Low back pain (LBP) is the most common cause of chronic pain. Numerous clinical scales are available for evaluating pain, but their objective criteria in the management of LBP patients remain unclear. This study aimed to determine an objective cutoff value for a change in the Pain Intensity Numerical Rating Scale (ΔPI-NRS) three months after LBP treatment. Its utility was compared with changes in six commonly used clinical scales in LBP patients: Pain Disability Assessment Scale (PDAS), Pain Self-Efficacy Questionnaire (PSEC), Pain Catastrophizing Scale (PCS), Athens Insomnia Scale (AIS), EuroQoL 5 Dimension (EQ5D), and Locomo 25. We included 161 LBP patients treated in two representative pain management centers. Patients were partitioned into two groups based on patient’s global impression of change (PGIC) three months after treatment: satisfied  and unsatisfied (3–7). Multivariate logistic regression analysis was performed to explore relevant scales in distinguishing the two groups. We found ΔPI-NRS to be most closely associated with PGIC status regardless of pre-treatment pain intensity, followed by ΔEQ5D, ΔPDAS, ΔPSEC, and ΔPCS. The ΔPI-NRS cutoff value for distinguishing the PGIC status was determined by ROC analysis to be 1.3–1.8 depending on pre-treatment PI-NRS, which was rounded up to ΔPI-NRS = 2 for general use. Spearman’s correlation coefficient revealed close relationships between ΔPI-NRS and the six other clinical scales. Therefore, we determined cutoff values of these scales in distinguishing the status of ΔPI-NRS≥2 vs. ΔPI-NRS<2 to be as follows: ΔPDAS, 6.71; ΔPSEC, 6.48; ΔPCS, 6.48; ΔAIS, 1.91; ΔEQ5D, 0.08; and ΔLocomo 25, 9.31. These can be used as definitive indicator of therapeutic outcome in the management of chronic LBP patients. Chronic low back pain (CLBP) has a major impact on the patient’s quality of life. It causes sleep interruption, fatigue, depressed mood, activity limitations, and restrictions in participation , 2. HoweIn the management of CLBP patients, pain intensity is most frequently measured on the 11-point Pain Intensity Numerical Rating Scale (PI-NRS), which ranges from no pain = 0 to the worst possible pain = 10 –5. As adThis study has four purposes: (1) to clarify the utility of ΔPI-NRS in reference to MCID based on the inherent variability of ΔPI-NRS among patients with CLBP, (2) to predict a cutoff value for ΔPI-NRS in distinguishing the status of PGIC: satisfied vs. non-satisfied, (3) to evaluate correlations between ΔPI-NRS and post-treatment changes in other clinical scales, and (4) to determine the threshold values of the other scales in distinguishing the status of ΔPI-NRS: improved vs. non-improved. We systematically investigated these aspects of ΔPI-NRS to verify its utility as a primary measure of pain relief by conducting multifaceted evaluations of CLBP patients who visited two representative pain management centers in Japan.This was a cross-sectional study conducted within the usual clinical care of CLBP patients. From among 585 chronic pain patients treated at two pain management centers in Aichi Medical University and Yamaguchi University between 2010 and 2018, 161 patients with CLBP were enrolled in this study after excluding 3 patients who dropped out or failed to complete the questionnaires at the 3-month follow-up. The patients suffered from CLBP with or without radiculopathy due to lumbar spinal stenosis, lumbar disc herniation, myofascial issues, and other causes of pain .The inclusion criteria in this study was the patients from 20 to 85 years with LBP which was defined as experiencing pain, discomfort and stiffness in the lower back from the 12th rib to the lumbar or lumbosacral area, including lower limb symptoms. Inclusion and exclusion criteria are listed in Therapeutic regimens for CLBP patients were provided based on the Pain Management Program (PMP). PMPs are rehabilitation-based multidisciplinary programs for people with chronic pain , 23. TheFor multifaceted clinical assessment of the patients’ conditions, we used the following seven well-established scales:Pain Disability Assessment Scale (PDAS): A scale for measuring lifestyle disabilities of chronic pain patients. Higher scores  indicate greater degrees of lifestyle disability [sability .The Hospital Anxiety and Depression Scale (HADS): A self-reported instrument used to evaluate depression and anxiety in clinical research. The HADS has advantages over other such assessments in that it is efficient in assessing both anxiety and depression. It is composed of 14 questionnaire items and was originally developed for a general medical rather than psychiatric field. Higher scores (0 to 21 points both for anxiety and depression) indicate greater degrees of anxiety and depression [Pain Catastrophizing Scale (PCS): Pain catastrophizing affects how individuals experience pain. The PCS assesses catastrophizing  about pain, with higher scores (0 to 52 points) indicating greater degrees of catastrophizing [ophizing .Pain Self-Efficacy Questionnaire (PSEQ): PSEQ is a 10-item questionnaire developed to assess the confidence of patients with ongoing pain in performing daily activities while in pain. The PSEQ is applicable to any type of persisting pain. It covers a range of functions, including household chores, socializing, work, and coping with pain without medication. Scores can range from 0 to 60, and higher scores indicate greater degrees of performing activities while in pain [ in pain .EuroQoL 5 Dimension (EQ-5D): The EQ-5D assesses  the outcome of health-related aspects of QOL . Zero indicates death and 1.0 indicates complete health [e health –7.Athens Insomnia Scale (AIS): This scale assesses the severity of insomnia using diagnostic criteria set forth by the International Classification of Diseases (ICD-10). The eight-item questionnaire evaluates sleep onset, night and early-morning waking, sleep time, sleep quality, frequency and duration of complaints, distress caused by the experience of insomnia, and interference with daily functioning [ctioning .Locomo 25: This was developed as a screening tool for locomotive syndrome by a Japanese orthopedic surgeon group in 2008. It consists of 25 questions aimed at musculoskeletal disorders such as walking disability, difficulty in daily living, or suffering pain within the body. Scores can range from 0 to 100, and higher scores indicate a greater degrees of performing activities while in pain [The PI-NRS, PDAS, HADS, PCS, EQ-5D, PSEQ, Locomo 25, and AIS were administered to 161 patients with CLBP before and 3 months after treatment during 2010 through 2018.Before and 3 months after the therapy, a PI-NRS score reported on a scale of 0−10 was obtained as an indicator of the average level of pain over the past 7 days . For mulTo detect clinically relevant changes in the PGIC, the concept of the transition method was used –19. The The post-treatment change in PI-NRS, or ΔPI-NRS, was calculated as (PI-NRS follow-up − PI-NRS baseline). We sought to predict the MCID and cutoff value for ΔPI-NRS using the anchor-based approach by setting PGIC as the anchor . TherefoThe effect ratio of observed between-group differences was defined as the difference in averages of scale changes (ΔS) or ΔPI-NRS for Group 1 and Group 2, Based on Cohen’s criteria , the MCITherefore, if These analyses were performed for three conditions according to the pre-treatment intensity of pain judged by the PI-NRS: moderate pain (PI-NRS = 4–6), severe pain (7–10), and moderate + severe pain (4–10). In performing the analyses, we excluded 29 LBP patients with mild intensity of pain (PI-NRS = 1–3) because of their lack of sufficient relevance in the evaluation of pain-based treatment effect.The reliability of ΔPI-NRS was evaluated in comparison with post-treatment changes in the other clinical scales of ΔPDAS, ΔHADS, ΔPCS, ΔPSEQ, ΔAIS, ΔLocomo 25, and ΔEQ5D by use of Spearman correlation coefficients. The relative importance of ΔPI-NRS as a marker of pain relief was also assessed by use of multivariate logistic regression analysis by setting the satisfied status of PGIC  as a binary objective variable and setting all other clinical scale changes as explanatory variables. We also investigated the clinical implication of the ΔPI-NRS cutoff value in relation to changes in the other clinical scales. For this objective, we partitioned CLBP patients at the cutoff value into two groups and examined how well other clinical scales could distinguish the ΔPI-NRS status by determining respective cutoff values and AUCs based on the ROC analysis.Patient characteristics and profiles of 12 clinical scales before and three months after treatment are respectively presented in Tables LBP patients were partitioned into two groups in reference to post-treatment PGIC: satisfied (PGIC = 1–2) and non-satisfied (PGIC = 3–7) groups. The utility of the clinical scales in distinguishing the status of satisfaction by PGIC was explored by the use of multivariate logistic regression analysis in three ways according to the pre-treatment level of pain by PI-NRS: groups of patients with moderate, severe, and moderate + severe pain . The finFor the analysis targeting the moderate and moderate + severe pain groups, ΔPI-NRS was the leading predictor of satisfaction status with P values of 0.00064 and 0.0001, respectively. Other significant predictors among the clinical scales were ΔEQ5D-Q2, ΔHADS-anxiety, and ΔAIS in the analysis of the moderate pain group and ΔEQ5D-Q2, ΔHADS-anxiety, ΔHADS-depr, and ΔAIS in the analysis of the moderate + severe pain group.In the analysis targeting the severe pretreatment pain group, ΔPI-NRS, ΔEQ5D-Q1, and ΔLocomo 25 showed nearly equal contribution in predicting a satisfactory status.Post-treatment changes (Δ) in 8 major clinical scales were compared between the two groups with and without satisfaction by PGIC. The degree of separation of the two groups by each clinical scale was evaluated by ROC analyses . The AUCThe optimal cutoff value was estimated as the ΔPI-NRS value at which sensitivity and specificity are equal. For the moderate, severe, and moderate + severe pain groups, the cutoff values for ΔPI-NRS were 1.3, 1.8, and 1.5, respectively . BecauseTo examine correlation among changes in the clinical scales associated with improvement in pain, i.e., ΔPI-NRS and ΔPDAS, ΔHADS (anxiety and depression), ΔPCS , ΔPSEQ, ΔAIS, ΔLocomo 25, and ΔEQ5D , Spearman’s correlation coefficients (rS) were computed as shown in Moderate to strong correlations were frequently observed among ΔPI-NRS and other clinical scales . NotablyWe applied the same method as was done for ΔPI-NRS to calculate MCIDs and cutoff values of ΔPDAS, ΔPSEC, ΔPCS, ΔAIS, ΔEQ5D, and ΔLocomo 25. The anchor for this analysis was the status of ΔPI-NRS partitioned at its cutoff value: ΔPI-NRS≥2 vs. ΔPI-NRS<2.The MCID and cutoff value in predicting ΔPI-NRS≥2 status were 4.67, 6.71 for ΔPDAS (score range: 0−60); 6.48, 6.48 for ΔPSEC (0−60); 5.05, 6.71 (0−52) for ΔPCS; 1.9, 1.64 for ΔAIS (0−24); 0.08, 0.053 for ΔEQ5D (0−1.0); and 7.5, 9.31 for ΔLocomo 25 (0−100) . These cIt is most important to set the objective goal in clinical after CLBP treatment because it is difficult that we make the patients with completely no pain. The patients with CLBP commonly have not only lumber dysfunction but also physical disability and psychosocial issues . The quaWe comprehensibly evaluated the physical disability and psychosocial conditions in patients with CLBP using self-administered multifaceted measures because these patients have multidimensional musculoskeletal, social, mental and cognitive disorders, and other issues , 29, 30.At our pain management centers, we evaluate the intensity of pain in patients with CLBP using the PI-NRS, PDAS, HADS, PCS, PSEQ, EQ-5D, AIS, and Locomo 25, which cover multifaceted issues , 32–33. When both clinicians and investigators calculate cutoff values for these measures, we think the patient’s perspective on the meaning of changes following treatment will become core outcome measures , 34–36. Several papers have reported cutoff values for chronic musculoskeletal pain , 39–40. In the measurement of pain relief in patients with trigeminal neuralgia, Sandhu et al. reported that the MCIDs for the 3 