire consisted of questions regarding their demographic data; medical and cancer history; intake of pain medications during the previous 24 hours; medication-induced adverse effects; minimal, mean, and maximal pain intensity at rest and movement during the previous 24 hours ; and the number of pain exacerbation episodes during the previous 24 hours. Data were also obtained on the recommended treatments noted in their physicians’ referral letters and in the medical records of hospitalized patients. Study participants also completed the short-form McGill Pain Questionnaire (SF-MPQ)Pain specialists were informed that their patients’ data would be collected for the study. However, to avoid treatment selection bias, the specialists were not informed of the study’s aim.The normality of data distribution of each variable was examined with the Shapiro–Wilk normality test. Data are presented as median (range) and/or mean± standard deviation (SD) for demographic variables, cancer parameters, pain intensities, SF-MPQ and SF-12 scores, and adverse effects.The pain specialists’ consultations were retrospectively analyzed and categorized as “unjustified” or “justified” based on their treatment recommendation. Referrals to pain specialists were categorized “unjustified” if the specialists’ treatment recommendations remained within the WHO ladder framework and included one or more of the following four recommendations: (1) changing drug dose or rotating to an alternative drug within the same analgesic ladder step; (2) adding a rescue medication; (3) moving to the next step of the WHO analgesic ladder; or (4) adding an adjuvant treatment. Referrals were categorized “justified” when specialists’ recommendations fell outside of the WHO ladder in the following cases: (1) an invasive procedure; (2) administration of a systemic drug other than an opioid ; (3) adding medical cannabis, which can only be carried out in Israel by a pain or palliative care specialist or by an oncologist; or (4) referral to radiation therapy, radio-isotope therapy, etc.Complete data were available for 73 patients . Their median age was 55 years .Cancer type was heterogeneous, with breast cancer being the most common type (18%), followed by lung (14%) and colon (11%) cancer. Additional cancer types included pancreatic cancer, female reproductive cancers, and others .Fifty-two patients (68%) had metastatic spread of their cancer to the following body regions: bones (26%), lungs (13%), liver (12%), other sites in the abdominal cavity (12%), lymph nodes (8%), and additional sites (10%). Notably, some patients (13%) had more than one metastatic site. The median cancer duration was 24 months .Pain duration was 6 months . Pain intensity at rest (NPS) was 7  and at movement 8 . Fifty-one patients (72%) experienced pain exacerbation episodes. The number of episodes was 2 . Although a majority of patients had fewer than 5 such episodes, four patients had 20, and one reported 30 pain exacerbation episodes.The most frequent pain location involved the extremities in 36 patients (47%) and included focal extremity pain, pain radiation from another site, or in the form of distal neuropathy. The second most common sites involved the chest and the abdomen in 32 (42%), followed by upper and lower back in 30 (39%), pelvis in 19 (25%), and head and neck in 8 (10%). Most patients had more than one painful site.Pain type was specified by a pain specialist as nociceptive in 52 patients (71%), neuropathic in 20 patients (27%), and visceral in 18 (25%). Hence, about one-quarter of the patients had a mixed type of pain. Pain was attributed to the cancer itself in 53 patients (73%) and to cancer treatment in 20 patients (27%).Seventy-one patients (97%) completed the SF-MPQ, and all patients completed the SF-12 questionnaire. The median MPQ score was 25 . The median SF-12 physical component score was 23 , and the median mental component score was 35 .At the referral evaluation, 56 patients (77%) were treated with opioids. Strong opioids alone were used by 51 patients, weak opioids were used by two, and a mixture of a strong and a weak opioid by three patients.Of those using opioids, long-acting oral or transdermal preparations were used by 43 patients (77%), immediate-release opioids by 41 (73%), and rapid-onset opioids (ROOs) by two patients (3%) only. An additional 13 patients were treated by parenteral opioids, typically intravenous morphine infusions with or without rescue boluses. Non-steroidal anti-inflammatory drugs (NSAIDs) or cox-2 inhibitors (Coxibs) were taken by 12 patients (16%), simple analgesics by 32 (44%), and adjuvant drugs by 20 (27%). Herbal cannabis was used by five patients (7%). Almost all patients (88%) took the analgesic medications as recommended by their referring physician. In contrast, four patients took analgesics not prescribed by their caregiver, on their own initiative. An additional five patients were only partially compliant with their physician’s recommendations and avoided using specific analgesics or took them at a lower dosage than was recommended.The most frequently reported adverse effects in our study are summarized in According to the administered medications, 69 patients (94%) were retrospectively categorized into one of the three WHO analgesic ladder steps. Three patients received only herbal cannabis, and one used only adjuvant drugs and therefore did not match any of the three formal steps. Fifty-four of the patients (74%) were compatible with step 3 of the ladder; three patients (4%) with step 2; and 12 patients (16%) with step 1. However, the mean pain intensity at rest and movement of the patients in all three WHO categories was 6 or above. This is also true for the four patients who received only adjuvant drugs or medical cannabis .r=0.31, P=0.807) or at movement .Spearman’s coefficient correlations were used to test relationships between the WHO analgesic step medications used and the mean pain intensities. No significant correlations could be demonstrated either at rest  were diagnosed with neuropathic pain by a pain specialist. Of