Background and objectives: There is a lack of good quality evidence regarding the effectiveness of transcutaneous electrical nerve stimulation (TENS) for chronic musculoskeletal pain, including chronic low back pain. High quality randomised controlled trials (RCTs) have been called for to establish effectiveness over and above placebo and some guidance has already been offered regarding the design of such trials. This article expands the discussion regarding the design of future TENS trials. There is qualitative evidence of the complexity of TENS as an intervention which should be considered in future TENS evaluations. This complexity includes multiple benefits reported by patients, depending on their chosen contexts of TENS use. The ideal content and delivery of support for patients to optimise TENS use also lacks consensus. There is no evidence that a TENS education package has been designed to support the complex set of behaviours and choices which experienced users suggest are required to optimise TENS benefits. Finally, clinical and research outcomes have not been contextualised and related to the specific strategies of use. Conclusions: We suggest that research is required to develop consensus about the content and delivery of training in TENS use for patients who live with pain, informed by the experience of patients, clinicians, and researchers. Once a consensus about the content of TENS training has been reached, there is then a need to develop a TENS training course (TTC) based on this content. An effective and acceptable TTC is needed to develop the knowledge and skills required to optimise TENS use, supporting patients to build confidence in using TENS in everyday life situations with the aim of reducing the impact of chronic pain on function and quality of life. Further research is required to extend the evidence base regarding appropriate, contextualised TENS patient-reported outcomes. The prevalence of moderate-to-severe non-cancer chronic pain across Europe has been reported as 19% ,3. Non-sTENS is a low voltage electrical stimulation aiming to relieve pain by activating sensory nerves. It can also be used to stimulate motor nerves when it is known as “acupuncture-like” TENS . TENS isThere is evidence to support the hypoalgesic effect of TENS from laboratory studies on humans using experimentally induced pain and from animal studies using tissue damage paradigms . The larTENS is recommended as an adjunct to core treatments for pain relief by the NICE guideline for osteoarthritis . There iThere is qualitative evidence of the complexity of TENS as an intervention ,8,22 whiOne example of contextualised use is to help with pain-related insomnia. Some users may only apply TENS at night to help them manage their pain to help them to fall asleep. One experienced TENS user explained:“…I’ve got to try and go to sleep with it on as well, so if I can’t go to sleep I will put the TENS on and go to sleep.”This reduction in pain-related insomnia might be overlooked in a TENS evaluation, despite it being the primary benefit for some patients, unless we enquire specifically about the context in which TENS is used.Another example of contextualised use is during a pain exacerbation, or pain flare-up. One experienced TENS user chose not to use TENS during everyday life as she was too busy to fit the device, and made indirect reference to the psychological benefits of TENS by describing the emotional suffering which she experienced during a pain flare:“Yeah, they’re awful. Those days I’ve just, I have said I would rather not be there on my bad days ‘cause they are just awful. They are horrible.”The modest pain relief which she reported helped to ameliorate this suffering. She completed a pain Visual Analogue Scale to indicate pain severity of 100 mm during a flare (the anchor described “pain as bad as possible”). She indicated a reduction in pain severity to 84 mm as a result of TENS use. This 16% pain reduction falls into the 10–20% pain reduction indicated by IMMPACT  as a minTENS training is often very poorly described within the literature, such that its content and delivery cannot be replicated. There are currently no national or international standards or guidelines to inform the delivery of TENS training in clinical settings, and we suggest that research is required to develop consensus about the content and delivery of training in TENS use for patients who live with pain, informed by the experience of patients, clinicians, and researchers. This consensus will inform the development of training and is needed to address fidelity issues in any future TENS evaluation to avoid research waste .There is currently no evidence that a TENS education package has been designed to support the complex set of behaviours and choices which experienced users suggest are required to optimise TENS benefits. A review of the literature identified only one study that considered TENS education . Only diInformation provided to patients before they try TENS Guidance to support the first trial of TENS Support offered to facilitate the development of skills (behaviours) to optimise TENS use in everyday lifeHow to reinforce these skills as part of TENS training, for example modelling, goalsetting, or record keeping using a TENS practice diary.Optimal follow-up support for patients, following the initial teaching session and trial.A consensus is required about several related issues:Once a consensus about the content of TENS training has been reached, there is a need to develop a TENS training course (TTC) based on this content. An effective and acceptable TTC is needed to develop the knowledge and skills required to optimise TENS use, supporting patients to build confidence in using TENS in everyday life situations with the aim of reducing the impact of chronic pain on function and quality of life. The effectiveness of TENS training can be determined by evaluating its impact on a patient’s confidence to use TENS in everyday situations. Provision of effective TENS training would provide a firm foundation for the assessment of the clinical effectiveness of TENS. TENS training is normally delivered face to face, either in one-to-one clinical encounters, or in group-based training courses for patients. An alternative approach of an internet-delivered TTC has potential benefits for healthcare services, as it can be delivered at a much lower cost than multiple individual or group appointments. Internet-based training would also support the delivery of a multi-centre trial. The burden of chronic musculoskeletal pain including the cost to healthcare has been outlined above, and optimised training in TENS has the potential to reduce this burden for patients, and therefore indirectly benefit healthcare by reducing costs such as GP consultations and medication prescriptions. An online course can also improve the accessibility of the training for patients in remote localities, reducing the need for patients to travel long distances for face-to-face appointments. Patients who cannot or prefer not to access an internet-based course could be offered face to face support from a clinician, but this clinician can optimise their TENS teaching by learning from the internet-based course designed for potential TENS users.Further research is required to extend the evidence base regarding the TENS patient-reported outcomes. Qualitative research has generated knowledge about the use and benefits of TENS reported by patients with chronic musculoskeletal pain ,8,22. ExThe findings of the in-depth qualitative work might not be representative of a wider population of TENS users, but a large-scale survey would expand our knowledge of the patient-reported benefits of TENS. The survey could be designed to generate data about the frequency of context-based, strategic use of TENS amongst this wider population and the survey questions could be informed by the existing in-depth qualitative research findings ,8. Data In summary, there is a lack of good quality evidence regarding the effectiveness of TENS for managing chronic pain and CLBP. TENS is a complex intervention with patient-reported outcomes dependent on their chosen context of use. There is no consensus regarding the optimal delivery of TENS training in a clinical or research setting. We argue that a broader research programme is required that will carry out the foundational research required to address these issues.


To identify predictors in patient profiles, and to develop, internally validate, and calibrate prediction models for the persistence of self-reported orofacial pain at the 6-month and 12-month follow-up in patients with myofascial pain.A cohort of 63 adult patients with moderate to severe chronic myofascial pain was included. Patient and disease characteristics at baseline were recorded as potential predictors. Patients` presence or absence of improvement of orofacial pain at follow-up was considered the outcome. Binary logistic regression analyses were used to develop the models. The performance and clinical values of the models were determined.Forty-three percent and 30% of the patients had persistence of orofacial pain at 6-month and 12-month follow-up, respectively. Pain elsewhere, depression, parafunctional activities, and mandibular function impairment (MFI) were significantly associated with persistence of the pain at 6-month follow-up, whereas depression, parafunctional activities, and MFI were significantly associated with persistence of the pain at 12-month follow-up. Both of the models showed good calibration and discrimination, with shrunken area under the curve (AUC) values of 0.73 and 0.76, respectively. The clinical added predictive values for ruling in the risk of the persistence were 0.30 and 0.31, respectively, and those for ruling it out were 0.25 and 0.20, respectively.Potential predictors for prediction of the persistence of self-reported orofacial pain at follow-up were identified. The calibration, discrimination, and clinical values of the models were acceptable.The models may assist clinicians in decision-making regarding the improvement of orofacial pain of individual patients during follow-up in clinical settings. Temporomandibular disorders (TMD) consist of a group of disorders involving the temporomandibular joint (TMJ), masticatory muscles, or both . MyofascUp to 80% of the patients with complaints of myofascial pain seek for consultation to get relieved from this pain . This hiTo date, several treatment options are available for myofascial pain, such as counseling , physiotThe aims of the present study were to (1) identify potential predictors in patient profiles that allow prediction of the persistence of self-reported orofacial pain in the follow-up in patients with myofascial pain; and (2) develop, internally validate, and calibrate models for prediction of the persistence of the pain during follow-up.The TRIPOD  statement  was follThe study was designed as a cohort study with patients’ self-reported chronic orofacial pain scores as the observational outcomes during a 12-month follow-up. Each patient received a total of six questionnaires at six predetermined time points. The questionnaires were given at patients’ first visit to the clinic and directly after completion of treatment. Then other questionnaires were sent to the patients at 3, 6, 9, and 12 months after the completion of treatment by mail. Patients were reminded by receiving a telephone call or a mail if the questionnaires were not returned within 2 to 3 weeks.The cohort at baseline involved 63 patients with complaints of pain in the orofacial region lasting for at least 1 month, who were referred by their dentist or medical practitioner to the clinic for Orofacial Pain and Dysfunction of Academic Centre for Dentistry Amsterdam (ACTA) between October 2003 