domains of the Brief Pain Inventory-Facial were 57% and 28% improvement in pain intensity for the worst and average pain, respectively, 75% improvement in interference with general activities of daily living, and 62% improvement in interference with facial activities of daily living . AnotherAs a next step, the cutoff values and the MCID were also determined for ΔPDAS, ΔPSEC, ΔPCS, ΔAIS, ΔEQ5D, and ΔLocomo 25 based on ΔPI-NRS (ΔPI-NRS≥2 or ΔPI-NRS<2) in the present study. To our best knowledge, this is the first report to reveal a meaningful threshold value for the treatment goal and the cutoff value for treatment effect for each of these clinical scales. Only limited cutoff values were reported previously, and no reports showed the meaningful threshold change for treatment. Yamashiro et al. reported that the cutoff value for the PDAS was 10. A score of over 41 points in the PSEQ means the patient has high self-efficacy, whereas that below 20 points indicates low self-efficacy . SullivaFrom another point of view, when medical staff observe a ΔPI-NRS of ≥2 in patients after treatment, we can interpret this to indicate that the CLBP patients have gotten well with satisfaction and improvement in the multifaceted scores measuring life disabilities, patient confidence with ongoing pain, pain catastrophizing, sleep disorder, QOL, and musculoskeletal disorders.In summary, as clinically significant threshold and treatment target in CLBP treatment, we revealed a ΔPI-NRS of ≥2 and the threshold scores for ΔPDAS of 6.71, ΔPSEC of 6.48, ΔPCS of 6.71, ΔAIS of 1.9, ΔEQ5D of 0.08, and ΔLocomo 25 of 9.31. We propose those definitive target scores as directly correlating with PGIC for use all of the medical staff in the management of CLBP patients.A limitation of this study is that the score cannot be generalized to all CLBP patients because the data were taken only from a short 3-month follow-up period and from CLBP patients treated in only two pain management centers. Second, it is inevitable to have some degree of inconsistencies between MCID score and cutoff values in some clinical scales like AIS and EQ5D, although we derived MCID in the same way as in the previous reports possibly due to insufficient number of cases enrolled. In the present study we adopted either the MCID or the cutoff value with higher score as indicative of more clinical utility.In conclusion, we revealed a new indicator in the evaluation of CLBP treatment. A ΔPI-NRS value of 2 is the key score in CLBP treatment.S1 Fig(DOCX)Click here for additional data file.


Reach Efficacy-Adoption Implementation Maintenance framework.Pain self-management support interventions were effective in controlled clinical trials and meta analyses. However, implementation of these complex interventions may not translate into identical effects. This paper evaluates the implementation of ANtiPain, a cancer pain self-management support intervention in routine clinical practice according to the N = 153 adult patients with cancer-related pain were recruited from 01/17 to 05/18 on 17 wards of 3 hospitals in Vienna, Austria. ANtiPain entailed a face-to-face in-hospital session by a trained nurse to prepare discharge according to key strategies, information on pain self-management, and skills building. After discharge, cancer-pain self-management was coached via phone calls. Patient-level data were collected at recruitment, and 2, 4 and 8 weeks after discharge via postal or online questionnaire. Primary outcome was pain interference with daily activities. Secondary outcomes included pain intensity, self-efficacy, and patient satisfaction. Organizational-level data  were collected by study or intervention nurses. The mixed model to analyze patient-level data included a random intercept and a random slope for individual and a random intercept for ward.In this cluster randomized study with a stepped wedge design, n = 2) and duration of phone calls (mean = 17 min). Only 16 (46%) of 35 trained nurses performed the intervention on nine wards. To deal with the loss of power, analyses were adapted. Overall effects on pain interference were not significant. However, effects were significant in sub analyses of the nine wards that recruited patients in the intervention period (p = .009). Regarding secondary outcomes, the group-by-time effect was significant for self-efficacy (p = .033), and patient satisfaction with information on pain-self-management (p = .002) and in-hospital pain management (p = .018).Recruitment was slower than expected and unevenly distributed over wards and hospitals. The face-to-face session was clinically feasible (mean duration = 33 min) as well as the mean amount (The implementation of ANtiPain improved meaningful patient outcomes on wards that applied the intervention routinely. Our analyses showed that the implementation benefited from being embedded in larger scale projects to improve cancer pain management and that the selection of wards with a high percentage of oncology patients may be crucial.NCT02891785 Date of registration: September 8, 2016.ClinicalTrials.gov Identifier:  The gold standard to establish an intervention’s efficacy is still the randomized controlled trial. However, supposing that one can rollout thus tested interventions into real life clinical practice with only minor changes may be misleading. Instead, reality is a bit more complicated . Implemecomplex health care interventions because they consist of several interacting components that are highly sensitive to context  ), actual time passed since T0 and the interaction between intervention status and time, where the interaction term (difference in slopes between patients before intervention and after intervention) was of primary interest. Hypotheses were tested at a significance level of α ≤ .05. The analysis of a stepped wedge design often includes a time trend, but this was not possible in our case due to the uneven distribution of observations over clusters by time and the lack of control patients in 9 wards.N = 17) are displayed in Table Characteristics of the participating wards N = 7 are disn = 40) or were not asked due to organizational reasons . Of the 273 patients who were asked, 153 consented to participate, resulting in a recruitment rate of 56% and representing only 50% of the desired 323 patients  patients were recruited, the majority on 5 of these 8 wards . This means that 29% of the wards, all within one hospital, recruited 68% of all participants. In contrast, on 9 wards (53%), no patients were recruited in the intervention period (Table p = .001). Despite a constant recruitment rate over time . In addition, at T2, n = 42 patients had dropped out of the study (dropout rate T2 = 27%) while n = 96 (63%) patients provided complete datasets  summer did not seem to be an ideal time for implementation because of summer holidays; and (2) placing the break in the middle of the recruitment time should theoretically not have resulted in an uneven distribution between control and intervention period . In total, 35 intervention nurses were trained within 19 training sessions. Median time for training was as planned 1h36min (range: 1h15min to 2 h).intervention completion rate was 74%  and “patient stay on the ward was too short” . Other reasons for not providing patients with the intervention included “spontaneous discharge”, “discharge to palliative care unit”, or “intervention nurse was not informed of discharge”. Of the 35 trained intervention nurses, 16 (46%) actually performed at least one intervention. The most frequent reason for nurses not performing any intervention was the lack of recruitment after the training was performed (14 [40%] intervention nurses). In total, 45 interventions were performed entailing a face-to-face session and a median of 2 (range: 0 to 4) phone calls. Mean duration of interventions was 33 min (range: 10 to 95). Mean duration of phone calls was 17 min (range: 1 to 37).The 74% Fig.  which meDemographic and clinical characteristics at baseline are displayed in Table The mixed model to analyze the primary outcome included a random intercept and a random slope for each individual and a random intercept for each ward. Two alternative models were fitted, one including additionally a random slope for each ward and the other one discarding the random effect for ward. According to the Bayesian Information Criterion these two models had a slightly worse model fit than the model we used. Furthermore, the exact choice of the random effect for ward had hardly any effect on test results for the fixed effects.p = .198). However, the group-by-time effect was significant when analyzing only the eight wards that provided patients before and after the intervention (p = .009). Figure p = .0497). No center effect was observed but bearing in mind that the number of observations in two of the three hospitals was quite small (Table Following the intention to treat maxim there was no significant difference between the slopes of the two groups p = .98. Howevp = .100), whereas smaller p-values were obtained for the eight wards with intervention patients (p = .011) and the 5 wards that recruited more than 10 patients (p = .040).When performing per-protocol analysis the observed effects of the intervention were systematically larger than for intention-to-treat analysis. The group-by-time effect was still not significant when considering all 17 wards (p = .033) and for self-reported health status (p = .037); for patient-related barriers towards pain management it was just not significant (p = .057). Two weeks after discharge, patients in the IG were significantly more satisfied with pain self-management support ; and with pain management in hospital .Line diagrams for secondary outcomes are shown in Fig. To our knowledge, this was the first study to evaluate aspects of implementation of a pain self-management support intervention in clinical practice according to the RE-AIM framework. In our study, we could observe statistically and clinically significant effects for those wards that had the chance to apply ANtiPain on a regular basis. This indicates, that the implementation of Antipain seems worthwhile under certain conditions. Careful consideration should be given to the settings, in which a routine application of ANtiPain may be reasonable. In our study, an estimated high proportion of oncology patients routinely treated on the wards was a prerequisite for the application of ANtiPain. Spending much effort in training and coaching intervention nurses in settings with only little proportions of oncology patients seems pointless. However, finding solutions for those patients with cancer-related pain who are hospitalized on wards with only little proportions of oncology patients may still be necessary. In our study, engaging intervention nurses from outside the wards’ teams to provide ANtiPain was limited and largely depending on the time patients stayed on the wards and on discharge procedures. The large proportion of patients who did not receive ANtiPain  shows this.Our study represents effects one may achieve with a supplementary patient-education approach such as ANtiPain. For institutions that take the challenge to improve patient-related outcomes regarding cancer pain management, ANtiPain may be viewed as one step in a circular quality improvement approach . By a ciOne of the most prominent limitations of our study was the uneven distribution of recruitment. Unfortunately, the stepped wedge design does not allow for unforeseeable changes that may happen in clinical settings such as the structural change that cause the low rate of oncology patients on ward 1 , 41. In Furthermore, baseline differences regarding pain intensity were observed. On the one hand, these baseline difference may be due to between cluster differences, e.g., ward 3 added 17 (11%) patients only in the control period with a baseline pain score clearly higher than the other wards (mean max pain = 8.2 versus 7.5). On the other hand, baseline differences may be due to within cluster differences. In the analysis, we accounted for these differences.Adoption are tested and supported [In our study, implementation was initiated from outside the institutions. We highly recommend embedding implementation