them, only 10 patients received adjuvant treatments in an attempt to treat the neuropathic pain.All patients were referred to pain specialist consultation by their physicians: 49 (67%) by hospital physicians; 24 (33%) by community physicians; 17 (23%) by internists; 15 (21%) by family practitioners; 10 (14%) by gynecologists; nine (12%) by oncologists; and six (8%) by surgeons. The remaining 16 (22%) patients were referred by other physicians from various medical fields.For 62 (85%) patients, recommendations remained within the WHO ladder as follows: 24 patients  were advised to change opioid analgesic dose; in four patients (5%) an adjuvant medication was added; 10 patients (14%) were advanced to the next WHO analgesic step; and eight patients (11%) were given a rescue medication. Sixteen patients (22%) required two simultaneous changes within the ladder (i.e. both an increasing opioid dose and the addition of a rescue medication).n=5) or in combination with other changes in the medical regimen within the WHO ladder. One patient was advised to undergo a nerve block, and another received a prescription for methylphenidate to manage opioid-induced excessive daytime sleepiness. As mentioned earlier, a recommendation for cannabis use in Israel can only be completed by a specialist in pain, palliative medicine, or oncology. Since none of the patients for whom medical cannabis was recommended were referred by an oncologist, their referrals were considered “justified.” Similarly, methylphenidate is not registered in Israel for reducing opioid-induced sedation, and its administration requires a special recommendation from a pain specialist.The remaining 11 patients (15%) required an intervention not included in the WHO ladder: in nine patients (11%) medical cannabis was prescribed either alone  were advised to receive a treatment that is not part of the WHO analgesic ladder. Most of these patients (six patients) were referred from a community clinic by their family practitioner. The rest were referred from the hospital by an internist (three patients), an oncologist (one patient), or an occupational physician (one patient). Conversely, the majority of referrals (85%) were categorized as “unjustified.”Although cancer pain represents a complex medical condition, the WHO analgesic ladder has a simple and logical structure, allowing widespread implementation by all physicians caring for cancer patients. Validation studies have shown that up to 73% of cancer-related pain can be reduced when the WHO guideline is properly implemented.Congruent with the literature,The main finding in the present study is that, contrary to our hypothesis, 85% of patients were advised by a pain specialist a treatment within the framework of the WHO three-step ladder. This implies that the pharmacological management of cancer-related pain provided by the WHO guideline was not reasonably utilized by non-pain specialists who care for such patients. A second important finding is that patients exhibited high compliance with the analgesic treatment prescribed by their referring physicians. Close to 90% of the patients reported analgesic consumption that was consistent with the analgesic regimen documented in their referral letter or in their hospital medical record. This is despite the high percentage of reported adverse effects by the patients in our study. These two findings imply that patients’ concerns about treatment side-effects are not the main reason for the observed suboptimal treatment in the patients. Rather, the main problem seems to be an incomplete implementation of the WHO guideline by non-pain specialist physicians. As shown in the literature,20Several additional factors point to significant gaps in the implementation of the WHO guideline for the management of cancer-related pain. First, 16 patients 22%) did not receive opioids although their reported mean pain was moderate to severe (with an NPS of 6 or greater). These patients were treated by either simple analgesics, an adjuvant drug, or medical cannabis. Notably, in recent years medical cannabis has emerged as a new player in the cancer-related pain treatment armamentarium and can be prescribed for this indication in at least some countries, although evidence for its effectiveness is still anecdotal at best.% did not25It is important to refer patients to pain specialist consultations if pain is not improving within a short time or if patients are experiencing intolerable side-effects of analgesia. However, given the poor availability of pain clinics, attempts to optimize analgesic treatment based on the WHO guideline are expected to be made prior to such referrals. Although all referred patients in the present study were treated prior to their referral, such treatment was not successful, and 85% of the patients were provided treatment by their pain specialist that is within the WHO ladder framework. We have not investigated the reasons for this poor adherence to the WHO guideline. Several providers’ barriers have been identified in the past, such as poor pain assessment, insufficient knowledge about pain treatments, and prioritizing cancer treatment over pain treatment.20However, patient-related barriers such as fears or unwillingness to take pain medicationOur findings and those of othersOne possible limitation of our study is the lack of a follow-up session for evaluating the outcome of the pain specialists’ recommendations. Seemingly, this could have resulted in a more comprehensive clinical picture. However, this was clearly beyond the scope of this study, which focused primarily on referrals to pain clinic consultations rather than on the outcome of these consultations.The pharmacological management of cancer-related pain provided by the WHO guideline was not reasonably utilized by non-pain specialists in our study. This is despite the high compliance of patients with the analgesic treatment prescribed by their referring physicians. Future studies should aim at a better understanding of cancer-related pain management barriers and improving pain management guideline adherence.