and November 2006.The inclusion criteria for the patients at their first visit to the clinic were as follows: (1) Patients were diagnosed with myofascial pain according to the RDC/TMD ; (2) PatThe patients were treated by clinicians experienced in the management of TMD patients. The provided conservative  treatments included counseling, occlusal splint, physiotherapy, cognitive behavior modification therapy, or combinations of these treatment modalities.The decision to end the treatment was based on the assessment of whether further treatment would be of substantial benefit to the patient. The initial treatments indicated for patients were proposed by the clinician who performed the intake examination. For uncomplicated patients, the type of treatment indicated for patients was discussed between the clinician who performed the intake examination and a senior consultant for a final decision. More complex patients were discussed in the multidisciplinary team , and the staff represented in the multidisciplinary team made the final decisions together. The final decision-making of the senior consultants and the multidisciplinary team was based on their expertise, experience, and knowledge as well as on patients` specific signs and symptoms in both physical and psychological aspects. Whether patients were regarded as uncomplicated or complicated was judged by clinicians based on their clinical expertise, experience, and knowledge as well as on patients` specific signs and symptoms.Pain elsewhere in the body was recorded with the question “Do you feel pain elsewhere in your body?” The answer was classified as “no” or “yes.”Previous treatment for complaints of TMD pain was recorded. The answer was classified as “no” or “yes.”Somatization over the past week was assessed with the somatization scale of the Dutch version of the Symptom Check List (SCL-90) , 20. TheDepression over the past week was assessed with the depression scale of the Dutch version of the SCL-90 , 20. ThePain chronicity (duration of TMD pain complaints) of each patient was recorded in months.Parafunctional activities of patients in the past 3 months were assessed with a three-scale oral parafunction questionnaire , 21. ThePatients’ chronic orofacial pain intensity was assessed with the CPI scale . The CPIPatients’ mandibular function impairment was assessed with the Mandibular Function Impairment Questionnaire (MFIQ) . The MFIPatients’ demographic characteristics, including gender and age, were recorded at baseline as predictors. Besides, the following predictors were also recorded at baseline as the potential predictors of the models Table :Pain elsChanges in orofacial pain intensity at 6-month or 12-month follow-up compared with the baseline were regarded as the outcome for the two models. The outcome was binary. In the present study, if a patient’s CPI score did not decrease by 37.9% or more at follow-up compared with the CPI score at baseline, the orofacial pain of the patients in the follow-up was considered to be “persistent.” Otherwise, orofacial pain was considered to be “improved.” This cutoff was based on the study conducted by Emshoff et al. . This cum = 30 imputed datasets with 10 iterations and used predictive mean matching (PMM) for imputing the missing values. All the potential predictors, the CPI score directly after completion of treatment, and the CPI scores at 3, 6, 9, and 12 months after the completion of treatment were included in the imputation model.Multiple imputation technique was used to handle the missing values via SPSS software 25 . We created P > 0.25 were removed from the models and predictors with P ≤ 0.25 remained in the model) was used to assess the association of potential predictors with the outcomes and to develop the prediction models. A less stringent threshold of P value of 0.25 was used in selection and exclusion of potential predictors because this could avoid that some important predictors were excluded inappropriately from the models due to large P values caused by small sample size [Multivariable binary logistic regression analysis with backward-selection (predictors with Regression models developed and tested in the same (derivation) dataset not always provide fully accurate predictions. That is, higher predictions will be found too high while low predictions will be found too low . TherefoP value of > 0.10 in the HL test indicates that the model fits the observed data [Calibration is defined as the agreement between predicted outcomes and observed outcomes . It reflved data .Discrimination is defined as the ability to differentiate between those with and those without the outcome event . The outThe optimal cutoff for the predicted probability of the models was defined as the predicted probability with the maximum sum of sensitivity and specificity in the receiver-operating characteristic curve (ROC).Clinical values of the models at the optimal cutoffs for predicted probability were assessed with the prevalence, positive predictive values (PPV), and negative predictive values (NPV) of patients with persistence of orofacial pain at follow-up. PPV was defined as the number of patients with persistence of orofacial pain as observed in reality in patients with persistence of orofacial pain as predicted by the models. NPV was defined as the number of patients with improvement as observed in reality in patients with improvement as predicted by the models. The (added) predictive value of the models at the certain cutoff for predicted probability for ruling in an increased risk in the persistence of orofacial pain at the follow-up was defined as PPV minus prevalence, while that for ruling out an increased risk in the persistence of orofacial pain was defined as NPV minus complement of prevalence.P) of persistence of orofacial pain is predicted with the following formula:β is the shrunken regression coefficient of a predictor in the models.We developed a clinical rule for prediction of the persistence of orofacial pain in the present study as to provide an estimate for individual patients of their absolute risk of the persistence of orofacial pain at the follow-up. For the final multivariate logistic regression models, the probability  using the package “psfmi.” The discrimination, calibration, and scoring system of the models were assessed based on the shrunken regression coefficients.For binary logistic regression analyses, the prediction model is considered reliable if the number of events per variable (EPV) is ≥ 10 , 35. TheAt baseline, a total of 63 patients were included in the analyses. Of these, 55 (87%) were female. The mean age was 40.4 ± 14.0 for women and 40.6 ± 14.2 for men. There were 51 and 45 patients included in the study at 6-month and 12-month follow-up, respectively. Forty-five percent (23/51) and 28% (13/45) of the patients were documented as persistence of orofacial pain at 6-month and 12-month follow-up, respectively.As for the missing values, MFI at baseline, the outcome variable at 6-month follow-up, and the outcome variable at 12-follow-up were missing in 4, 12, and 18 patients, respectively, while the remaining variables had no missing values. After multiple imputation, 43% (27/63) and 30% (19/63) of the patients had the persistence of orofacial pain at 6-month and 12-month follow-up, respectively. Table P > 0.25 with removal) for prediction of the persistence of orofacial pain at 6-month and 12-month follow-up. In the multivariate analysis, patients with the presence of pain elsewhere, more depression, more parafunctional activities, and less mandibular function impairment at baseline were more likely to have persistence of orofacial pain at 6-month follow-up, whereas patients with more depression, more parafunctional activities and less mandibular function impairment at baseline were more likely to have persistence of orofacial pain at 12-month follow-up.Table The shrinkage factors of the models for persistence of orofacial pain at 6-month and 12-month follow-up were 0.81 and 0.89, respectively. The AUCs of the models at 6-month and 12-month follow-up were 0.77 : 0.50 0.92) and 0.78 (95% CI: 0.47 0.94), respectively. The shrunken AUCs of the models at 6-month and 12-month follow-up were 0.73 and 0.76, respectively, which indicated that the discrimination of the two models was acceptable. The calibration plots showed that there was a good fit between the predicted probability and actual probability of the persistence of orofacial pain in both models, considering that most plotted dots in both models were lying close to the diagonal line  of persistence of orofacial pain in the patients group. If a patient is predicted to have an improvement in the follow-up based on the models, the posterior probability of the improvement in the follow-up of this patient can be increased by 0.25 and 0.20, respectively, when compared with the prevalence of improvement of orofacial pain in the patients group. This indicated that the clinical added values of the two models were sufficient for both ruling in and out the persistence of orofacial pain at follow-up.Only patients with a moderate to severe orofacial pain were included in the development of the prediction models. This was because in case patients with myofascial pain only have very mild or even no obvious self-reported chronic orofacial pain at baseline, there is almost no ability to have a significant improvement in orofacial pain in the follow-up. Those patients are very likely to be classified into the event group incorrectly even though they are not bothered by pain, thus making the models biased. Therefore, the two models in the study can only be applicable for patients with myofascial pain with moderate to severe self-reported chronic orofacial pain at baseline.P value of 0.25 was used in modeling for selection and exclusion of potential predictors. However, in order to lower the risk that some unimportant predictors were included inappropriately in the model when the cutoff of P value is increased, all the potential predictors were pre-screened by clinicians based on their clinical experience and knowledge before data analysis. Therefore, in this way, the negative consequence caused by small sample size could be reduced to a large extent.A smaller number of events relative to the high number of predictors are a common limitation for multivariable prediction models. The present study did not meet the criterion of EPV ≥ 10 , 35 becaAnother limitation of the study is that the models were not developed based on the most recent data. Instead, the data were obtained between 2003 and 2006. Changes in practice over time can limit the application of the prediction models . For exaIn the future, researchers are suggested to use a larger sample size to externally validate and update the models based on the most recent samples of patients with myofascial pain before the models can be applied in clinical practice.Pain elsewhere, depression, parafunctional activities, and mandibular function impairment at baseline were important predictors for the persistence of orofacial pain at 6-month follow-up, whereas depression, parafunctional activities, and mandibular function impairment at baseline were important predictors for the persistence of orofacial pain at 12-month follow-up. The multivariate logistic regression models for prediction of persistence of orofacial pain at follow-up were developed and internally validated. The added predictive values may be sufficient for both ruling in and ruling out the persistence of orofacial at follow-up. The models may assist clinicians in decision-making regarding the improvement of orofacial pain of individual patients during follow-up in clinical settings. External validation of the model is needed before considering the implementation of the model in clinical practice.