in a larger scale project of pain management improvement because patient-related barriers only represent “one side of the medal” . In hospupported .Surprisingly, effects on patient-related barriers to pain management were small and non-significant even though in the pilot studies these effects already were significant despite the small sample size. Even though still in the range of protocol adherence, protocol performance in EvANtiPain differed from that in the pilot studies , 16. As In terms of resources needed for successful implementation, the 1.5-h training for intervention nurses seems the minimum input intervention nurses need for optimal application of ANtiPain. This short training was only possible because exceptionally skilled intervention nurses were chosen. Probably, the academic detailing approach may be better applied when communicative skills are addressed in an additional training session for the intervention nurses. On the other hand, a reduction of patient-related barriers not necessarily translated directly into improved pain-related outcomes . In our The good news is: implementation of pain self-management support in hospitalized patients shortly before discharge is worthwhile. However, the implementation is only under specific circumstances reasonable. (1) The pain self-management support program needs to be adaptable to different clinical settings and treatment paths entailing essential core components and a flexible structure. (2) The implementation of self-management support may better be embedded in a larger scale program to improve pain management with a multi-professional focus. (3) A critical proportion of oncology patients of 50 to 70% oncology patients on the ward to achieve a certain level of “routine” seems necessary. Solutions for those wards with less than 50% oncology patients may depend largely on time of stay as well as on discharge and treatment standards.Additional file 1. Supplemental material Figure 5: Target-performance recruitment.Additional file 2. Supplementary Table 1: Demographic and clinical characteristics of patients who dropped out versus patients who completed the study.


Transcutaneous electrical nerve stimulation (TENS) is a treatment option for cancer pain, but the evidence is inconclusive. We aimed to evaluate the efficacy and safety of TENS.A blinded, randomized, sham-controlled pilot cross-over trial (NCT02655289) was conducted on an inpatient specialist palliative care ward. We included adult inpatients with cancer pain ≥ 3 on an 11-point numerical rating scale (NRS). Intensity-modulated high TENS (IMT) was compared with placebo TENS (PBT). Patients used both modes according to their preferred application scheme during 24 h with a 24-h washout phase. The primary outcome was change in average pain intensity on the NRS during the preceding 24 h. Responders were patients with at least a “slight improvement.”N = 20). The primary outcome did not differ between groups . However, responder rates were higher in IMT . Two patients experienced an uncomfortable feeling caused by the current, one after IMT and one after PBT. Seven patients (35%) desired a TENS prescription. Women and patients with incident pain were most likely to benefit from TENS.Of 632 patients screened, 25 were randomized (sequence IMT-PBT = 13 and PBT-IMT = 12). Finally, 11 patients in IMT-PBT and 9 in PBT-IMT completed the study  contains supplementary material, which is available to authorized users. Cancer pain is a leading symptom on palliative care units (ca. 80% of patients) , 2. As aThough TENS is recommended in most palliative care and cancer pain textbooks , 4, contTherefore, the primary aim was to evaluate efficacy and safety of TENS in addition to standard care for advanced cancer pain patients. The secondary aim of this study was the exploratory identification of subgroups that do or do not benefit from TENS.ClinicalTrials.gov Identifier NCT02655289). Patients were recruited from the inpatient specialist palliative care ward and the acute pain service of the University Medical Center Freiburg, Germany.This was a blinded, randomized, sham-controlled pilot cross-over trial  Statement’s extension for non-pharmacological treatments (NPTs)  in the preceding 24 h. Pain could have been caused by the tumor itself (cancer pain), cancer-directed therapy, or by an association with the tumor, e.g., being bedridden or daily activities. Patients had to have received specialist palliative care for at least 24 h in the inpatient palliative care ward or by the acute pain service. There were no limitations concerning tumor site and type of cancer pain (neuropathic and nociceptive pain).The exclusion criteria were verbal or cognitive inability to use TENS or to answer the questionnaire, high probability of dying within the next week according to the treating physician, and pain that was not directly or indirectly related to the tumor . In addition, we used the following TENS contraindications , 14: eleintensity-modulated TENS (IMT) with 100 Hz. The patients were advised to choose a “strong but comfortable” intensity [A dual channel TENS device  was used at the site of pain in the intervention (IMT) and placebo TENS (PBT) phase. Patients were instructed by an experienced researcher who received training and supervision of a senior physician. The intervention used ntensity , 15 and ntensity .IMT and PBT were used by patients individually, i.e., they were free to turn TENS on or off as they pleased, according to their own perceived benefit.continuous mode with 100 Hz and a fixed intensity, which was either slightly or not perceptible at all. For the sake of adequate blinding, we instructed the patients that two active TENS modes were compared. Patients were informed that the TENS device could be turned on according to individual needs and that the sensory threshold would probably not be reached in this TENS mode. The TENS device was activated for PBT with an intensity that was mostly perceptible for a few seconds and then fell below the sensory threshold through habituation. The display and flashing light of the device in the PBT mode looked and behaved exactly as in the IMT mode [PBT, or sham-controlled TENS, was based on the IMT mode .Most outcomes were based on the Brief Pain Inventory (BPI) , 19 and The primary outcome was change of mean pain intensity in the preceding 24 h, measured on an 11-point NRS before and after the 24-h IMT or PBT phase and after the flexible follow-up.Secondary outcomes of the BPI over the 24 h period included change of worst pain intensity, change of least pain intensity, and BPI items that may have been affected by pain: general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life. Some outcomes were measured on other scales: change of pain perception during TENS application on a 7-point verbal rating scale (VRS), number and percentage of responders defined as patients with at least a “slight improvement” on the abovementioned 7-point VRS. Question 30 from the European Organization for Research and Treatment of Cancer quality of life questionnaire C30 (EORTC QLQ-C30)  was usedMedication with an influence on pain  was documented at baseline and during the study, i.e., if a new drug was added or removed, or if the dose of a drug was increased or decreased by > 50% . FurtherThe patients were screened by treating physicians in the inpatient palliative care ward and the acute pain service. Eligible patients were contacted by the study team to obtain informed consent for study participation. A senior physician was responsible for the randomization list, enabled a concealed central allocation, and patients were directly randomized after giving informed consent. Randomization was performed according to a random, computer-generated list with an allocation ratio of 1:1.The senior physician was not involved in the provision of the intervention or data assessment. TENS was started immediately after allocation to the sequence, and patients were instructed that two active TENS modes were compared in this study.Patients, researchers, the outcome assessor, and the biometrician were blinded concerning the mode of intervention. Thus, the researcher placed the electrodes without knowing the TENS mode. TENS was subsequently activated (IMT or PBT) by a non-blinded treating physician who was not involved in the data collection, data analysis, or the preparation of the manuscript. Patients were instructed not to tell anything about their perceptions of the TENS mode to the research team and had to turn off the TENS device during answering the questionnaire.Patients used the first TENS mode during the first 24-h phase (period 1). After the 24 h washout phase, the patient crossed over to the other TENS mode for another 24 h (period 2). After the main part of the study (period 1 and period 2), patients could decide whether to continue with one of the TENS modes (IMT or PBT) for a flexible short-term follow-up or to stop the study (see study design: Online Resource t tests of the within-subject sums of the result from both periods were used to check carry-over effects (p ≥ 0.05: carry-over effect is negligible) [t tests were calculated for within-subject differences of change scores from both periods , according to the recommendations by Li et al. [We aimed to include 20 patients in this pilot trial to assess the effects and safety (primary aim), and gather valuable information for a fully powered multicenter study. This cross-over trial was analyzed according the recommendations by Wellek and Blettner  and Li eligible) . Paired i et al. . NumbersAs subgroup analysis (secondary aim), we explored characteristics from patients that benefited or did not benefit from TENS regarding average pain intensity in the preceding 24 h. Benefit was defined as difference of more than minus one for change scores (primary outcome) and post treatment scores when subtracting IMT minus PBT, and/or change scores within groups  of more than minus one on the NRS .Patients with complete data for period 1 and period 2 were analyzed per-protocol  and wereAll tests for the secondary outcomes were exploratory. The tests were performed two-tailed using an alpha level of 0.05. The statistical analysis was performed using R (RStudio Version 3.4.2) .N = 20).Participants were recruited from February 2016 to February 2018. We screened 632 patients on the inpatient palliative care ward  stopped the study after completing both sequences and were not available for the short-term follow-up, e.g., because of the burden in using TENS  or no perceived effect    in IMT and for 5.7 h (SD 5.0) in PBT based on the record from the TENS device. In contrast, the TENS use in sequence PBT-IMT was 7.1 h (SD 6.3) in IMT and 8.4 h (SD 6.2) in PBT. In total, TENS was used for 9.1 h (SD 7.5) in IMT and for 7.0 h (SD 5.6) in PBT during the 24-h period .The change of pain perception during the TENS application is shown in Table The analysis of changes within IMT indicated that patients experienced a decrease in average pain, worst pain, least pain, mood, walking ability, and relations Table . In PBT,Figure One out of 20 (5%) patients perceived the electric current as uncomfortable after the IMT phase and 1/20 (5%) after the PBT phase. No other TENS-related adverse events were reported. Four patients (20%) generally criticized that cables were impractical and one (5%) patient felt disturbed by the electrodes.After testing both TENS modes, 7/20 (35%) patients requested a prescription for the TENS device in order to use TENS after discharge.Online Resources With regard to change in average pain intensity (primary outcome), we observed no differences between IMT and PBT. However, results indicated higher responder rates for IMT as secondary outcome. TENS was safe and well accepted.There were no statistically significant differences between groups. These findings are supported by other RCTs, which evaluated TENS in cancer patients –11. HoweInterestingly, our results indicate that IMT had more responders than PBT as measured on the 7-point VRS (responder criterion: at least a “slight improvement”) for change of pain perception during TENS application. This important finding is strengthened by another cross-over RCT, in which the