The purpose of this study was to evaluate the clinical outcomes of treatment of non-odontogenic atypical orofacial pain using botulinum toxin-A.This study involved seven patients  who had non-odontogenic orofacial pain  and visited the Seoul National University Bundang Hospital between 2015 and 2017. All medication therapies were preceded by botulinum toxin-A injections, followed by injections in the insignificant effects of medication therapies. Five of the seven patients received intraoral injections in the gingival vestibule or mucosa, while the remaining two received extraoral injections in the masseter and temporal muscle areas.In five of the seven patients, pain after botulinum toxin-A injection was significantly reduced. Most of the patients who underwent surgery for dental implantation or facial nerve reconstruction recovered after injections. However, the pain did not disappear in two patients who reported experiencing persistent pain without any cause.The use of botulinum toxin-A for the treatment of non-odontogenic neuropathic orofacial pain is clinically useful. It is more effective to administer botulinum toxin-A in combination with other medications and physical therapy to improve pain.The online version of this article (10.1186/s40902-018-0159-z) contains supplementary material, which is available to authorized users. When pain occurs in the orofacial area, it is very important to identify and diagnose its cause. Orofacial pain can be classified into temporomandibular joint disorders, muscle disorders, angiogenic pain, neuropathic pain, cardiogenic pain, and atypical facial pain .Tissue or nerve damage causes inflammation, and the initial inflammatory response plays a very important role in the onset of neuropathic pain. Especially, the structures of the trigeminal nervous system are placed in a closed space, so that the pressure generation due to inflammation can cause nerve damage. After the apparent trauma experience such as dental surgery such as implant, extraction, orthognathic surgery, endodontic treatment, and fracture, it continues to suffer from burning pain. The neuropathic pain, which is presumed to be caused by trauma, is called painful traumatic trigeminal neuropathy and is distinguished from classical trigeminal neuralgia , 2.Atypical facial pain may be defined as a diffuse pain deep within the tissue, which persists without an obvious disease or cause. Pain patterns range from dull, tingling, to sharp or throbbing pain. The duration of the pain may range from intermittent to persistent. This type of pain is difficult to treat because symptoms vary and its cause is unclear. In some cases, medications such as analgesics, tricyclic antidepressants, and anticonvulsants are effective, but in many cases, medication alone is not sufficient for treatment. Recently, treatment with botulinum toxin-A has been introduced .Clostridium botulinum. It plays a role in suppressing extracellular release of synaptic vesicles by acting on the nerve endings at the neuron junctions of mammals. It also affects autonomic nerves by inhibiting the release of acetylcholine from nerve junctions in the sweat glands and smooth muscles. Based on this principle, botulinum toxin-A can be applied for the treatment of neuromuscular diseases, especially focal tension disorders or seizures. Although botulinum toxin-A is very effective for direct muscle relaxation, it may also modulate pain through peripheral nociceptors by inhibiting the exocytosis of various neurotransmitters [Botulinum toxin is a type of neurotoxin produced by smitters , 4. The Among the patients who visited the dental clinic of Seoul National University Bundang Hospital between 2015 and 2017, we studied seven patients who complained of non-odontogenic orofacial pain. Five patients were diagnosed with painful traumatic trigeminal neuropathy and two others were diagnosed with atypical orofacial pain. This study was conducted with the approval of the Institutional Review Board of the Seoul National University Bundang Hospital (IRB No. B-1802-453-107). All patients were treated with medication and physical therapy. However, these methods were either ineffective or had minimal effect. Botulinum toxin-A (BTX-A) injection therapy was therefore performed. The age, sex distribution, diagnosis, and treatment methods and course of patients were summarized using their medical records  was administered twice a day for 2 weeks, and the symptoms were alleviated, but the tightened pain on the bilateral sides of the nose persisted. The dose was therefore increased for another 2 weeks. Most of the pain was alleviated, but the pain that occurred when she moved her mouth was still present. She therefore received the medication for two additional weeks. The frequency and severity of the pain was reduced, but side effects such as headache and dizziness occurred; therefore, 10 mg of amitriptyline  was administered once a day before bedtime and capsaicin ointment  was applied locally at the site of the pain. A stent was made in the maxilla and capsaicin ointment was applied