Over 50% of the 34 million people who suffer from diabetes mellitus (DM) are affected by diabetic neuropathy. Painful diabetic neuropathy (PDN) impacts 40–50% of that group (8.5 million patients) and is associated with a significant source of disability and economic burden. Though new neuromodulation options have been successful in recent clinical trials (NCT03228420), still there are many barriers that restrict patients from access to these therapies. We seek to examine our tertiary care center  experience with PDN management by leveraging our clinical database to assess patient referral patterns and utilization of neuromodulation. We identified all patients with a diagnosis of diabetes type 1 (CODE: E10.xx) or diabetes type 2 (CODE: E11.xx) AND neuralgia/neuropathic pain (CODE: M79.2) or neuropathy (CODE: G90.09) or chronic pain (CODE: G89.4) or limb pain (CODE: M79.6) OR diabetic neuropathy (CODE: E11.4) who saw endocrinology, neurology, and/or neurosurgery from January 1, 2019, to December 31, 2019. We then determined which patients had received pain medications and/or neuromodulation to divide the cohort into three groups: no treatment, conservative treatment, and neuromodulation treatment. The cohorts were compared with chi-square or one-way ANOVA with multiple comparisons to analyze the differences. A total of 2,635 PDN patients were identified, of which 700 received no treatment for PDN, 1,906 received medication(s), and 29 received neuromodulation . The patients who received pain medications for PDN visited neurology more often than the pain specialists. Of the patients that received neuromodulation, 24 had seen neurology, 6 neurology pain, and 3 anesthesia pain. They averaged 2.78 pain medications prior to implant. Approximately 41% of the patients in the conservative management group were prescribed three or more medications. Of the 1,935 treated patients, only 1.5% of the patients received neuromodulation. The patients on three or more pain medications without symptomatic relief may be potential candidates for neuromodulation. An opportunity, therefore, exists to educate providers on the benefits of neuromodulation procedures. Diabetic neuropathies result from a multifaceted disease process and impact approximately half of diabetic patients worldwide . The paiDespite the availability of effective management strategies, the utilization of such treatments remains unclear. Given the complex nature of the diabetic neuropathic pain and the range of treatment options available, it is likely that an optimized and coordinated multi-disciplinary approach, such as neuromodulation, will be superior to management by any single discipline. Such a coordinated approach will benefit by focused evaluation of treatment utilization and efficacy to refine the future strategies and access to care.This study aimed to explore the referral patterns of patients with PDN at a tertiary academic medical center with a multi-disciplinary pain practice to determine the utilization of neuromodulation as a treatment for neuropathic pain. We aimed to compare no treatment, conservative treatment, and neuromodulation treatment cohorts based on the diagnoses, referrals, therapeutic strategies, and/or demographic information.To determine our experience with the referral patterns of patients with diabetic neuropathy, we partnered with our clinical bioinformatics team. Specifically, all patients who saw endocrinology, neurology, and/or neurosurgery at our tertiary care center between January 1, 2019, and January 2, 2020, were identified using the billing codes for a diagnosis of diabetes mellitus (DM) type 1 (CODE: E10.xx) or DM type 2 (CODE: E11.xx) AND neuralgia/neuropathic pain (CODE: M79.2) or neuropathy (CODE:G90.09) or chronic pain (CODE: G89.4) or limb pain (CODE: M79.6) OR diabetic neuropathy (CODE: E11.4). The notes of patients were manually examined to verify the diagnosis of painful neuropathy. We applied a custom bioinformatics platform to data from our clinical data warehouse to investigate the experience of our tertiary care center with PDN management based on referral patterns .All patient charts were reviewed for usage of conservative treatment by gabapentin, pregabalin, duloxetine, venlafaxine, topiramate, carbamazepine, oxcarbazepine, amitriptyline, nortriptyline, lidocaine, capsaicin, and cannabis. Patients who underwent neuromodulation received either intrathecal therapy, SCS, or DRGS, which was determined using Current Procedural Terminology (CPT) codes . The study was approved by our institutional review board (IRB).Following the retrieval of all patient identification numbers by CPT codes, data mining was performed to elicit the patient diagnoses, laboratories, medications, and provider meetings using SQL queries on the Albany Medical Center large data warehouse. Subsequently, a natural language processing algorithm was used to perform the text classification. We identified the patients with PDN diagnosis and confirmed by manual chart review. Finally, we retrieved all neuromodulation procedures performed and cross-referenced this list with these patients to enable separation into conservative treatment and neuromodulation cohorts.In our total and neuromodulation cohorts identified in the billing code search, we gathered demographic information on age, sex, and DM type. The patient visits to providers from endocrinology, general neurology, pain neurology (anesthesia), and/or neurosurgery were documented. The number of past and current prescribed pain medications per patient was recorded.t-tests, and chi-squares. The demographic data of the three cohorts were compared using chi-square, unpaired t-test, or one-way ANOVA with Tukey's correction for multiple comparisons. Data were analyzed using GraphPad Prism 8 . A p < 0.05 was considered to be statistically significant.Comparative differences in the utilization of various PDN treatment options were analyzed using correlation analyses, unpaired N = 5) and those with no data in their medical records were excluded (N = 106), leaving a total dataset of N = 2,635 patients for further analysis. The total included patient population was further separated into three cohorts: (1) no treatment (N = 700), (2) treatment with conservative/pharmacologic pain medications only , and (3) treatment with neuromodulation (N = 29). The three cohorts were compared on the basis of sex, age, diabetes status (DM type 1 or 2)  were treated for neuralgia/neuropathic pain, neuropathy, chronic pain, limb pain, or diabetic neuropathy at our center. Patients aged 18 years old or younger ( 1 or 2) , patient 1 or 2) , and pai 1 or 2) .CI of difference, adjusted p-value 2.061 [0.726–3.397], p < 0.001). Age was not statistically significant between untreated and neuromodulation cohorts. Sex and DM type differed using chi-square analysis between the no treatment and conservative treatment cohorts only . Patients prescribed three or more pain medications were more likely to be female  (p < 0.001). For the no treatment group, 651/700 (93.00%) patients carried a diagnosis of type 2 DM vs. 1,704/1,906 (89.40%) patients on the conservative management.Sex, age, and diabetes type (type 1 or type 2) among the three cohorts were compared . We dete< 0.001)  and were2 = 341.795, p < 0.001), neurology pain , and to anesthesia pain . Compared with no treatment patients, the conservative treatment patients more frequently saw endocrinology , neurology , anesthesia pain , and neurosurgery . Of the patients that received neuromodulation, 24 had seen general neurology, 6 pain neurology, and 3 anesthesia pain specialists.We applied our bioinformatics pipeline to delineate provider visits for the three treatment cohorts . Visits To identify a population of patients on the conservative pain management that may be candidates for neuromodulation therapy, we divided these patients into two groups: patients that were prescribed one–two medications and patients that were prescribed three or more medications. We chose three or more medications since this is typically the number of medications that the patients must fail to respond to in a neuromodulation clinical trial design. Patients who have tried multiple medications may be candidates for neuromodulation . In the Diabetes mellitus affects a substantial proportion of the global population 34 million) . Of thes4 millionWe identified a total of 2,635 PDN patients. Of these cases, 700 received no treatment for PDN, 1,906 received medication, and 29 received neuromodulation. Effectively, only 1.5% of the treated patients received neuromodulation over the 1-year period that we analyzed. A patient cohort referred to neurosurgery was more similar in age and sex to the conservative treatment cohort than the no treatment cohort.Using the criterion of patients that are on three or more pain medications without symptomatic relief, we stratified a group of conservatively treated patients as candidates for neuromodulation therapy. This benchmark is the typical for medication trial and failure prior to neuromodulation in a clinical trial design. Indeed, it is not atypical for chronic pain patients to be prescribed even 6–11 pain medications over time as reflected in our data. We identified nearly 41% of the conservatively treated patients having prescriptions for more than three pain medications. These patients were more likely to be female , 15 and Neuromodulation therapies are ever-expanding with increased efficacy and indications for long-term management of chronic pain. These advances are outpacing those new non-opioid pharmaceuticals for pain management and have lower potential for abuse. This study aimed to understand the number of potential candidates for neuromodulation and the providers they visited. Endocrinology appears to be referring patients adequately for PDN management based on their number of visits and the number of patients that go for neurology. Further, 24/29 patients came from neurology providers, in contrast to 5 that were seen by a pain neurology provider. An opportunity to partner with general neurology for care of these patients in neuromodulation exists. A potential exists for more than 40% additional patients to be referred. It should be noted, however, that these medications may have been prescribed for symptoms related to pain disorders other than PDN, such as headache or back/neck related symptoms. As we have no way of parsing that information, consideration of prescribed pain medications may aid in the identification of potential neuromodulation referrals.N = 2,635 total), the study is observational and future studies, therefore, should plan to prospectively evaluate the efficacy of neuromodulation for PDN. The study investigates a 1-year time period. The number of subjects in the neuromodulation cohort (N = 29) was small with respect to the no treatment (N = 700) and conservative treatment  cohorts, yielding lower statistical power. However, this low number also reflects the underutilization of neuromodulation therapy for PDN, and we establish a significant proportion of patients undergoing the conservative treatment as neuromodulation candidates. Many older patients with multiple comorbidities may have treatment failure but cannot take multiple medications due to poor tolerance to side effects or drug interactions, which may have impacted our results in these age groups. It will be informative in future studies that apply a modified bioinformatics data handling and analysis pipeline to document the temporal sequence of patient progression from one provider to another during management to determine the critical points where multi-disciplinary intervention can be optimized.Although our study discusses important findings on the medical management of PDN and the utilization of neuromodulation for PDN patients, there are several limitations. While a large sample size is used (We aimed to explore the referral patterns of PDN patients at our tertiary academic medical center that contains a multi-disciplinary pain practice to determine the utilization of neuromodulation as a treatment for neuropathic pain. The majority of patients with PDN were referred from endocrinology to general neurology, and 40% of those patients were on multiple medications and may be candidates of neuromodulation therapy. These results, therefore, warrant education of providers regarding the potential benefits of neuromodulation procedures.jpilitsis@yahoo.com.The datasets presented in this article are not readily available because the dataset generated and analyzed in the current study is comprised of private patient information, gathered from patient charts, and therefore is not publicly available. The anonymized dataset can be made available from the corresponding author upon reasonable request. Requests to access the datasets should be directed to The studies involving human participants were reviewed and approved by Institutional Review Board at Albany Medical Center. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.JP conceived and coordinated the study, provided patient care, directed chart review and analysis, and assisted in writing the manuscript. ZO, AH, AM, OK, and MD assisted in writing the manuscript. AM, ZO, and AH composed figures and tables. CA and VS provided patient care and patient data. AM, AH, MD, and OK performed chart review and statistical analysis. AH developed the bioinformatics pipeline for analysis of chart data. All authors contributed to manuscript editing and approved the final submission.JP is a consultant for Boston Scientific, Nevro, Medtronic, Saluda, and Abbott and receives grant support from Medtronic, Boston Scientific, Abbott, Nevro, NIH 2R01CA166379-06, and NIH U44NS115111. She is the medical advisor for Aim Medical Robotics and Karuna and has stock equity. VS is a consultant for Boston Scientific and Medtronic. CA is a consultant for Teva, Lilly, Allergan, Amgen, Novartis, and Flowonix. He provides research support to Teva and Allergan. He has stock in Pfizer. He is part of the Speaker's Bureau for Theranica, Tercera, Teva, Lilly, Allergan, Amgen, Novartis, and Flowonix. AH has stock equity in EEG Sense and Aviv Scientific. The remaining 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