authors also observed a difference between active TENS and PBT on the VRS but not on the NRS scale . TherefoIn IMT, the items worst pain, mood, walking ability, and relations showed a mean change of one or more on an 11-point NRS in the IMT phase, which was suggested as clinically relevant . AdditioFor PBT, only changes in average pain and worst pain were observed. Similar to IMT, the changes in average pain were slightly below the threshold of clinical relevance as explained above , 30. HowComparable changes within groups were also reported in other RCTs for average pain and worst pain , pain atThe results underline that different outcome measures should be assessed since reduced pain perception could result in increased activity levels implying changes in physical function and psycho-social outcomes , 15.With regard to safety, IMT was well accepted and safe in this study. These results are comparable with the analysis of another RCT . The sixAmong all benefit subgroup analyses, we believe that two findings are noteworthy even though the results were descriptive and the sample size was very small.In palliative care and in the field of cancer pain management, gender issues are currently becoming increasingly recognized and future research in this area is advocated –36. InteIn the field of cancer pain, incident cancer pain has been identified as a condition with room for improvement in terms of the available treatment options . TherefoThe strength of this study is the cross-over design that allowed patients to be their own control and have a balance of covariates . The genThough the washout phase of other RCTs –11, 31 dAlso, we considered methodological recommendations for clinical trials evaluating TENS for pain treatment that covered the domains allocation, application, and assessment . AccordiFinally, RCT data concerning TENS from the specialist palliative care setting is extremely scarce. Our study showed that using TENS was feasible in patients with advanced cancer on an inpatient palliative care ward. It provides valuable data on efficacy and safety, and hereby enhances the evidence base of TENS for advanced cancer patients.A shortcoming of this study is that effects may have been underestimated because the pain intensity was low at baseline and outcomes were not measured during the peak effect of TENS, i.e., immediately after stopping TENS . The resMost patients had some sensation during the PBT phase and patients were told that two active TENS modes were compared. This may have led to the considerable effects within the PBT phase and, consequently, to small differences between groups. A third group, e.g., no TENS, could have been of help for assessing the possibly large placebo effect. In general, it should be considered that only a minority of the screened patients on the inpatient palliative care ward was eligible .For the sake of generalizability, we included patients with various types of cancer, sites of pain and types of pain, which enhanced heterogeneity of the sample. In contrast to trials assessing pain therapy in chronic non-cancer pain conditions , the priWe closely followed the study protocol (NCT02655289). There were only two minor deviations: no block randomization and no recruitment via palliative care consultant service


ClinicalTrials.gov, System Identifier: NCT01524666). Participants diagnosed with painful SFN and autonomic dysfunctions were treated with 2.67 g/day agmatine sulfate (AgmaSet® capsules containing G-Agmatine® brand of agmatine sulfate) for a period of 2 months. Before the beginning (baseline) and at the end of the treatment period, participants answered the established 12-item neuropathic pain questionnaire specifically developed to distinguish symptoms associated with neuropathy and to quantify their severity. Secondary outcomes included other treatment options and a safety assessment. Twelve patients were recruited, and 11 patients—8 diagnosed with diabetic neuropathy, two with idiopathic neuropathy and one with inflammatory neuropathy—completed the study. All patients showed improvement in neuropathic pain to a varied extent. The average decrease in pain intensity was 26.0 rating points, corresponding to a 46.4% reduction in overall pain (p < 0.00001). The results suggest that dietary agmatine sulfate has a significant effect in reducing neuropathic pain intensity associated with painful SFN resistant to treatment with conventional neuropathic pain medications. Larger randomized placebo-controlled studies are expected to establish agmatine sulfate as a preferred treatment.Peripheral neuropathies associated with painful small fiber neuropathy (SFN) are complex conditions, resistant to treatment with conventional medications. Previous clinical studies strongly support the use of dietary agmatine as a safe and effective treatment for neuropathic pain. Based on this evidence, we conducted an open-label consecutive case series study to evaluate the effectiveness of agmatine in neuropathies associated with painful SFN (Study Registry:  Pain is a strikingly prevalent symptom in our society. It has been estimated that 20.4% of American adults have chronic pain of various etiologies . ApproxiPainful SFN is difficult to treat. Currently, the first line of treatment for neuropathic pain involves antidepressants such as serotonin norepinephrine reuptake inhibitors (SNRIs), or tricyclic antidepressants (TCAs) and anticonvulsants  ,6,7,8. HTopical therapies have had mixed results, but lidocaine, capsaicin and amitriptyline show promise . OpioidsThere clearly is an urgent unmet need to develop safer and more effective therapies for neuropathies and neuropathic pain. To this end, we sought to assess the effectiveness of the neuroprotective dietary ingredient agmatine ,18,19 inSubstantial preclinical evidence suggests the utility of agmatine in treating a wide spectrum of complex nervous system diseases ,21. Prev2(CH2)4NH2C(NH= )NH], is a ubiquitous molecule found in low amounts in a wide variety of plant-, fish- and animal-derived foodstuffs [Agmatine, decarboxylated arginine [ formation; polyamine metabolism; protein ADP-ribosylation and hence signaling pathways; matrix metalloproteases (MMPs); enzymes implicated in nerve cell death and neuropathic pain; and advanced glycation end (AGE)-product formation, a process involved in the pathology of diabetes and neurodegenerative diseases . ConceivA concerning caveat of the previous clinical trials was that after the short two-week treatment period, the effectiveness of agmatine treatment gradually dissipated . This suTherefore, in the present study, we set up a study to assess the effectiveness of a two-month long oral agmatine sulfate treatment for patients diagnosed with neuropathies associated with painful SFN.ClinicalTrials.gov Protocol Registration System  before starting patient recruitment. The study was conducted in accordance with the Declaration of Helsinki between 2013 and 2017.An open-label uncontrolled consecutive case series study was conducted to assess the therapeutic effectiveness of oral agmatine sulfate in patients with neuropathies associated with painful SFN. Therapeutic effectiveness was evaluated by measuring neuropathy-related pain sensations. Safety and tolerability were also monitored as secondary outcomes. The study was approved by the Institutional Review Boards of JFK Medical Center, Edison, NJ  and was registered with Women and men, 18 years or older, diagnosed with chronic pain secondary to SFN were considered for inclusion in the study. The type of neuropathy was established following thorough medical history review, comprehensive physical and neurological examination and laboratory analyses of blood samples. Diagnosis of SFN was confirmed by the following methods: microscopic assessment of reduced intraepidermal nerve fiber density in minimally invasive 3 mm skin biopsies ; and by ® , in size 0 gelatin capsules, each containing 445 mg of G-Agmatine® brand of agmatine sulfate. AgmaSet® is manufactured under cGMP (current Good Manufacturing Practice) conditions in an accredited facility in the USA. The treatment regimen consisted of 6 capsules per day . During the studies, participants could use any concomitant conventional treatments, but other experimental medications were disallowed.Eligible patients diagnosed with SFN who agreed to participate in the study read and signed the informed consent form. One day following baseline measures, patients began taking 2.67 g agmatine sulfate daily for 2 months. The treatment duration was selected based on unpublished observations of hundreds of people indicating that agmatine sulfate exerts its beneficial effects within 4 to 6 weeks and that treatment must be maintained for as long as symptoms last. Agmatine sulfate was supplied as a nutraceutical dietary supplement, AgmaSetParticipants answered a neuropathic pain questionnaire before starting the medication (baseline) and again after the two-month treatment. The 12-item neuropathic pain questionnaire (NPQ) was developed and tested by Krause and Backonja  specificSafety as a secondary outcome was evaluated by analyses of clinical examinations and patients’ interviews. Tolerability was assessed based on the number of participants who failed to complete the study, of their free will or as a result of adverse effects.All records and data were identified by participants’ code number. All “source data” documents are stored in individual files and kept at the principal investigators’ department.p ≤ 0.05.The results of each patient’s questionnaire at baseline (pretreatment) were compared with those at the end of the study. Pain descriptors were further analyzed according to Krause and Backonja , and chaTwelve patients diagnosed with SFN were recruited to the study. One patient discontinued the treatment after a few days because “the medication had a bad taste”. No other side effect was reported and none of the participants showed any agmatine treatment-related abnormality as assessed by clinical examinations and laboratory analyses.Eight of the patients had used one or more conventional neuropathic pain medications prior to starting and concurrently while taking agmatine; these medications included duloxetine, gabapentin, pregabalin, NSAIDS, topical lidocaine and tramadol .p < 0.00001).As indicated in p < 0.0001). Numbness, tingling and burning, the symptoms most clinically associated with neuropathic pain, were the most highly rated at the onset of the study with a mean pain level of more than 70 rating points. These three symptoms also showed the greatest reductions after treatment with agmatine, by an order of magnitude, with an average decrease greater than 31.6 rating points after treatment (significant at p < 0.001). Reductions in the electric, squeezing and increased pain due to touch categories did not reach statistical significance , or TCAs (tricyclic antidepressants) and anticonvulsants  ,5,6,7,8.While the results of this study are encouraging, there are several major limitations, as follows. (1) It was an open-label uncontrolled study. For example, a randomized placebo-controlled study would account for the possible effects of concomitant treatments. (2) It consisted of a small sample size. For example, a larger sample would enable the assessment of gender, age or BMI differences. (3) It did not employ objective follow-up measures such as skin biopsies, ANSAR and QSART measures to assess whether neuropathic pain improvement measures are associated with the structure and function recovery of small nerve fibers; in this regard, longer follow-up periods than the two-month period used in the present study will be required.In summary, this pilot study suggests that agmatine sulfate has a significant effect in reducing overall pain intensity in patients with SFN resistant to treatment with conventional neuropathic pain medications. The inadequate effectiveness of current pharmacotherapy underscores the importance of the continued research and development into agmatine as a novel treatment for neuropathies. Further randomized placebo-controlled studies, conducted over properly extended periods with adequate numbers of participants, are required to establish agmatine sulfate as a preferred treatment.