to the stent for 20 min. This stent was to be worn three times a day. However, no improvement was observed and the pain worsened. Thus, 100 mg of Neurontin  was administered three times daily. Electric acupuncture stimulation therapy -8® ) was performed four times at 2-week intervals, but the burning and throbbing pain on the upper lip and tenderness of the palatal area remained. The medication of the patient was changed to 300 mg of Trileptal  which was administered twice daily. Although there was a slight improvement, she still complained of persistent pain. In the upper part of the mucosa, 250 U of Dysport  was injected. As a transient side effect, food was spilled due to the unnatural movement of the lips at meal time, but the pain was significantly reduced. Three months later, the second injection of Dysport 250 U was performed. Thereafter, the pain was alleviated and the treatment was terminated.A 52-year-old woman was referred to an oral and maxillofacial surgeon because of intermittent severe pain in the left facial area after facial nerve reconstruction during plastic surgery. During examination, the patient complained of general stiff pain in the facial region including the left zygoma, masseter, and temporomandibular joint area. There were also symptoms of excessive salivation in the left cheek. The patient was diagnosed with painful traumatic trigeminal neuropathy. Taking Trileptal did not improve the pain; therefore, it was replaced with Neurontin. At the same time, 25 U of Innotox  was injected into the left masseter and physical therapy was performed. Physical therapy was performed five times with Sellalux , a low-level laser treatment unit, every 1 to 2 months. Two weeks after the first injection, the pain was significantly reduced. However, it persisted in the lower left eye and around the zygoma. Six months later, the second injection was performed with the same dose. Even though almost all the pain was alleviated, she still complained of pain in the stylomastoid foramen area under her left ear. Three months later, a third injection of 25 U of Innotox was performed and the pain was markedly reduced to a tolerable level.All seven patients involved in this study were women with ages from 52 to 71 years. Five of the seven patients complained of pain in the oral mucosa, vestibule, teeth, and around the lips. Two of the patients complained of facial pain in the zygoma, masseter, and temporal muscle. The primary drugs used were carbamazepine, oxcarbazepine, gabapentin, pregabalin, amitriptyline, and nortriptyline. Physical therapy with either soft laser or EAST was performed additionally in most cases. Two of the patients were treated with Tegretol (carbamazepine), six were treated with Trileptal (oxcarbazepine), six were treated with Neurontin (gabapentin), two were treated with Lyrica , one was treated with amitriptyline, and three were treated with Sensival (nortriptyline). Laser therapy was performed on all seven patients, while EAST was performed on two patients. Of the seven patients, five patients complained of oral pain. They received injections at the affected site. The remaining two patients received injections outside the oral cavity, specifically in the masseter and temporal muscles. Three types of BTX-A were used: Meditoxin , Innotox, and Dysport , and the number of injections ranged from at least once to a maximum of three times every 3 months. In five of the patients with painful traumatic trigeminal neuropathy, pain was significantly reduced after BTX-A injection. The neuropathic pain in all patients who received implant surgery or facial nerve reconstruction was improved. However, in two patients with atypical orofacial pain who complained of persistent pain without any causative factors, the pain did not disappear after the injection. These patients were referred to the anesthesiology department for stellate ganglion block (SGB), but this treatment was not effective either , analgesics, antidepressants, sedatives, muscle relaxants, and steroids. It is most important to diagnose the type and cause of facial pain and select the appropriate medication , 8. PhysIn this study, the dose of BTX-A used varied from 20 to 200 U. These differences in injection dose are due to differences in the conversion ratio of BTX-A. An onabotulinum toxin-A (ONA) to abobotulinum toxin-A (ABO) conversion ratio is approximately 1:3 to 1:4. And a new botulinum toxin type A (NBoNT) to onabotulinum toxin-A (ONA) conversion ratio is approximately 1:1. Meditoxin and Innotox are included in new botulinum toxin type A (NBoNT). Dysport is included in abobotulinum toxin-A (ABO) , 18. AllCombining BTX-A injections with other treatments for traumatic trigeminal neuropathic pain that does not respond to conventional medication and physical therapies may be clinically useful. However, it is important to explain the complications of this treatment such as transient facial asymmetry to patients and to perform the treatment only after obtaining the patient’s consent.Additional file 1:Case form and result of data. (XLSX 13 kb)