To investigate the association of pain with frailty in patients with localized prostate cancer (PC) who underwent robot‐assisted laparoscopic radical prostatectomy (RARP).Between January 2017 and June 2019, we prospectively evaluated the geriatric 8 (G8) score, simplified frailty index (sFI), and numerical rating scale (NRS) of 154 patients with localized PC who underwent RARP at our institution. NRS was measured on preoperative day 0, postoperative days 1, 2, 3, and at discharge. Moderate to severe pain was defined as NRS ≥ 5, whereas frailty was defined as G8 ≤ 14. The primary objectives of this study were to investigate the effects of moderate to severe pain (NRS ≥ 5) on frailty, postoperative complications, and the use of analgesics after RARP. Our secondary objectives were the effect of frailty on postoperative complications and the use of analgesics.The median age of participants was 69 years. Of 154 patients, 37 (24%) and 61 (40%) were classified to have NRS ≥ 5 and G8 ≤ 14, respectively. Patients with NRS > 5 presented significantly association with G8 < 14, whereas they did not show the association with sFI, complication, or analgesics. Multivariate logistic regression analysis showed that G8 ≤ 14 was significantly associated with NRS ≥ 5. Frailty was not significantly associated with postoperative complications and analgesics.Frailty was significantly associated with moderate to severe pain after RARP, and might be a potential predictor of postoperative pain. Frail patients require individual care to avoid painful experiences. All participants provided written or verbal informed consent. The study was registered on the UMIN‐CTR (UMIN000038969).2.2This prospective observational study planned to enroll 180 patients within 30 months based on the annual number of RARPs performed in our hospital, accounting for a 15% withdrawal/refusal rate. No statistical sample size calculation was performed, because no previous evidence has been reported on the effect of frailty on postoperative pain. We enrolled 181 patients with localized PC who were treated at the Hirosaki University Hospital between January 2017 and June 2019. The inclusion criteria called for patients with localized PC who were treated with RARP. Procedures of RARP and standard pelvic lymph node dissection were performed using the basic technique described previously.2.3The patient variables evaluated at diagnosis were age, sex, Eastern Cooperative Oncology Group performance status (ECOG PS), serum prostate‐specific antigen (PSA), hypertension (HTN), cardiovascular disease (CVD), diabetes mellitus (DM), chronic respiratory disease (CRD), instrumental activities of daily living (IADL), the American Society of Anesthesiologists (ASA) physical status classification score, Gleason score, clinical stage, and D’Amico risk classification. Postoperative complications were evaluated using Clavien–Dindo classification.2.4We assessed frailty using the G8 screening tool and sFI . G8, which includes eight items in multiple geriatric assessment domains, was administered at the initial outpatient clinic visit. The G8 score ranges from 0 to 17, with a frailty cutoff of ≤14.2.5We used a numerical rating scale (NRS) for the quantitative evaluation of pain. NRS was measured on preoperative day 0, postoperative days 1, 2, 3, and at discharge as a self‐reported survey.2.6The anesthetic management and postoperative analgesia of patients was consistent and was not modified during this study. RARP was performed using general anesthesia, which consisted of remifentanil, ketamine, and propofol. At the end of the surgery, intravenous morphine (5‐10 mg) or fentanyl (2‐4 μg/kg) was administered as boluses for an opioid rotation. Thereafter, intravenous patient‐controlled analgesia using morphine (20‐30 mg/day) or fentanyl (400‐500 μg/day) with ketamine (20 mg/day) was administered to manage postoperative pain within 2 days. All patients used the same composition of patient‐controlled analgesia with a total volume of 50 ml for 48 hours.2.7The primary objectives of this study were to assess the effect of moderate to severe pain (NRS ≥ 5) on frailty, postoperative complications, and the use of analgesics after RARP. Secondary objectives were evaluating the effect of frailty on postoperative complications and the use of analgesics. The exploratory objectives included (1) the association between frailty and time‐dependent change of NRS, (2) the association between maximum NRS (maximum pain) and total NRS , (3) the optimal cutoff value evaluation of G8 for NRS ≥ 5 using the receiver operating characteristic (ROC) curve and area under the curve (AUC), and (4) the association between the G8 and sFI.2.8χ2 test. Quantitative variables were expressed as means ± standard deviation. The significance of between‐group differences was determined using Student's t test for normally distributed data or the Mann–Whitney U test for nonnormally distributed data. A P‐value < .05 was considered statistically significant. Odds ratio (OR) with 95% confidence intervals (95% CI) were calculated using the multivariate logistic regression model for NRS ≥ 5 after controlling for potential confounders including age, frailty (G8 ≤ 14), analgesic score, and any complications.Statistical analysis was performed with GraphPad Prism 7.00 , Bell Curve for Excel , and R 3.3.3 . Categorical variables were compared using Fisher's exact test or the 33.1P = .487). Also, the complication rate was not significantly different between the patients with and without PLND . The median total analgesic score in patients with NRS < 5 and those with NRS ≥ 5 was 2  and 1  (P = 0.451).Of 181 patients, we excluded six patients who were treated with open radical prostatectomy and 21 patients who did not provide any response to the NRS questionnaire. This left us with a total of 154 patients for the analysis. The median age, PSA, G8, length of hospital‐stay, ASA score, and analgesic score were 69 years, 8.74 ng/mL, 14 days, 2, and 2, respectively. The number of patients who experienced grade 1, 2, and 3 complications were 19 (12%), 4 (2.6%), and 1 (0.7%), respectively. Of the 154 study participants, 37 (24%) and 61 (40%) patients were classified to have NRS ≥ 5 and G8 ≤ 14, respectively. The median NRS on days 0, 1, 2, 3, and at discharge were 0, 3, 2, 1, and 0, respectively. Meanwhile, the median value of total pain (sum of NRS) was 6, and the number of patients with moderate to severe pain (NRS ≥ 5) was 37 (24%). The maximum value of NRS was observed on postoperative day 1 in 153 (99.3%) patients. There was no significant difference in background between patients with NRS < 5 and those with NRS ≥ 5 .Patients with NRS ≥ 5 were significantly associated with G8 ≤ 14 than those with NRS < 5 Figure , whereas3.3The G8 score was not significantly associated with postoperative complications Figure  and the 3.4R2 = .705, P < .001) . The optimal cutoff value of G8 for the NRS of ≥5 was defined as 14 with an AUC of 0.625 .The time‐dependent change in NRS scores between G8 > 14 and ≤ 14 and between sFI 0–1 and 2–5 was shown in Figure ) Figure . The lin) Figure  and betw) Figure  was very5 Figure . A G8 sc5 Figure . The lin4In this prospective observational study, we found that G8 ≤ 14 was an independent risk factor for postoperative moderate to severe pain after RARP. As our results suggested that use of analgesics and postoperative complications were not significantly different, these factors were potentially not associated with postoperative moderate to severe pain. Moreover, our results support the cutoff of G8 ≤ 14 for postoperative pain in patients with localized PC. To our knowledge, this is the first study to evaluate the effect of frailty on postoperative pain after RARP.P < .001). As frail patients do not have enough capacity to handle stress, they find it difficult to deal with painful postoperative experiences, which might be not as severe in patients without frailty. For this reason, intolerable pain may lead to difficulty in early ambulation and resumption of eating, thereby resulting in unfavorable postoperative outcomes for patients with frailty. Although longitudinal studies are required to help us understand the causal relationship between pain and frailty, pain might play a key role in frailty.The key finding of our study was that patients with frailty might be sensitive to pain than those without frailty. We speculate that patients with painful experiences such as complications may require greater amounts of analgesics compared with patients without severe pain or complications. However, total analgesic score and complication rate were not significantly different between patients with NRS < 5 and those with NRS ≥ 5. These results may suggest that NRS reveals not only physical pain, but also psychological pain. However, our analgesic score was not validated and further study is necessary to address this issue. A cross‐sectional study suggested that a higher level of frailty is associated with a higher risk of adverse physical and psychological health situations.n = 23 104) suggested that there was a significant association between frailty (modified frailty index [mFI]) and postoperative Clavien–Dindo IV complications after RARP.P < .005) in comparison with patients without frailty. Therefore, RARP was not recommended for patients with frailty because of worsening outcomes. These findings suggested that frailty might be a useful tool in identifying the optimal patients for surgical interventions. Our previous study revealed that frailty was significantly higher in patients with muscle‐invasive bladder cancer who underwent nonsurgical therapy than in those who underwent radical cystectomy .Although our study failed to show an association between frailty and incidence of postoperative complications after RARP, a previous study using the American College of Surgeons National Surgical Quality Improvement Program (ACS‐NSQIP) database  after RARP needs to debate. As the sFI was the comorbidity‐based frailty, it was suggested that the significant association of comorbidity‐based frailty tools with severe (Clavien‐Dindo grade IV or V) postoperative complications.κ = 0.381) among the three frailty tools.We observed no significant association between frailty in G8 and sFI. Although both tools were developed for frailty measurement, consensus between different frailty assessment tools remains controversial to date. Our previous study comparing the Fried phenotype (FP) frailty, G8, and frailty discriminant score indicated fair agreement , because our national insurance system covers hospitalization costs. We could not select hospital stay as a primary endpoint because of the universal insurance system used in Japan. Also, the sample size was not enough to evaluate longitudinal changes over time as well as the aspect of confounding introduced by repeated measurements. Despite these limitations, the study demonstrates the clinical value of frailty on postoperative pain in patients with RARP. Our results suggested that frailty is a key factor for pain management in clinical practice. Further study is necessary to validate our findings.The study limitations include the small sample size, selection bias, and unmeasurable confounding factors. We could not address the association of frailty with the type of pain because of data unavailability. The results may not be generalized to other countries because of racial and regional differences. For example, the median duration of hospital stay was not significantly different between patients with NRS < 5 and those with NRS ≥ 5 (15 vs 14 days, In conclusion, frailty was significantly associated with moderate to severe pain after RARP and might be a potential predictor of postoperative pain. Frail patients require individual care to avoid painful postoperative experiences.The authors have no conflicts of interest to declare.Conception and design: Shingo Hatakeyama, Chikara Ohyama; Acquisition of data: Masaki Momota, Osamu Soma, Naoki Fujita, Kyo Togashi, Tomoko Hamaya, Itsuto Hamano, Teppei Okamoto, Hayato Yamamoto, Tohru Yoneyama, Takahiro Yoneyama, Yasuhiro Hashimoto; Analysis and interpretation of data: Masaki Momota, Shingo Hatakeyama, Itsuto Hamano; Drafting of the manuscript: Masaki Momota, Shingo Hatakeyama; Critical revision of the manuscript: Chikara Ohyama; Statistical analysis: Shingo Hatakeyama, Tohru Yoneyama; Funding: Shingo Hatakeyama, Chikara Ohyama, Tohru Yoneyama; Administrative, technical, and material support: Tohru Yoneyama.