Spinal cord stimulators (SCS) have been gaining momentum in the last decade as their role in the management of chronic pain has become more apparent. Our intention was to search, analyze and highlight the effects of spinal cord stimulators on end-organ perfusion. We also looked at vascular diseases of atherosclerotic and nonatherosclerotic nature by examining objective evidence of improved circulation, pain control, limb salvage, and quality of life. We paid specific attention to disease processes such as cerebral hypoperfusion, Chronic-Critical Limb Ischemia, Intractable Angina Pectoris (IAP), Raynaud’s syndrome and Thromboangiitis Obliterans.We performed a Medline database search for medical literature relevant to Spinal cord stimulators encompassing the years 1950 to 2019. Search terms included “Spinal cord stimulator,” plus one of the following search terms: vasculopathy, stroke, cerebral blood flow, angina pectoris, diabetic ulcers, chronic critical leg ischemia, thromboangiitis obliterans and peripheral vascular disease. We included both clinical and experimental human studies that investigated the effect of SCS’s on end-organ perfusion. We also investigated the pathophysiological mechanism of action of SCS’s on the vasculature. We found 497 articles of which 43 more relevant and impactful articles investigating the hemodynamic effects of SCS and its possible mechanism were selected. Animal studies were excluded from the literature review as they provided heterogeneity. In addition to reporting literature supporting the use of stimulators for currently FDA approved uses, we also actively looked for potential future uses. Spinal Cord stimulators showed improvement in cerebral blood flow, increased capillary recruitment, and better quality of life in many studies. Patients also had increased exercise capacity and a significant reduction in the use of narcotic drug use and daily anginal attacks in patients suffering from IAP. Spinal cord stimulators (SCS) have been gaining more attention in recent years for their ability to help control pain. Currently, the FDA has approved SCS for failed back surgery syndrome (FBSS), chronic painful peripheral neuropathy, multiple sclerosis, complex regional pain syndrome, postherpetic neuralgia, and phantom limb pain. The FDA is currently looking into end-stage PVD and refractory angina as there is strong literature support flowing in from countries abroad. Nonetheless, some insurance companies within the United States have already begun to cover SCS for these disease processes as off-label treatments .A Spinal cord stimulator is an implantable neuromodulation device that sends electrical currents to select areas of the spinal cord for the treatment of chronic pain. It consists of an electrode lead, extension cable, pulse generator, and programmer. There are two types of leads, percutaneous and paddle, and each have their own advantages and disadvantages. Percutaneous leads can be used for the initial screening trial and be permanently placed but have a disadvantage of lead migration. On the other hand, paddle leads are implanted via partial or complete laminectomy and provide more stability and less risk of migration. The electrode is connected to an internal pulse generator which is either of the non-rechargeable or rechargeable type and is programmed by an external transcutaneous telemetry device. Patients have the liberty to turn on/off the device and control the stimulation amplitude and frequency to better aid in pain relief -2.Records dating as far back as 130 AD when Roman physicians would place the black torpedo fish across the painful site and let it discharge electricity until the pain was relieved. Towards the early 20th century, 1919, the first electrical stimulator known as the Electreat was first introduced and designed for therapeutic use by Dr. Charles Willie Kent. Gaining interest, in 1965, the Gate Control theory by Melzack and Wall painted a fundamental concept of how the stimulators worked to provide analgesia. They proposed that nerves responsible for carrying pain and touch/vibratory sensation terminated in the posterior dorsal columns of the spinal cord. From there, a “gate” that could be acted upon by both non-nociceptive signals and nociceptive signals could allow for or deny the passage of the pain signal to make it to the central nervous system. Finally, two years later in 1967, Shealy et al published a case study of the first implanted SCS and its relief of chronic pain in their patient. Further, they also described a difference between acute and chronic pain stating the patient had relief from his chronic pain; however, he retained the ability to sense pinprick stimuli. This further lent support to the gate control theory of pain and SCS’s use in treatment [The spinothalamic tract and the dorsal column tract both enter the spinal cord through the dorsal horn which carries afferent large-diameter, myelinated fibers for proprioception, discriminative touch and vibration called AB fibers. It also carries smaller myelinated and unmyelinated fibers for pain and temperature. Turning on the stimulator activates the AB fibers inhibiting the radicular pain by activating the A-delta and C fibers respectively . In animAnother theory of mechanistic action is known as the sympathetic response theory. The idea behind this is that SCS decreases efferent sympathetic activity, thus decreasing alpha-1 activity in the vasculature and causing the release of vasoconstriction. The literature currently sites both working in concert to ultimately cause an increase in lower extremity blood flow, while at the same time suppressing nociceptor signals to the brain, all resulting in better pain and symptom control . Since tCerebral blood flowMany experimental models have widely investigated the effects of SCSs on cerebral blood flow (CBF) and found that placement of the stimulator on the cervical spine has can increase the CBF . For manIntractable Angina PectorisThe use of spinal cord stimulation (SCS) for Angina was first described in 1987 . Spinal The Electrical Stimulation versus Coronary artery Bypass surgery (ESBY) study compared Spinal cord stimulation (SCS) to Coronary artery bypass grafting (CABG) in high surgical risk. Patients with no prognostic or mortality benefit from Coronary artery bypass grafting (CABG). Both groups showed similar results regarding symptom relief, assessed by a decrease in anginal attack frequency and use of short-acting nitrates. The Coronary artery bypass group (CABG) group performed better on exercise tests with less ischemic ST changes on stress EKG. On the other hand, the CABG group had higher mortality and cerebrovascular morbidity compared to the spinal cord stimulator (SCS) group . A couplPeripheral vascular diseaseAccording to the CDC, peripheral vascular disease (PVD) is a rising concern as the number of patients affected by the disease process is increasing. Currently, it is estimated that over 200 million people worldwide and 8.5 million people in the United States alone are affected, with a prevalence as high as 20% in individuals over 60 years old. The presentation of PVD ranges from asymptomatic to debilitating as a progressive disease continuum with an estimated general population awareness of 25% -22. PVD Non Reconstructable Chronic Critical Leg Ischemia2 <30 mmHg), also implying disease chronicity and differentiating it from acute limb ischemia. The study also noted 5-10% of asymptomatic PAD patients will progress to CLI within 5 years and of those patients presenting with CLI, 30% will undergo amputation and another 25% will have died within 6 months [On the latter, more severe end of the disease spectrum of organic PVD is chronic critical leg ischemia (CCLI), which is characterized by severe ulceration of distal extremities and debilitating ischemic pain even at rest. In 2007 the TransAtlantic Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II) updated the guidelines of peripheral arterial disease (PAD) stating that the term critical leg ischemia (CLI) includes “all patients with chronic ischemic rest pain, ulcers or gangrene attributable to objectively proven arterial occlusive disease”  and one Controlled clinical trial (CCT)) for evaluating the efficacy of SCS in NR-CCLI patients. The meta-analysis included all data in accordance with the TASC II criteria of CCLI and non-reconstructability at the discretion of the treating physician. However, the Cochrane article excluded the functional types of PVD such as Raynaud's and Breugar’s disease as well as milder forms of organic types of PVD such as intermittent claudication. The analysis compared SCS patient groups to conservatively managed patient groups , looking primarily at limb salvage and secondarily at pain relief, wound healing, SCS complications, quality of life, and costs. According to the Cochrane analysis, “all studies showed a trend towards a better amputation-free salvage in the SCS group” as low as p=0.08 in the Spincemaille et al. study ,27.2 (Oxygenation) relative to the overall group showed a stronger trend in limb salvage with p values of 0.17 versus 0.47, respectively as in the ESES study [2 measured at baseline was 10mmHg in the SCS group and 12 mmHg in the conservative group. After treatment, TcPO2 was found to be significantly better in the SCS group at 21 mmHg and 11 mmHg in the conservative group (p<0.001) [Subgroup analysis in patients selected by initial TcPOES study ,28. The ES study ,28-30. LES study . Both thES study ,30. Morep<0.001) . Accordip<0.001) ,27,30. Hp<0.001) .2 values at 18-month post-treatment and found patients with a low TcPO2 before SCS treatment (<10mmHg) had limb survival at 77.8% and higher limb survival (89.5%) in patients with a baseline of 10-30 mmHg with sustained TcPO2 at 30 mmHg after 18 months in both groups. The study subsequently concluded that “SCS is an effective therapy in improving limb survival in patients with peripheral vascular disease” [2 (baseline = TcPO2 19mmHg) and a decrease of 15.3% in TcPCO2 in SCS patients (baseline TcPCO2 52mmHg) with a p-value of <0.001. However, more convincing evidence was in the reported dynamic capillaroscopy reading which showed an increase in capillary recruitment  and mean capillary density  post-stimulation. The study further reported an increase in pain relief with no additional painkillers required in 80% of the SCS patients [In summary, the Cochrane review entailing studies prior to the year 2003 did not investigate mortality; however, it shed light on the improvement of limb salvage rates and better pain control ,31. Anotdisease” . A smallpatients .Thrombangiitis obliterans2, systolic perfusion via plethysmography and complete limb preservation with resolution of ischemic rest pain in SCS implanted patients who had concurrently decreased tobacco use (<3 cigarettes/day) at three months and four year follow up; the TcPO2 was found to be increased in the smoking group from 16 to 40 mmHg (p=0.002) at three months and sustained at 0.4 for four years at the last documented follow up, p=0.003 [Buerger disease or thrombangiitis obliterans (TAO), is a non-atherosclerotic segmentally occlusive inflammatory vascular disease affecting small and medium arteries and veins with a male dominant 3:1) prevalence . This di p=0.003 . A very  prevalen p=0.003 .2 and limb salvage [In our extensive search, we found 4 more case reports highlighting the effects of SCS in a total of 9 patients that met the criteria of TAO that