Patients with substance use disorders are more likely than those without to have a self-directed hospital discharge, putting them at risk for poor health outcomes including progressing illness, readmissions, and death. Inadequate pain management has been identified as a potential motivator of self-directed discharge in this patient population. The objective of this study was to describe the association between acute pain and self-directed discharges among persons with opioid-related conditions; the presence of chronic pain in self-directed discharges was likewise considered.We employed a large database of all hospitalizations at acute care hospitals during 2017 in the city of Philadelphia to identify adults with opioid-related conditions and compare the characteristics of admissions ending with routine discharge versus those ending in self-directed discharge. We examined all adult discharges with an ICD-10 diagnoses related to opioid use or poisoning and inspected the diagnostic data to systematically identify acute pain for the listed primary diagnosis and explore patterning in chronic pain diagnoses with respect to discharge outcomes.Sixteen percent of the 7972 admissions involving opioid-related conditions culminated in self-directed discharge, which was more than five times higher than in the general population. Self-directed discharge rates were positively associated with polysubstance use, nicotine dependence, depression, and homelessness. Among the 955 patients with at least one self-directed discharge, 15.4% had up to 16 additional self-directed discharges during the 12-month observation period. Those admitted with an acutely painful diagnosis were almost twice as likely to complete a self-directed discharge, and for patients with multiple admissions, rates of acutely painful diagnoses increased with each admission coinciding with a cascading pattern of worsening infectious morbidity over time. Chronic pain diagnoses were inconsistent for those patients with multiple admissions, appearing, for the same patient, in one admission but not others; those with inconsistent documentation of chronic pain were substantially more likely to self-discharge.These findings underscore the importance of pain care in disrupting a process of self-directed discharge, intensifying harm, and preventable financial cost and suffering. Each admission represents a potential opportunity to provide harm reduction and treatment interventions addressing both substance use and pain.The online version contains supplementary material available at 10.1186/s12954-021-00581-6. Patients with opioid-related conditions, including opioid dependence and opioid use disorder (OUD), are commonly hospitalized for the treatment of infections, trauma or other emergent conditions, with admission rates increasing as the opioid overdose crisis continues –3. Unfor‘Discharge in these patients reported as high as 38% . The expTo explore the role of pain in self-directed discharges, we employed a large non-confidential database of all hospitalizations during 2017 in the city of Philadelphia to identify adults with opioid-related conditions and compare the characteristics of admissions ending with routine discharge versus those ending in self-directed discharge. We applied multiple schemas to the diagnostic data to systematically identify acute pain for the listed primary diagnosis, and explore patterning in chronic pain diagnoses with respect to admission outcomes. Finally, we described characteristics of a subset of patients with multiple self-directed discharges over the course of the year, demonstrating worsening health status and increasing costs over time. The overall goal of these analyses was to explore the role of pain in self-directed discharge and to identify potential approaches to prevent patients who have been historically marginalized from experiencing avoidable harm and suffering.To examine the relationship between pain and self-directed discharge, we used a cohort study design in which the population of patients admitted to an acute care setting in the city of Philadelphia with an ICD-10 code diagnosis related to opioid use were followed prospectively over a 12-month period. We also examined the role of pain as a risk factor for subsequent self-directed discharge.In this study, we conducted a secondary descriptive analysis of a large database  of all inpatient admissions from all 17 general acute care hospitals in the city of Philadelphia between January 1, 2017 and December 31, 2017. All admissions were retrieved for adults between the ages of 18 and 64 at general acute hospitals with diagnostic codes related to opioid use  or opioid poisoning (T400X1A-T40692A). The study was deemed Exempt (Category 4) from IRB oversight by the Institutional Review Board of the University of Pennsylvania (Protocol # 832523).The PHC4 is a state agency whose mission is to reduce avoidable healthcare spending. A data record for each inpatient admission is submitted to the PHC4 on a quarterly basis, excluding Veterans Administration Hospitals. To minimize the data collection burden on reporting facilities, the majority of data provided is based on the Uniform Billing standards, thus encounter data are generally extracted from facility billing systems, with multiple bills for the same encounter rolled into a single encounter record. Data are submitted via a secure web-based data upload process. Facilities with overall error rates at or below 15% are provided reports listing data identified as invalid, and asked to make corrections, and facilities with over 15% of their records in error are asked to correct and resubmit their data. Following corrections, the database is closed to any further changes and made available for purchase. With respect to the availability of data and materials, the PHC4 dataset is not publicly available because the data are proprietary in nature.Patient discharge status was determined by a code used to indicate the patient disposition upon discharge as supplied by the facility; those coded as “left against medical advice or discontinued care” were classified as self-directed discharge for the purposes of these analyses. To characterize self-directed discharges, we utilized the ICD-10 diagnosis code indicating the reason for admission as supplied by the facility. The PHC4 data only specifies the quarter of admission, not the exact date, thus to understand the temporal relationship between admissions for patients with multiple discharges, we created an indicator reflecting the standardized-quarter of discharge, with the discharges appearing first indicated by 1 even if occurring in the second or subsequent quarters. For example, the indicators would equal 1, 2, 2, and 3, respectively, for a patient with one discharge in the second quarter, two in the third quarter and one in the fourth quarter.Demographics of the sample considered in the analysis include race, ethnicity, gender, and age. Housing instability was identified by diagnostic codes for homelessness, housing insecurity, and problems related to housing and economic circumstances. Patients were coded as nicotine dependent if they had an ICD indicator for nicotine dependence during at least one hospital admission and were coded as polysubstance users if they had dependence or poisoning for cannabis, cocaine, stimulants, or depressants noted during at least one hospital admission. To explore the role of infectious pathologies we separated a list of injection-related infections developed by Coye and colleagues into three subcategories: skin and soft tissue infections, sepsis and bacteremia, or bone, joint and vascular infections  . We explored patterning in self-directed discharge rates based on the presence of acute and chronic pain indictors with Chi-square tests. Logistic regression was conducted to understand how chronic and acute pain indicators correlate with self-directed discharge, adjusting for LOS, sex, age, and housing insecurity. Finally, because a substantial number of patients experienced more than one admission during the 12-month observation period, we described as groups those patients with zero, one, two to five, and six or more self-directed discharges. Cochran-Armitage Trend Tests were conducted to explore the dose response relationship between number of self-directed discharges and patient characteristics. Three case studies are provided to exemplify the progression of pain and disease across multiple self-directed discharges. Inconsistent documentation of chronic pain in those patients with multiple diagnoses was noted and the degree to which these “missing” diagnoses predicted self-directed discharge also inspected. Analyses were completed using SAS 9.4 .p < 0.0001), and those with self-directed discharge were also significantly younger . As anticipated, median LOS was significantly shorter for those with self-directed discharge in comparison to routine discharge   involved an opioid-related condition among 5877 unique patients  of all primary admitting diagnoses were identified as acutely painful. Patients with acute pain were over 1.5 times as likely to have a self-directed discharge 20.3%) as patients without an acutely painful primary diagnosis (13.0%). For those patients with multiple admissions, the presence of acute pain increased dramatically and consistently as patients accumulated self-directed discharges; for patients with six previous self-directed discharges, 90% of the admitting diagnosis were acutely painful  . Among those with multiple admissions, missing chronic pain indicators were substantially more common among patients with unstable housing  compared to the 7138 admissions definitely not following a self-directed discharge . Hospitalizations involving bone, joint, and vascular infections were almost twice as costly on average as hospitalizations involving skin-related infections .Among the 955 patients with at least one self-directed discharge, 147 (15.4%) had between one and 16 additional self-directed discharges. There was a positive and graded relationship of the number of self-directed discharges to infections, polysubstance use, homelessness, nicotine dependence, depression and average total spending Table . PatientThe 392 hospitalizations which definitely occurred after a self-directed discharge, resulted in charges totaling $26,040,983, for which the primary payer was overwhelmingly Medicaid (79.4%) or Medicare (9.2%). Another 442 discharges occurred in the same quarter as—and therefore potentially after—a self-directed discharge, and resulted in hospitalization charges totaling $26,081,336, with Medicaid (75.6%) and Medicare (13.8%) once again the primary source of reimbursement. Patients were identified as lacking health insurance in only 0.5% of these 834 discharges.A major chronic pain diagnosis reduced the odds of self-directed discharge , while the presence of acute pain  to bacteremia (×2) to sepsis due to streptococcus (×2) to sepsis due to methicillin resistant Staphylococcus aureus. Intervening admissions were related to cellulitis of the right (×1) and left (×2) lower limbs and acute embolism and thrombosis of right (×1), left (×1) and bilateral (×1) femoral veins. Procedures administered included transesophageal ultrasound of the heart and aorta, superior vena cava infusion, and drainage of the left knee joint. The patient was identified as having nicotine and cocaine dependence in addition to opioid use disorder and opioid dependence diagnoses. The patient also had diagnosis of chronic hepatitis C, major depressive disorder, and was noted to be experiencing homelessness on 5 admissions. One admission related to a “fall down embankment” and another related to an assault. Payment for this patient’s hospitalization was provided by Medicaid, Blue Cros,s, and government sources and total costs associated with the care received was $775,823.46.Patient was admitted to a general acute care hospital 20 times during the first 9 months of 2017, three times through urgent care and the remainder through the emergency room. Seventeen of the admissions resulted in a self-directed discharge, with lengths of stay for those discharges ranging from 0 to 13 days. The patient had an opioid dependence diagnosis, and one admission was related to overdose; the patient was also diagnosed with cocaine use disorder and nicotine dependence. All but one admission was for a painful condition. Admitting diagnoses progressed from cellulitis of the left (×8) and right (×2) upper limb, to extradural and subdural abscess (×2), to intraspinal abscess and granuloma (×1), to sepsis due to methicillin resistant Staphylococcus aureus (×2). The patient’s course was complicated by insulin-dependent Type 2 diabetes with hyperglycemia, and two admissions were related to open wounds and chronic skin ulcers. Procedures administered included superior vena cava infusion and drainage of the intracranial epidural space and of the buttock. On several admissions, anxiety disorder and major depressive disorder were identified. One admission also related directly to a fall. This patient had Medicaid insurance coverage and total costs associated with hospitalization was $871,666.50.Patient was admitted to a general acute care hospital 16 times in 2017, each time through the emergency room. All but the first discharge was a self-directed discharge, with lengths of stay for those discharges ranging from 0 to 3 days. Although the patient had opioid use disorder and opioid dependence diagnoses, none of the admissions were related to overdose. All his admissions were for painful, infectious conditions. Specifically, the patient was admitted with a primary or secondary diagnosis of cellulitis of the right lower extremity nine times, which progressed to an osteomyelitis of the right tibia by the 12th admission. Procedures administered include bronchial endoscopy and cardiac fluoroscopy. Also noted were diagnoses of cocaine use disorder, cannabis dependence, alcohol dependence, and nicotine dependence; on eight of the admissions, the patient was noted to be experiencing homelessness. This patient had Medicaid insurance coverage and total hospitalization costs associated with care received was $490,742.71.The results of these analyses extend previous research documenting high rates of self-directed discharges among individuals with SUD , 18. In It is likely that the factors that result in self-directed discharges from the hospital also keep patients from seeking care in these settings, allowing infections to worsen prior to treatment . People Of those with multiple self-directed discharges, polysubstance use and nicotine dependence were common; these patients also had higher rates of homelessness than persons who did not self-discharge. Consistent with the literature, polysubstance (including nicotine) use is extremely common among persons with SUD , as are Poorly treated pain is often cited as a reason why patients with SUD engage in a self-directed discharge –35. ThisA substantial minority of the sample (15.4%) had multiple self-directed discharges over the course of the 12-month observation period. Rates of polysubstance use, nicotine dependence, and depression increased with the number of self-directed discharges, and were present in 100% of patients who had six or more self-directed discharges. Addressing the overlapping mental health and social vulnerabilities of these patients is challenging and incompletely addressed within existing acute care models. The imbedding of addiction medicine specialists within the acute care hospital setting may be one approach to address some of these concerns. However, research suggests that the benefits of such programs may be limited  unless aAlthough pain and untreated OUD appear to be related to self-directed discharge in this cohort, it is likely the result of multiple intersecting factors. Significant numbers of persons self-discharging are nicotine dependent, and due to strict non-smoking policies in hospital settings, nicotine withdrawal or craving may motivate self-directed discharge . SimilarThe primary limitation of the study is reliance on high-level coded data, precluding nuanced understanding of patient experiences and why they chose self-directed discharge. In addition, the opioid-related diagnostic codes are not specific to OUD, thus patients who did not meet diagnostic criteria for a SUD were likely included in the sample. The data are also limited to 1 year providing only partial visibility into the hospitalization history of the patient population. Although coded by independent nurse experts, there may have been errors in conditions classified as acutely painful. Moreover, only the primary diagnoses were assessed as acutely painful; patients admitted with a non-acutely painful primary diagnosis  may have also had co-occurring acute pain from another condition . Further complicating interpretation in this opioid-using sample is the potential confounding effect of opioid-induced hyperalgesia , such thIndividuals admitted to the hospital who have an opioid-related diagnosis are more likely than those without to experience self-directed discharge. Rates of self-directed discharge likely reflect unrecognized or poorly managed pain. Notably, a significant number of these patients experience multiple and repeated self-directed discharges from acute care settings, with worsening morbidity and increased cost over time. Clear from these findings is the phenomenally high cost of inadequate care represented by self-directed discharge and short hospital stays for patients who require longer-term in-patient care, suggesting the need for substantial reform in the delivery of acute care. In that each hospital admission represents a potential opportunity to provide harm reduction and treatment interventions addressing both substance use and pain, self-directed discharges related to un- or under-treated SUD as well as acute and chronic pain would likely decline if these were consistently and compassionately provided.Additional file 1. ICD-10 Codes used to identify opioid poisoning, opioid dependence, chronic pain indicators, chronic overlpping pain conditions, infection, homelessness, other substance use and depression.


Postoperative neck pain has been reported as an unsolved postoperative complication of surgery for cervical ossification of the posterior longitudinal ligament (OPLL). The aim of the present study was to elucidate factors having a significant association with postoperative deterioration of neck pain in cervical OPLL patients. We studied a cohort of patients in a prospective registry of 478 patients who had undergone cervical spine surgery for cervical OPLL. We excluded those without evaluation of preoperative neck pain. Therefore, 438 patients were included in the present study. Neck pain was evaluated with the visual analogue scale . Postoperative neck pain deterioration was defined as a ≥20 mm increase of VAS neck pain. Patient factors, neurological status, imaging factors and surgical factors were assessed. Univariate analyses followed by multivariate analysis using stepwise logistic regression was performed. Six months after surgery, 50 (11.6%) patients showed postoperative neck pain deterioration and 76 (17.4%) patients showed postoperative neck pain deterioration 2 years after surgery. Six months after surgery, the rate of neck pain deterioration was significantly higher in patients who had undergone posterior surgery. Two years after surgery, the number of levels fused was significantly correlated with neck pain deterioration.  Ossification of the posterior longitudinal ligament (OPLL), widely observed in Asian people, is ectopic ligamentous ossification that can cause spinal cord or nerve root compression, or both, when the ossification foci thicken ,2,3. ForWe studied a cohort of patients in a prospective registry of 478 patients who had undergone cervical spine surgery for myelopathy caused by cervical OPLL. Among those patients, we excluded those without evaluation of preoperative neck pain. We ultimately included 438 patients with treated cervical OPLL , Table 1Surgical procedures included in the present registry were as follows: Laminoplasty includes both open-door laminoplasty and French-door laminoplasty. Struts to keep laminae enlarged includes plate, a hydroxyapatite spacer and an autologous spinous process were used. Posterior decompression and fusion means posterior instrumented fusion combined with laminoplasty/laminectomy. Anterior decompression and fusion consists of corpectomy and floating/extirpation of ossified lesions and bone grafts augmented with a plate. A-P means anterior decompression and posterior instrumented fusion. Indication for surgical treatment was based on myelopathy causing impairment of activities of daily living. Precise surgical indication, choice of surgical procedures and detailed surgical procedures are different at each institution. Surgeons belonging to each institution performed surgeries; therefore, 72 surgeons performed surgery in the present registry.Neck pain was evaluated with the visual analogue scale  preoperatively, then 6 months and 2 years after surgery. Postoperative neck pain deterioration was defined as a ≥20 mm increase of VAS neck pain. Patient factors, including age at surgery, sex, body mass index, disease duration and diabetes mellitus, were assessed. Neurological status was assessed with the Japanese Orthopedic Association score for evaluating cervical myelopathy . Neck pain 2 years after surgery (38.5 ± 30.7 mm) did not show a significant change compared with preoperative neck pain (p = 0.39). Fifty (11.6%) patients showed postoperative neck pain deterioration 6 months after surgery, whereas the remaining 438 (88.4%) patients showed no deterioration and 76 (17.4%) patients showed postoperative neck pain deterioration 2 years after surgery  to 36.6 ± 29.1 mm ( surgery . The estp = 0.02, p < 0.01, p = 0.02, p = 0.02, Among 50 patients showing postoperative neck pain deterioration 6 months after surgery, 23 showed attenuation of neck pain, and the remaining 27 showed no recovery from neck pain. Thus, neck pain deterioration in 49 of 76 patients occurred between 6 months and 2 years after surgery. Six months after surgery, the rate of neck pain deterioration was significantly higher in patients who had undergone laminoplasty or PDF than in those who had undergone ADF or A-P (The present results showed that a posterior approach was significantly associated with postoperative neck pain deterioration 6 months after surgery. In addition, there was no significant difference in the proportion of those with neck pain deterioration between patients who had undergone PDF or LMP. This suggests that the surgical invasion to posterior paraspinal muscles might cause postoperative neck pain. Previous reports revealed a significant association between muscle invasion and postoperative neck pain, specifically axial pain ,11. HosoTwo years after surgery there was a significant association between neck pain deterioration and the number of levels fused, but not surgical procedures. This suggests that there is no significant influence of a posterior approach-related paraspinal muscle injury to neck pain deterioration in the mid-to-long term. By contrast, the number of levels fused was significantly associated with postoperative neck pain deterioration. We found that the neck pain in 49 of 388 patients without neck pain deterioration 6 months after surgery worsened between 6 months and 2 years after surgery. In addition, the neck pain in 23 of 50 patients with neck pain deterioration 6 months after surgery reduced between 6 months and 2 years after surgery. The number of levels fused was significantly associated with this late neck pain deterioration, whereas the type of surgical procedure was not significantly associated with this late neck pain deterioration. These lines of evidence suggest that the number of levels fused might be independent of posterior surgery-related muscle damage. The significant association between number of levels fused and neck pain deterioration suggests that limited mobility of the cervical spine might cause neck pain. Previous reports indicated that excessive longer external fixation using a neck collar can cause greater neck pain than a shorter time of external fixation after cervical spine surgery . MoreoveA major limitation of the present study is that the present registry lacks sagittal alignment parameters, although recent studies revealed the close relationship between cervical sagittal alignment impairment and neck pain deterioration. Posterior surgery, even in fusion surgery, can lead to sagittal alignment worsening after surgery. Therefore, the assessment of sagittal alignment will be mandatory for elucidating the precise etiology of neck pain deterioration. Thus, a collection of sagittal alignment parameters should be considered in the near future. Another possible limitation is the lack of detailed pain data about its characteristics, precise location and relationship to motion, and so forth.The precise etiology of neck pain deterioration after surgery remains to be fully elucidated; however, the present results suggest that the number of fusion levels must be kept at the minimum necessary to avoid postoperative neck pain after surgery for OPLL.A posterior approach was significantly associated with neck pain deterioration 6 months after surgery for cervical OPLL, and the number of levels fused was significantly associated with neck pain deterioration 2 years after the surgery.