had failed first-line treatment with medications and surgical interventions such as prostaglandin- analouge Iloprost, and bypass grafting. Seven out of the total nine patients among the four reports showed resolution of ulcers, pain control not requiring narcotics, marked improvement in TcPO salvage , 38-40. Secondary Raynaud Syndrome and Diabetes MellitusSince the use of SCS is not a gold standard and has been offered to select patients as palliative or alternative treatment, the number of studies on the effect of SCS is limited to case reports in regards to Secondary Raynaud Syndrome (SRS) and Diabetes Mellitus (DM). However, one retrospective single centered study reported increased systolic finger perfusion increased on an average of 25 mmHg and sustained even after four years. The report also documented no ischemic attacks, improvement in the quality of life and pain reduction in the SCS group for SRS patients . One casDiscussionSpinal cord stimulators have shown great potential in treating end-organ perfusion in various studies and involving various organs, most notably the brain, heart, and integumentary system. The brain is very sensitive to changes in CBF and in order to function optimally, regional and global oxygen demands must be maintained. This is especially important when physiological conditions change in the face of dysautoregulation as seen following an acute ischemic stroke or delayed cerebral ischemia after a subarachnoid hemorrhage causing impaired CBF and progressive structural damage . FurtherThe anti-anginal effect of Spinal cord stimulation (SCS) is less understood and more conflicting compared to their effects in the limbs and brain. Proposed Hypothesis include inhibition of the nociceptive impulse generated from the spinothalamic tract via enhancement of the release of inhibitory gamma-aminobutyric acid (GABA) from the dorsal horn interneurons . The molPatients with PVD tend to suffer from symptoms including severe limb pain, claudication and ischemia/necrosis of limbs. Although advances with endovascular surgery have greatly increased diagnostic and symptomatic therapy, there is still a large number of patients who cannot tolerate intervention or are poor surgical candidates. However, even with revascularization or vessel bypass, a lot of these patients will ultimately receive an amputation . In critTreating the symptoms of patients with end-stage PVD has been the mainstay treatment for many years with amputation, unfortunately, being the end-all and final treatment option for many patients. Interestingly, patients that underwent SCS had a strong trend towards amputation-free salvage of the affected limbs compared to those that were treated with conservative treatment, with many patients having clinical improvement in the ischemic ulcers and improvement from ischemic rest pain to mild claudication ,27-29. IOverall, the quality of evidence is low for many of the reported studies worldwide. Nonetheless, some high powered studies have shown to reduce the risk of amputation, and offer an optimal nonsurgical alternative for CLI treatment. In conclusion, SCS has shown a strong statistical trend towards significance in select patients through subgroup analysis. Interestingly, cervical, thoracic or lumbar placement of the SCS has shown to correlate with improvement in disease pathology Table . Early rSpinal Cord stimulators have a well-documented and long history for their analgesic properties. SCS’s have an already established role in patients suffering from chronic pain and evidently have potential in healing vasculopathies. We believe SCS have a place as an alternative and nonsurgical treatment for many vasculopathies; however, while we realize that SCS may not be applicable to everyone, SCS definitely has a niche in a subset of patients on the later more severe side of end stage vasculopathy in which small changes in microperfusion can help immensely. This population of treatable patients is yet to be identified and future research should aim towards more suitable patients. A larger sample and randomized clinical trials are needed in order to compare the efficacy of spinal cord stimulators to sole medical management as well as other modalities in refractory angina. So far, Spinal cord Stimulators use is only proven to relieve Anginal symptoms; more Clinical trials targeting their ability to affect coronary blood flow/reserve are needed. Studies targeting Spinal cord stimulators in management of Heart failure (HF) and ventricular arrhythmias are very limited and mostly on animals. More trials are needed to establish if they can be used in patients with Heart failure or in those at risk for developing ventricular arrhythmias. Finally, the cost and availability of Spinal cord stimulators remain an issue and more studies targeting the cost-effectiveness of their use in the target population are recommended. The effect of SCS on CBF is relatively new and requires more investigation; however, many preliminary studies have shown a potential benefit to a select patient population. Spinal cord stimulators have a potential microcirculatory benefit for select patients suffering from the aforementioned vasculopathies. However, we believe further high-quality research is needed and should be directed towards the cost-effectiveness of administering conservative approaches versus spinal cord stimulators as an alternative treatment option.


Objectives: Studies have proven that improving patients' acceptance of chronic pain could be an effective therapy for alleviating pain and other symptoms. Our objectives were to investigate the correlation between chronic pain acceptance and clinical variables in ankylosing spondylitis (AS), and the prediction role of chronic pain acceptance for biologics treatment.Methods: First, 167 AS patients were recruited to complete a series of questionnaires, including the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Chronic Pain Acceptance Questionnaire (CPAQ), Hospital Anxiety and Depression Scale (HADS), and Tampa Scale for Kinesiophobia (TSK). Bivariate correlation analysis was utilized to investigate the correlation between pain acceptance and clinical variables. Based on the level of chronic pain acceptance and serum C-reactive protein (CRP), patients were separated into four subgroups. Then, another 68 patients initiating anti-tumor necrosis factor (TNF) treatment were recruited to complete the questionnaires at baseline (T0) and 3 months after treatment (T3). The changes in clinical variables and treatment response were compared between multiple subgroups.Results: Chronic pain acceptance had strong correlations with anxiety, depression and fear of movement, and moderate correlations with BASFI and pain intensity. Both activity engagement (AE) and pain willingness (PW) had significant correlations with pain intensity, BASFI and psychological status. In addition, AE had a significant correlation with disease duration, while PW had a significant correlation with ASDAS-CRP. Subgroup analysis showed that patients with low chronic pain acceptance and high levels of serum CRP had the highest BASDAI. Among patients initiating anti-TNF treatment, those with high pain acceptance and high levels of serum CRP achieved the most obvious reduction in BASDAI after 3 months treatment.Conclusion: Pain acceptance is a new tool to assess pain in AS which may also reflect physical and psychological status. Clinicians should identify high-risk patients with low chronic pain acceptance and high levels of serum CRP, and give psychological and pharmacological intervention promptly. Moreover, the combination of baseline chronic pain acceptance and serum CRP level could be used to predict the treatment response in AS patients initiating biologics treatment. Ankylosing spondylitis (AS) is a chronic inflammatory arthritis that most often affects the sacroiliac joint and spine . The majIn recent years, acceptance and commitment therapy (ACT) aiming to increase patients' acceptance of chronic pain has confirmed to be beneficial to alleviate pain , 6. The To measure the level of chronic pain acceptance, Geisser et al. developed a 34-item Chronic Pain Acceptance Questionnaire (CPAQ-34) . Later, The objectives of this study were to investigate the correlation between chronic pain acceptance and clinical variables including disease duration, pain intensity, disease activity, activity limitations, depression, anxiety and fear of movement, and to explore the prediction role of chronic pain acceptance for biologics treatment.At first, 167 AS patients were recruited for the cross-sectional study. Then, another 68 AS patients initiating anti-tumor necrosis factor (TNF) treatment were recruited to explore the prediction role of chronic pain acceptance for biologics treatment. All the patients were recruited from the Department of Rheumatology and Immunology of Shanghai Changzheng Hospital from April 2016 to September 2017. Patients who had accompanying malignant tumors or other rheumatic diseases and those who were unable to comprehend and answer the questionnaires were excluded. AS was diagnosed by two rheumatologists according to the modified New York criteria .After consenting to this study, participants were given a series of questionnaires to complete. These questionnaires included a form for demographic data, the Bath Ankylosing Spondylitis Disease Activity Index (BASDAI), Bath Ankylosing Spondylitis Functional Index (BASFI), Chronic Pain Acceptance Questionnaire (CPAQ), Hospital Anxiety and Depression Scale (HADS), and Tampa Scale for Kinesiophobia (TSK). The 68 patients initiating anti-TNF treatment were tested at baseline (T0) and 3 months after treatment (T3). All the participants completed the questionnaires independently. This study was approved by the Ethics Committee of Shanghai Changzheng Hospital.Disease activity of AS was measured by the BASDAI and Ankylosing Spondylitis Disease Activity Score-CRP (ASDAS-CRP). BASDAI consists of six items associated with five major manifestations, including fatigue, axial joint pain, peripheral joint pain, localized tenderness, and morning stiffness . ASDAS-CCPAQ-20 was utilized to evaluate the chronic pain acceptance in AS. It is composed of two subscales: pain willingness (PW) and activity engagement (AE) , 8. The Based on the levels of CRP and CPAQ score, all the patients were separated into four subgroups . The cut-off value to define low and high CRP, low and high CPAQ were 10 mg/L and 46.8, respectively.U-test was subsequently used for post-hoc analyses with a Bonferroni-corrected p-value. A p-value of <0.05 was considered statistically significant. All data were analyzed using Statistical Package for the Social Science (SPSS) version 25.0 .The qualitative variables were presented as frequency and percentages. The quantitative variables were presented as mean and SD. Pearson correlation coefficient was utilizing to perform correlation analysis. The Kruskal-Wallis test (for continuous variables) and chi-square test  were utilized to compare different variables between multiple subgroups. The Mann-Whitney 2. Percentages of patients with peripheral arthritis, enthesitis and uveitis were 30.5, 43.5 and 5.3%, respectively. In addition, 59.3% of the patients had morning stiffness. AS patients had a medium level of CPAQ, averaging at 62.4 (SD = 24.7). For clinical variables, CRP averaged at 13.4 (SD = 12.6) mg/L, while the BASDAI, BASFI, and ASDAS-CRP averaged at 3.8 (SD = 1.9), 3.9 (SD = 2.1), and 2.2 (SD = 0.7), respectively. On the HADS, anxiety averaged at 8.5 (SD = 4.6), and depression averaged at 8.4 (SD = 4.2). The TSK averaged at 36.9 (SD = 12.3)  years on average. The disease duration averaged 10.4 (SD = 7.9) years. The average body mass index was 23.6 (SD = 10.5) kg/m = 12.3) . The char = −0.60, p < 0.05), depression  and TSK , moderate correlations with BASFI  and pain intensity , and no significant correlations with disease duration , BASDAI , ASDAS-CRP , and CRP . Both AE and PW had significant correlations with pain intensity , BASFI , anxiety , depression , and TSK . In addition, AE had a significant correlation with disease duration , while PW had a significant correlation with ASDAS-CRP  (CPAQ had strong correlations with anxiety ( < 0.05) .All 167 participants were separated into four groups according to the level of CRP and CPAQ. Subgroup analysis showed that the BASDAI and BASFI were highest in group 3 (low CPAQ and high CRP) and lowest in group 2 (high CPAQ and low CRP). Group 1 (low CPAQ and low CRP) and group 4 (high CPAQ and high CRP) were at the medium level. In addition, group 3 and group 4 had higher ASDAS-CRP than group 1 and group 2, while there were no significant differences between group 3 and group 4 as well as between group 1 and group 2. As for anxiety, depression and TSK, groups with low CPAQ (group 1 and group 3) had higher scores than groups with high CPAQ (group 2 and group 4), while there were no significant differences between group 1 and group 3 or between group 2 and group 4 .The 68 patients initiating anti-TNF treatment were separated into four cohorts according to CPAQ and CRP at baseline as previous described . Three mTo the best of our knowledge, this is the first study to uncover the role of chronic pain acceptance in AS. The mean CPAQ score acquired from all the 167 participants was 62.4 SD = 24.7), which was lower than that of patients with rheumatoid arthritis, as reported by Ahlstrand et al.  was not included to define disease activity and inflammation more accurately. To date, there is no gold standard for the assessment of disease activity in AS. Sometimes CRP and BASDAI may not reflect the actual disease activity and inflammation, and MRI is mostly used for diagnostic purposes . SecondlTaken together, we found that lower chronic pain acceptance was correlated with higher pain intensity, higher BASFI and worse psychological status in AS. Pain acceptance is a new tool to assess pain in AS which may also reflect physical and psychological status. Patients with lower levels of chronic pain acceptance and higher levels of serum CRP are more likely to have higher BASDAI. Thus, it is necessary for clinicians to identify these individuals and provide psychological and pharmacological interventions promptly. Moreover, the combination of baseline chronic pain acceptance and serum CRP level could be used to predict the treatment response in AS patients initiating biologics treatment.The datasets generated for this study are available on request to the corresponding author.The studies involving human participants were reviewed and approved by Shanghai Changzheng hospital. The patients/participants provided their written informed consent to participate in this study.HX, TL, and YL conceived and conducted the study. TL and YL analyzed, interpreted the data, and participated in drafting manuscript. HX, TL, and YL revised the manuscript. XW, RS, and JY made substantial contributions to the participant recruitment and data collection. All the authors read and approved the final manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


This study aimed to evaluate whether the presence of awake bruxism was associated with temporomandibular dysfunction symptoms, pain threshold at pressure, pain vigilance, oral health-related quality of life (OHRQoL), and anxiety and depression symptoms in patients undergoing orthodontic treatment.  This observational study followed patients who had started receiving orthodontic treatment for six months. The following variables were measured three times : pressure pain threshold (PPT) in the right and left masseter, anterior temporalis, and temporomandibular joint (TMJ), and right forearm; pain vigilance and awareness questionnaire; and shortened form of the oral health impact profile (OHIP-14). Anxiety and depression symptoms were measured using the Beck anxiety inventory and the Beck depression inventory, respectively. The patients were divided into two main groups according to the presence (n=56) and absence (n=58) of possible awake bruxism. The multi-way analysis of variance (ANOVA) was applied on the date (p=0.050). TMJ and/or muscle pain were not observed in both groups. Time, sex, age group, and awake bruxism did not affect the PPT in the masticatory muscles and pain vigilance (p>0.050). However, the primary effect of awake bruxism was observed when anxiety  and depression  levels were higher and the OHRQoL was lower . The patients with self-reported awake bruxism undergoing an orthodontic treatment did not develop TMJ/masticatory muscle pain. The self-reported awake bruxism is associated with higher anxiety and depression levels and a poorer OHRQoL in patients during the orthodontic treatment. However, the evolution of new definitions and diagnostic criteria for bruxism has great repercussions for the possible relationship between bruxism and craniofacial pain.1Furthermore, the updated international consensus proposed a bruxism grading system to determine whether a certain bruxism assessment method actually offers a credible outcome. In addition, methods often used in the classification system for the bruxism diagnosis, such as self-report and clinical inspection, have been indicated as some of the only best leads to diagnose probable sleep or awake bruxism, and instrumental approaches are required for definitive bruxism assessments.2Awake bruxism is a masticatory muscle activity during wakefulness that is characterized by repetitive or sustained tooth contact and/or by bracing or thrusting of the mandible, and is not a movement disorder in otherwise healthy individuals.5 The hypothesis often discussed is the possible positive relationship between either awake or sleep bruxism and craniofacial pain is still a commonly held view in the clinical practice5, and sometimes even presented as a real and simple cause/effect relationship. In line with the perspective that pain-related temporomandibular disorders (TMD) must be envisaged within a biopsychosocial model of illness, and efforts to understand painful temporomandibular disorders along with other chronic pain conditions in a biopsychosocial context have been made.8 This implies that the association between bruxism and painful temporomandibular disorders has become much more complex.5Until now, the possible relationship between bruxism and symptoms of temporomandibular disorders is still controversial in the literature due to the complexity of etiology and diagnostic of both disorders.9 Therefore, this study evaluates whether the presence of awake bruxism was associated with the occurrence of temporomandibular dysfunction symptoms, pain threshold at pressure, pain vigilance, oral health-related quality of life (OHRQoL), and anxiety and depression symptoms in patients undergoing orthodontic treatment. This study hypothesized a priori that patients with awake bruxism would present differences in deep pain sensitivity, pain vigilance, anxiety and depression symptoms, and OHRQoL, when compared with those without awake bruxism.Orthodontists should be aware of the presence of general and awake bruxism in particular and their possible implications during an orthodontic treatment, such as the excessive use of the jaw and possible association with dental structure , TMJ, and masticatory muscle damage.The ethical approval was obtained from the Human Research Ethics Committee of the University of São Paulo, Brazil . The participants were informed about the examination procedures and assured of the confidentiality of the collected information. Finally, all participants signed an informed consent form before their inclusion in this study.The participants’ recruitment was performed by selecting all the patients who started orthodontic treatment with fixed devices in the period from October 2013 to December 2015 in different specialization post-graduate programs in orthodontics. The study was conducted by three examiners who underwent training and calibration to ensure greater reliability for the data collected at different moments of the study. The minimum desired sample size for this study was calculated using an odds ratio (OR) of 2.0; the test power was 70.0% (β= .10), and the standard error was 5% (α= .05).This observational study followed patients who had started orthodontic treatment with fixed appliance for six months. The patients receiving treatment using removable appliances were not included in the sample. Initially, 162 patients were assessed for eligibility in several orthodontic specialization courses.6 In addition, the exclusion criteria were the following: a) the presence of chronic orofacial pain, such as TMD or primary headache disorders; b) frequent cervical pain, fibromyalgia, and congenital or developmental disorders . A detailed medical interview/anamnesis and a clinical examination were performed to fulfill the inclusion and exclusion criteria. No further tests were performed, such as imaging or blood tests.The inclusion criteria were the following: a) age between 13 and 60 years; b) absence of temporomandibular disorder (TMD) pain, which was assessed through the third question of the Research Diagnostic Criteria for Temporomandibular Disorders (RDC/TMD) questionnaire: “Have you felt pain on the face, in places such as the cheek (jaw) region, by the side of the head, in front of the ear or in the ear, in the last 4 weeks?”. 11 c) Beck anxiety inventory (BAI);12 d) Beck depression inventory (BDI);12 and e) shortened form of the oral health impact profile (OHIP-14).13The following variables were measured: a) pressure pain threshold (PPT); b) pain vigilance and awareness questionnaire (PVAQ);®, Cotia, São Paulo, Brazil). Measurements were obtained with the patient sitting comfortably in an upright position while the examiner pressed the 1-cm2 tip at a rate of approximately 0.5 Kg/cm2/s. The patients were instructed to press the stop button at the first painful sensation. It was highlighted that the purpose was to measure the minimal amount of pressure at the first perception of pain, and not the pain tolerance. The PPT was determined as the arithmetic mean of two measurements and the average of right and left sides were considered for the statistical analysis (see Statistics).The PPT of right and left masseter, anterior temporalis and temporomandibular joint (TMJ), and right forearm was measured using a digital algometer  to 5  and the final score is the sum of all individual items. The psychometric properties of the original version have shown acceptable values for retention  and reliability .12The anxiety symptoms were measured using the Beck Anxiety Inventory (BAI). This self-report questionnaire comprises 21 items and is used to measure the severity of anxiety. The items are rated on a 4-point scale, ranging from 0  to 3 (severely), and the final score is the sum of all individual items. Accordingly, the BAI scores range from 0 to 63, where the higher scores indicated higher anxiety symptoms. This study used the validated version for Portuguese, which showed good psychometrics .12The depression symptoms were measured using the Beck Anxiety Inventory (BAI). This self-report questionnaire comprises 21 items and is used to measure the severity of depression. The items are rated on a 4-point scale, ranging from 0  to 3 (severely) and the final score is the sum of all individual items. Accordingly, the BDI-II scores range from 0 to 63, where the higher scores indicated higher depression symptoms. This study used the validated version for Brazilian Portuguese, which showed good psychometrics .15This self-report questionnaire consists of 14 questions divided into seven domains: functional limitation, physical pain, psychological discomfort, physical disability, psychological disability, social disability, and handicap. The items are rated on a 5-point scale, ranging from 0 (never) to 4 , and the final score is the sum of all individual items. Accordingly, the OHIP-14 scores range from 0 to 56, where the higher scores indicated poor quality of life related to oral health. This study used the validated version for Brazilian Portuguese, which showed good psychometrics .16 nonetheless, this study has not applied the full questionnaire. The patients’ group with awake bruxism was composed according to the answers regularly, often, or always. The patients’ group without awake bruxism was composed according to the following answers: “never”, “sometimes”.After the enrollment, the patients were divided into two main groups according to the presence/absence of self-reported awake bruxism. This information was obtained from questions about daytime grinding or clenching of the teeth, which were adapted from the Oral Behavior Checklist (OBC);17 adolescents (aged 10 to 19 years inclusive) and adults (older than 19 years of age).For the age control, the sample was also divided into two groups according to the guidelines of the World Health Organization (WHO) for age groups:The variables were assessed at three time-points: T0 = baseline, i.e., just before the moment of installation of the fixed apparatus; T1 = one-month after the installation of the fixed apparatus; and T2 = six-months after the installation of the fixed apparatus.Quantitative data  were presented as means and standard deviation (SD) along with the sex distribution. Data normality was assessed using the Kolmogorov-Smirnov test. A log10 transformation was performed when the test results were significant, considering an alpha level of 5% (p<0.050).post hoc analyses were performed using the Tukey’s Honestly Statistical Difference (HSD). The significance level was set at 5% (p=0.050).A five-way Analysis of Variance (ANOVA) was applied as following: the repeated factor time (3 levels) and the factors site (4 levels), age group (2 levels), sex (2 levels), and awake bruxism (2 levels) were computed to compare the PPT values. In addition, a four-way ANOVA was applied as following: the repeated factor time (3 levels) and the factors age group (2 levels), sex (2 levels), and awake bruxism (2 levels) were computed to compare PVAQ, BAI, BDI, and OHIP-14 values. When appropriate, One hundred and fourteen healthy participants fulfilled the eligibility criteria and were enrolled in this study. The mean age (SD) of the sample was 24.7 (11.1) and 52% of them were women. In addition, 49% reported awake bruxism, where the mean age (SD) was 27.3 (12.5) and 64% of them were women. The remainder 51% did not report awake bruxism, their mean age (SD) was 22.2 (9.1) and 41% of them were women. No main effects of time, sex, age group, and awake bruxism were observed on the PPT of masticatory muscles. However, site had a main effect , where the AT and the forearm showed higher thresholds than the masseter and the TMJ (Tukey: p<0.001). Also, there was an interaction between time and sex  where the women’s thresholds at T0 were lower than T2 values (Tukey: p=0.005) and men’s thresholds at T0 (Tukey: p=0.032).There were no main effects of time, sex and age group, or awake bruxism on the pain vigilance (p>0.050). Also, there were no main effects of time, sex, and age group on the anxiety and depression symptoms. However, there was a main effect of awake bruxism where its presence was related with higher anxiety  and depression  levels. Finally, although there were no main effects of time, sex, and age group on the ORHQoL (p>0.050), a worse ORHQoL was reported by patients with awake bruxism .Patients with self-reported awake bruxism undergoing orthodontic treatment did not develop TMJ/masticatory muscle pain. The exclusion of patients affected by previous TMJ pain might have biased the study sample. That might have influenced the composition of an artificially “healthier” sample, and, as a possible consequence, decrease the association “strength” between the presence awake bruxism and the pain-related symptoms.This observational study evaluated the impact of awake bruxism on deep pain sensitivity, pain vigilance, anxiety and depression symptoms, and OHRQoL in patients during orthodontic treatment. The main results were: a) self-reported awake bruxism and six months of orthodontic treatment do not significantly influence the PPT of masticatory muscles in patients without signs and symptoms of TMD pain; b) higher anxiety and depression levels and a worse OHRQoL are found in patients who report awake bruxism regardless of the orthodontic treatment follow-up and age group.19 Although it is not possible to make definitive conclusions about the relationship between the presence of awake bruxism and orthodontic treatment, the results of this study showed that the orthodontic treatment and the presence of awake bruxism did not trigger the appearance of signs and symptoms of TMD pain, as no patients have complained of painful TMD after 6 months. These findings agree with the evidence that orthodontic treatment does not necessarily increase the risk of developing TMD.20The role of bruxism in the masticatory muscle sensitivity has been questioned.21 This evidence weakens the hypothesis that repetitive effort of the masticatory muscles motivated by bruxism episodes would be a risk factor for the development and maintenance of persistent muscle pain. The so called vicious-cycle theory, which was proposed to elucidate the relationship between bruxism episodes and the severity of pain, has not yet demonstrated convincing and definitive acceptance.22The results of no influence of neither the self-reported awake bruxism nor the orthodontic treatment on deep pain sensitivity also agree with experimental data, where healthy subjects demonstrated only low levels of pain and fatigue after an experimental tooth clenching paradigm, which was not associated with an altered release of serotonin, glutamate, lactate, or pyruvate.23 Michelotti, et al.24 (2012) demonstrated that the effects of an experimental occlusal interference differ between individuals reporting a high or low frequency of wake-time oral parafunctions. The interference caused more occlusal discomfort in the high frequency of wake-time oral parafunctions group (HFP) than in the low frequency of wake-time oral parafunctions group and was associated with a significant increase in masticatory muscle pain and headache only in the HFP group. In this study, occlusal alterations resulting from the initial stages of orthodontic treatment associated with self-reported awake bruxism did not contribute to the appearance of symptoms of temporomandibular dysfunction during orthodontic treatment. Furthermore, the presence of awake bruxism was not associated with vigilance pain. New studies may be conducted evaluating the processes of attention in orthodontics, such as somatosensory amplification and hypervigilance.24 Clinical experience suggests that individuals with bodily hypervigilance also present with occlusal hypervigilance and continuously check their occlusion.25 The reaction to an occlusal alteration resulting from the initial stages of orthodontic treatment may be different in individuals with occlusal hypervigilance, which could justify some patients’ difficulty in adapting to the orthodontic treatment.Recently it was suggested that individuals with a high degree of oral parafunctional behavior, such as awake bruxism, have some increased occlusal sensitivity.The studies involving occlusion, orthodontics, and TMD up to the present moment have focused on the incidence and prevalence of dysfunctions in certain samples, seeking to establish the relative risk of this disease. However, since temporomandibular disorders are complex entities, the relationship between these entities should be seen in the pain models, inserting the biopsychosocial perspective in the evaluations. In the researchers’ understanding, this is the first study to investigate the signs and symptoms of TMD in orthodontic patients, which also approaches the psychosocial aspects in the same sample.29 The literature is scarce regarding information assessing anxiety and depression symptoms in patients during orthodontic treatment. Even though the results did not found a significant effect of the orthodontic treatment on psychosocial variables, the impact of awake bruxism on anxiety and depression symptoms and quality of life reinforce previous findings. They have showed an association with psychosocial factors, such as stress, disturbed personality, anxiety; psychopathological factors, such as smoking, consumption of alcohol and caffeine; and genetic factors.31 Traditional assumptions that peripheral factors such as occlusal discrepancies and deviations of the facial anatomy would be possible causes of bruxism have been discredited.32Previous studies have highlighted the need to consider the psychological dimensions before and during the orthodontic treatment.1 However, it is also important to note that self-reported measures of oral parafunction have showed greater prognostic value than clinical assessment;33 b) the relatively large range between the follow-ups would have decreased the chance to detect transient changes, in particular the ones related to pain sensitivity, e.g., experimental data has showed that PPT is reduced after placing orthodontic separators.34Clinicians should be aware of the patients’ psychological traits before starting orthodontic treatment, because these traits may be related to the presence of awake bruxism and to a significant impact on quality of life, compromising the patient’s adaptation during orthodontic treatment. In addition, previous identification of patients with awake bruxism may have implications for the design of the treatment plans on measures, such as cognitive behavioral approaches that can be included and help patients understand their need for relaxed mastication muscles maintenance. This study has some limitations: a) the last international consensus defined and graded sleep and awake bruxism and determined that the self-reported diagnosis is classified as possible bruxism. In this study, the diagnosis of bruxism was performed without any clinical examination, which represents a lower grade of bruxism diagnosis uncertainty (“possible”) according to the international bruxism group.The self-reported awake bruxism is associated with higher anxiety and depression symptoms and poorer OHRQoL in patients during orthodontic treatment. On the other hand, short-term orthodontic treatment does not impact on deep pain sensitivity, pain vigilance, degree of anxiety and depression, and OHRQoL.