The purpose of the present study was to translate and cross-culturally adapt the King’s Parkinson’s Disease Pain Scale (KPPS) into Bulgarian and to investigate its psychometric properties in order to provide a validated Parkinson’s disease-specific pain instrument in Bulgarian language (KPPS-BG).Translation into Bulgarian and a cultural adaptation were performed to obtain KPPS-BG. A total of 162 patients with idiopathic Parkinson’s disease were screened for pain using the complementary to the KPPS questionnaire – King’s Parkinson’s Disease Pain Questionnaire (KPPQ). KPPS-BG domain and total scores were calculated and internal consistency, construct validity and test-retest reliability were examined for 129 patients having one or more positive items in the KPPQ-BG.79.6 % of the patients reported one or more types of pain. The most common type was musculoskeletal pain (83.7 %), followed by nocturnal pain (55.0 %), fluctuation-related pain (50.1 %), radicular pain (43.4 %), chronic pain (31.0 %), discoloration, edema/swelling (27.1 %) and, oro-facial pain (14.3 %). Mean KPPS-BG total score was 21.1 ± 17.3 SD. KPPS-BG showed a good reliability . The test-retest reliability of the KPPS-BG was high and the intraclass correlation coefficient was 0.92, demonstrating а good repeatability. KPPS-BG total score was higher in patients with postural instability gait difficulty motor subtype, compared to tremor-dominant or indeterminate subtype. Significant positive correlations were found between KPPS-BG total score and modified H&Y, Movement Disorders Society Unified Parkinson’s Disease Rating Scale part III.The KPPS-BG constitutes a reliable, comprehensive and useful tool for pain assessment in native Bulgarian patients with Parkinson’s disease. Pain has been reported as symptom of Parkinson’s disease (PD) since the first description of the disorder . In receBased on the assessment using general, non-PD specific tools, pain is estimated to occurs in up to 85 % of the patients with PD . This maUntil recently, there was no specific validated diagnostic tool for detecting pain in PD. Different specific and non-specific pain scales were used that have not been adopted to and validated for PD patients , 12, 13.Chaudhuri et al.  have creThe clinical assessment of pain in PD patients in Bulgaria is usually underperformed. Questionnaires or studies on the reliability and validity of instruments assessing pain in patients with Parkinson`s disease in the Bulgarian language do not exist. The aim of the present study is translation, adaptation and validation of the King’s Parkinson’s Disease Pain Scale in Bulgarian language (KPPS-BG) in order to use it as a reliable instrument intended for clinical monitoring the pain in Bulgarian patients with PD.Participants were recruited from the Department of Movement Disorders of the University Hospital for Active Treatment in Neurology and Psychiatry, “St Naum” Sofia, Bulgaria. All inpatient and outpatient treated during the study period were screened for eligibility. Assessment was done by a senior neurologist, specialized in movement disorders.In the study were enrolled 162 patients aged 18 years or more with diagnosed idiopathic PD based on the UK Parkinson’s Disease Society Brain Bank criteria . All subDemographic and clinical data were collected upon the first visit. All patients were assessed by using the modified Hoehn and Yahr (H&Y) scale for rating the stage of a patient’s disease progression  and the All patients gave written informed consents prior to participation, approved by the Ethics Committee of the University Hospital for Active Treatment in Neurology and Psychiatry “St Naum”, Sofia. The study was conducted in accordance with the ethical standards set forth on the Declaration of Helsinki. The participants were free to withdraw from the study at any time.Following a permission granted by the authors and according to their requirements the original English versions of the KPPS   were traTen patients with various age and educational levels were tested with the pre-final questionnaire and scale (KPPQ-BG and KPPS-BG). They were invited to verbally evaluate the clarity of the content of the items and their comprehensibility. Patients have been filling KPPQ-BG in the presence of a medical specialist, who was helping them out where needed. After filling the questionnaire the patients give answers concerning the severity and frequency of the available pain. The medical specialist calculates the score of each domain and the total score of KPPS-BG.The following language adaptations were performed: “around their joints” was replaced by “around the joints”, “around the liver, stomach or bowels” was replaced by “in the area of the liver, stomach or bowels” and “aching pain” was replaced by “pain”.Patients declared that they have not encountered difficulties in completing the questionnaire with the help from the relevant specialist, granted upon such need a request and in answering the questions on the rater-interview–based scale.The back-translated version of the questionnaire and scale were discussed with the authors of the KPPQ and KPPS. After some amendments the final versions KPPQ-BG and KPPS-BG were again back-translated and approved by the authors for validation and for usе in Bulgarian PD patients.The KPPS-BG consist of the same 14 items as KPPQ-BG, which are distributed into seven domains as follow: (1) Musculoskeletal pain (1 item); (2) Chronic pain (2 items); (3) Fluctuation-related pain (3 items); (4) Nocturnal pain (2 items); (5) Oro-facial pain (3 items); (6) Discoloration, oedema/swelling (2 items); (7) Radicular pain (1 item). Patients need to rank the described sense of pain for each item by the severity in a 4-point Likert scale  and frequency in a 5-point Likert scale . The range of possible KPPS-BG total scores is from 0 to 168. Higher score values indicate higher levels of pain.In total 162 patients with PD were tested with KPPQ-BG. Face-to-face clinical interview was conducted comprising two steps. In the first one, all patients had to fill the KPPQ-BG, answering “Yes” or “No” for all 14 items. Only patients with 1 or more positive answers were evaluated by KPPS-BG. The KPPS-BG domain and total scores were calculated for 129 patients. 43 randomly selected patients were interviewed again after two weeks to evaluate test-retest reliability .Descriptive statistics were used for calculating the mean scores of the KPPS-BG and sociodemographic and clinical data. Item discrimination was evaluated using item-to-total score correlation that is criteria for discarding items. The item-to-total score correlation of 0.20 has been given as the cut-off point below which items can be discarded . ТherefoThe test-retest reliability was evaluated by calculating the intraclass correlation coefficient (ICC) using the two-way mixed effect models according to classification of Shrout and Fleiss (1979) . The relThe analyses were performed using the computer software Statistica 8.0 for Windows (Stat Soft Inc. USA).Mean age of participants in the investigation was 65.4 ± 8.4 (range 40–80 years). There were only few participants younger than 50 years (4.7 %). The majority of the PD patients were within the age range of 50–70 years (63.5 %). Both sexes were equally represented. The mean duration of the disease was 6.6 ± 5.7 years. Sixty-three patients (48.8 %) reported disease durations of 6–10 years and 22 (17 %) of over 10 years. Twenty-three patients  were newly diagnosed and drug naive. Sociodemographic and clinical characteristic of patients with KPPS-BG score > 0 are presented in Table All 129 patients with symptoms of pain over the last month completed KPPQ-BG manually. Based on the patients’ answers, pain severity and frequency were quantitatively measured and the КPPS-BG score was calculated. Missing information on any of the items was not observed . Eight of the patients (6.2 %) had ambiguities related to the words “abnormal” and “involuntary” in question number 5 of the KPPQ-BG and additionally explanations were provided by the interviewing medical specialist. In some cases, additional explanations were required for other items.There were no significant differences between the distribution of the positive responses of the Bulgarian and mixed British and Romanian populations using English version of KPPS, for most of the questions. Only in item 4 and domain 4 the responses of the Bulgarian patients were significantly different Table .Table 2Internal consistency was calculated using Cronbach’s alpha coefficient, based on the data obtained from the first examination (n = 129). The value of Cronbach’s alpha for the total scale KPPS-BG was 0.75, which showed good internal reliability. The item-total correlations were 0.21 or greater for 13 items, ranged from 0.21 (item 3) to 0.72 (item 14). The item 12: “Burning sensation in the mouth” have values of item-total correlations < 0.20, which defines it as poorly informative and gives reason to exclude it from the subsequent analysis (Table The test-retest reliability of the KPPS-BG was high and the intraclass correlation coefficient (ICC) was 0.92  = 0.82–0.98). All items showed high positive correlations between the first and second exam (range from 0.78 to 0.98), which exceeded the recommended value of 0.75  and show that items contained in the KPPS-BG had a good repeatability Table .s)  Table . The meaFigure p < 0.001). A post hoc Mann-Whitney U-test showed significant difference of KPPS-BG total scores between patients with TD subtype vs. PIGD (p < 0.001) only. The mean score of TD was 13.5 ± 2.5, median 7, for PIGD was 28.3 ± 19.1, median 23 and Indeterminate subtype- 15.4 ± 7.1, median 16. That result shows a good discriminative validity of KPPS-BG.Discriminate construct validity was tested by difference between KPPS-BG total score and motor subtype of PD using Kruskal-Wallis ANOVA with three levels (Tremor-dominant (TD), Postural Instability Gait Disorder (PIGD) and Indeterminate). There was a significant effect of the PD motor subtype on the KPPS-BG total score  = 26.26, Pain is a subjective, physiological and psychological experience, influenced by sociocultural factors . In the Almost 80 % of our patients reported one or more types of pain. In a recently published cross-sectional study, the authors reported a pain frequency of 88.6 % . SilverdIn the present study, the most common type of pain was musculoskeletal 83.7 %), which is in line with the results of some previous studies , 23, 31, %, whichSignificant differences between the Bulgarian and other populations were observed for item 4 and nocturnal pain domain. Pain deep within the body (item 4) refers to the central pain. It has been reported by 12 % of our patients. These results are in line with other studies where this type of pain was estimated to be present in up to 10 % of PD patients . However55.0 % of patients in the present study suffered from nocturnal pain. This domain shows a large variability among different studies , 31 The The mean scores of all domains of the KPPS-BG were similar to those observed in the original validation  except fThe mean total score of KPPS-BG was 21.1 ± 17.3 and median 17, which is within the range of those reported by other authors , 15. In Item 12. Burning sensation in the mouth demonstrated an item-to-total score correlation below 0.20. Hence, this item was determined as low informative and unreliable for the Bulgarian population.We have observed a statistical correlation between modified H&Y stage, MDS-UPDRS III and the total score KPPS-BG . Тhe observed positive correlations reflect the domination of the musculosceletal, fluctuation-related, nocturnal and orofacial pain in the overall score. Similar data was published , 15, 23.The significant difference of KPPS-BG total scores between patients with various motor subtypes of the disease is published also for the Mexican population . PatientKPPS-BG detected pain as an initial symptom of the disease in 5.43 % of the patients.6.2 % of the participants required further clarification with regard to the words “abnormal” and “involuntary” in item 5. In some cases, additional explanations were required for other items. This allows us to propose the use of the questionnaire and scale in the presence of a medical specialist who is trained to recognize the specific taxonomy of pain in PD.Due to the lack of consensus on the diagnosis and therapy, pain in PD is still insufficiently managed in routine clinical practice. In the present study, this is reflected by means of the finding that 79.63 % of the participants reported one or more types of pain, but only 10.85 % received medications for pain relief.The current study has some limitations: The main one is the small sample size for the test-retest reliability. Only those patients that came to a follow-up visit two weeks after the first assessment and could be examined by the same senior neurologist were included. This could be a potential source of bias. However, the results are in line with previous studies. Second, the number of patients with advanced disease (modified H&Y stage 4 and 5) is underrepresented, mainly due to the exclusion criteria. Third, the methodological design of the study is not а case-control. Therefore, no control group was included. All assessments are made in on medication phase.Pain is a common, disabling and influencing the patient’s QoL non-motor symptom in PD, but still a challenge for the clinicians. Standardized outcome measurements would help developing consensus on pain management in PD. As many other tools, KPPS was provided in English language and tailored to suit the specifics of the Anglo-Saxon culture. Translation and application in another language requires linguistic and cultural adaptation and a statistical validation. In this study, the KPPS was translated, cross-culturally adapted, and validated into Bulgarian language for the first time. Results of the present study demonstrate that the KPPS-BG has good reliability and validity. The Cronbach’s α 0,75 of total scale indicate good level of internal consistency. Our results showed that KPPS-BG constitutes a useful pain assessment tool evaluating the frequency and severity of pain associated with PD. It can also be useful for monitoring the therapeutic management of PD-related pain. This study supports the use of the KPPS as an intercultural comparable assessment tool.


Typically, in both cohorts, normal nerve conduction studies and reduced intraepidermal nerve fiber densities were observed in the sampled patient subsets. In LGI1 antibody patients, pain responded to immunotherapy (p = 0.008), often rapidly, with greater residual patient‐rated impairment observed in CASPR2 antibody patients (p = 0.019). Serum CASPR2 antibodies, but not LGI1 antibodies, bound in vitro to unmyelinated human sensory neurons and rodent dorsal root ganglia, suggesting pathophysiological differences that may underlie our clinical observations. ANN NEUROL 2021;90:683–690Pain is a under‐recognized association of leucine‐rich glioma‐inactivated 1 (LGI1) and contactin‐associated protein‐like 2 (CASPR2) antibodies. Of 147 patients with these autoantibodies, pain was experienced by 17 of 33 (52%) with CASPR2‐ versus 20 of 108 (19%) with LGI1 antibodies ( Patients with autoantibodies against leucine‐rich glioma‐inactivated 1 (LGI1) and contactin‐associated protein‐like 2 (CASPR2) most often present with autoimmune encephalitisThe Douleur Neuropathique 4 (DN4) was used to define neuropathic pain at disease nadir by a score ≥ 3 .Patient‐Reported Outcome Measurement Information System Pain Interference  was used to quantify pain interference at nadir of pain, after immunotherapy, and at latest follow‐up .Five‐level EuroQol 5‐dimension quality of life assessment (EQ‐5D) and EQ‐5D visual analogue scale were used to evaluate functional domains and self‐reported quality of life  at latest follow‐up.Patients with antibodies against LGI1 (n = 108), CASPR2 (n = 33), or both targets (n = 6) were identified from the Oxford Autoimmune Neurology Group's clinical assessments, including 37 patients from previous studies.Intraepidermal nerve fiber density (IENFD) was determined from skin biopsiesThe first available serum sample was tested using (1) live cell‐based assays (CBAs) for LGI1 and CASPR2 antibodies, with samples defined as positive at serum endpoint dilutions ≧1:20 for LGI1 and ≧1:100 for CASPR2 antibodiesGraphPad  Prism (v8.0) and Adobe Illustrator were used for statistical analyses/figures. Fisher exact test was used to compare binary discrete and Mann–Whitney test to compare continuous variables. Informed consent from patients and controls was obtained with approvals REC16/YH/0013 and 14/SC/0280. Animal work complied with UK Home Office license Ref.P1DBEBAB9.A 66‐year‐old previously well female presented with 18 months of pain, which commenced as a hot sensation in both feet. Subsequently, she developed shooting pains in her thighs, buttocks, arms, and torso, stereotyped episodes of burning pain described as “being tortured with stinging nettles”, and persistent severe hyperesthesia with a glove and stocking distribution also involving her torso. Symptoms were triggered by heat and movement, and severely restricted activities. Three neurologists observed normal nerve conduction studies and diagnosed her with fibromyalgia or psychogenic pain. A fourth found LGI1 antibodies (endpoint dilution of 1:640) and markedly reduced skin IENFD. High‐dose prednisone resulted in complete symptom resolution within 2 days, and a marked fall in PROMIS‐PI ratings, from 36/40 to 8/40. Nine months later, a patient‐initiated corticosteroid wean was associated with a relapse of pain, which partially responded to reinitiation of corticosteroids and plasma exchange.This patient prompted us to examine pain across a large cohort of patients with LGI1 and/or CASPR2 antibodies.Antibodies against LGI1 (n = 108), CASPR2 (n = 33), or both targets (n = 6) were detected using live CBAs , and 2 of 6 with both antibodies  of the CASPR2‐antibody cohort versus 19% (20/108) with LGI1 antibodies . At nadir of pain, both groups had comparable DN4 and PROMIS‐PI scores with neuropathic pain in 7 of 12 (58%) LGI1 and 8 of 9 (89%) CASPR2 antibody patients : this was particularly pronounced in those with neuropathic pain . The lower PROMIS‐PI scores in LGI1 antibody patients were sustained at latest (median = 5 years) follow‐up  and, at this time point, CASPR2 antibody patients lower overall self‐reported health (p = 0.019), with greater concerns in the domains of mobility (p = 0.014), usual activities (p = 0.019), and anxiety/ depression .Patients were administered a median of 2 conventional analgesic agents  and a median of 2 immunotherapies . Improvement of pain with conventional analgesic trials was reported in approximately half of both LGI1  and CASPR2 antibody  patients. In contrast, 18 of 22 (82%) immunotherapy trials in LGI1 antibody patients resulted in a rapid improvement in pain, over a median of 14 days (range = 2–21), compared to 5 of 13 (38%) in CASPR2 antibody patients  following onset of pain Fig . One patp = 0.019) and live rodent DRG neurons . All CASPR2 antibody binding was abrogated in DRG cultures derived from a CASPR2 knockout mouse  the first structured neuropathic pain evaluations using validated clinical and laboratory tools; (2) ascertainment of transferable measures of QOL for future cross‐comparisons; (3) long‐term follow‐up data; and (4) the study of strictly autoantibody‐mediated conditions, by exclusion of voltage‐gated potassium channel antibody–positive patients without LGI1/CASPR2 reactivities.In summary, here, by contrasting LGI1 and CASPR2 antibody patients, we advance established differences between their clinical presentations and HLA associations to now differentiate their pain in terms of its relative frequency, clinical characteristics, short‐ and longer‐term therapeutic responses, and the underlying neurobiology. Our detailed characterization of "autoimmune pain" syndromesS.Ra. and S.R.I. contributed to conception and design of the study, as well as acquisition and analysis of data and drafting a significant portion of the manuscript or figures. All coauthors contributed to acquisition and analysis of data, in addition to editing and approval of the final draft.J.D. and D.L.B. have a patent relating to the use of CASPR2 for the treatment of excess neuronal activity in pain and epilepsy (PCT/GB2017/052909). S.R.I. and P.W are coapplicants and receive royalties on a licensed patent application WO/2010/046716 (UK patent no. PCT/GB2009/051441) entitled "Neurological Autoimmune Disorders." All other authors have no relevant disclosures.TABLE S1. Comparison of leucine‐rich glioma‐inactivated 1 (LGI1) and contactin‐associated protein‐like 2 (CASPR2) antibody–positive patients with pain. aFisher exact test was used to compare binary discrete variables between the LGI1 and CASPR2 pain groups. The Mann–Whitney test was used to compare continuous variables. Probability values are not corrected for multiple comparisons. Double‐positive patients were excluded from statistical analysis due to the small sample size. bDouleur Neuropathique 4 (DN4) scores out of 10 . Scores > 3 are considered to represent neuropathic pain in the absence of physical examination. cPatients who had multiple trials of conventional analgesia or immunotherapy agents were classified as having "any improvement" if any one of the multiple medication trials in each category resulted in any improvement in their pain.Click here for additional data file.