Separate linear mixed models were built to estimate the effect of anxiety or depression on repeatedly measured PROs following PRI. Data were analyzed using SPSS software. The analysis included 102 patients. Most mean baseline PROs were significantly worse in anxious or depressed patients than in nonanxious or nondepressed patients: Anxiety NRS-BP (p = 0.007), ODI (p < 0.001); Depression NRS-BP (p = 0.026), NRS-LP (p < 0.001), ODI (p < 0.001). All patients showed a clinically meaningful reduction in pain and functional improvement over a 12-month follow-up. There was no significant difference in the estimated overall mean PRO between all patients (p > 0.05). In conclusion, anxiety and depression are associated with worse PROs before and after PRI. However, patients with underlying depression or anxiety can expect a similar gain in PRO compared to patients without depressive or anxious symptoms.The aim of this study was to research the influence of psychological confounders on patient-reported outcomes (PROs) after lumbar infiltration therapies of periradicular infiltrations (PRI). Patients who underwent PRI in a single center between June 2018 and December 2019 were included. PRI was performed in patients with predominantly unilateral lumbar radiculopathy which existed for at least 6 weeks based on single-level nerve root compression , confirmed by morphological imaging. The numeric pain rating scale (NRS) for back pain (BP) and leg pain (LP) and the Oswestry Disability Index (ODI) were assessed preinterventionally, on the first day (only NRS) and at 6 weeks, and then 3, 6, and 12 months postinterventionally. The minimally clinically important difference (MCID) served as the threshold for the therapeutic effectiveness evaluation. The health-related quality of life (SF-36) was recorded preinterventionally and after 12 months. Based on the Hospital Anxiety and Depression Scale, the patients were dichotomized into depressed or nondepressed and anxious or nonanxious. Categorical data were evaluated using Fisher’s exact test, and continuous data were evaluated using Student’s  Degenerative changes in the lumbar spine are a common cause of chronic back pain (LBP) and radiculopathic pain (RP), physical limitations, and a reduced health-related quality of life. Moreover, they are associated with significant social and health care costs in Western societies and have a growing lifetime prevalence ,2,3. TheThis study aimed to compare the outcome of patients after PRI with and without psychological confounders to support clinical decision making in this patient population. Our primary hypothesis was that patients with anxiety and/or depression before PRI would show less pain and functional improvement than patients without such confounders. Our secondary hypothesis was that patients with anxiety and/or depression have more pain and lower function before and after PRI.Patients from a database researching the diagnostic value of PRI at a university spine center between June 2018 and December 2019 were included in this retrospective, single-center, cohort study after screening for inclusion/exclusion criteria. This manuscript adheres to the applicable STROBE guidelines . The incTo avoid a study bias the exclusion criteria were previous surgeries on the affected spine segment and bilateral radicular complaints, and multilevel pathologies in the MRI of the lumbar spine. Furthermore, patients with an increased peri-interventional risk profile due to other diseases were excluded: e.g., clotting disorders, insufficiently controlled diabetes mellitus, intake of oral anticoagulants, leukocytosis and increased CRP, known allergy to local anesthetics or steroids, and known infections and/or cancer diseases. Patients who had an absolute surgical indication due to acute serious neurological deficits  were also excluded from the study. Regarding other possible confounders in terms of treatment success, patients with known addictive disorders or proven psychological pain were also excluded.The present study was approved by the local ethics committee (2022-2852-Daten) and performed according to the Declaration of Helsinki 1975. All patients routinely signed informed consent for anonymously processing their data. Due to the retrospective design of the study, no study-specific consent form was signed. During the screening of electronic patient files, the selection criteria used were in the form of a fully completed Hospital Anxiety and Depression Scale (HADS) before the intervention. A flowchart of the patients included in the analysis is shown in ®, MIBE GmbH Arzneimittel, Sandersdorf-Brehna, Germany; Lidocaine hydrochloride) + 0.5 mL corticosteroid . Before injection, needle aspiration was performed to prevent vascular spread. Due to CT-guided needle positioning, no contrast agent was used.Patients were treated under sterile conditions and placed in the prone position on the table of the CT scanner . During PRI treatment, the needles were positioned lateral to the midline at the level of the affected nerve root via a transforaminal approach ,18. The The scores presented below are summarized in The patient’s back pain and leg pain perceptions were assessed using a numerical rating scale . The German version of Oswestry Disability Index (ODI) was used to determine functional restriction. The ODI has become one of the most used measures of disability in back pain. A very high level of test–retest reliability was found (r = 0.91) in the literature. The total ODI score ranges from 0 (no disability) to 100 (maximum disability) ,20. The To research the clinical improvement  of patients with and without anxiety and depression, the subgroups’ patient-reported outcomes (PROs) with positive and negative HADS scores were compared . In the t test for independent samples, and the normal distribution of the data was assessed in advance using the Kolmogorov-Smirnov test. Categorical data were evaluated using Fisher’s exact test, and continuous data were evaluated using Student’s t test. Separate linear mixed models were built to estimate the effect of anxiety or depression on repeatedly measured PROs  following PRI. The effects were adjusted for the respective baseline PRO and the timepoints of assessment. The two-sided level of significance was 0.05 for all statistical tests.This work’s statistical evaluation was carried out using the software SPSS Statistics Version 28 for Macintosh . The demographic data were checked using Student’s A total of 102 patients were available for data analysis with a complete 12-month follow-up and completely available HADS . The patMost of the mean baseline PROs were significantly worse in anxious or depressed patients than in nonanxious or nondepressed patients .Regarding pain and functional improvement after PRI, both anxious and nonanxious patients, as well as depressed and nondepressed patients showed a reduction in pain  and functional improvement over a 12-month follow-up A–C. In pHowever, based on separate baseline PRO-adjusted linear mixed models, there was no significant difference in the estimated overall mean PRO improvement between anxious and nonanxious and depressed and nondepressed patients .No differences between the groups were observed regarding the side effects after CT-based PRI. A total of 12 patients (12%) reported slightly transient and self-limiting side effects (1–4 h). These effects included numbness in the leg (eight patients); headache (two patients); and mild allergy, including redness of the face (two patients). No serious adverse events were reported during the 12-month observation period.The aim of the present study was to compare the outcome of patients after PRI with and without psychological confounders. Here, we report that anxious and nonanxious patients, as well as depressed and nondepressed patients showed a reduction in back pain and associated leg pain and functional improvement following CT-guided PRI over a 12-month follow-up. Regarding our primary hypothesis, we found no significant difference in the estimated overall mean PRO improvement between anxious or nonanxious and depressed or nondepressed patients. Even with MCID taken into account, the reduction in pain and improvement in function were clinically meaningful in both anxious and depressed patients. Conversely, anxiety and depression had a negative influence on pain and function at the baseline level. The subgroups also showed higher pain levels and functional impairment over the entire observation period. Our results underline the known fact that depression and anxiety can increase back pain and decrease functionality . FurtherSeveral limitations should be considered in interpreting our results. First, changes in psychological status after intervention were not evaluated. The present study focused on the effect of the preinterventional psychological status on the clinical outcome. Therefore, the psychological status after the intervention was not included. This status may change after interventional treatment. Furthermore, in the present study, the HADS was used as a screening method for the presence of anxiety and depression and not the possibly known diagnosis of anxiety disorder or depression of the patients concerned. Thus, we are not allowed to obtain information on a possibly already existing antidepressant or anxiolytic therapy. This must be considered when interpreting the results.Second, we only collected the work status. However, other confounders that may affect postinterventional clinical results, such as social and educational background, were not recorded. However, it is known that such factors can influence the clinical outcome after lumbar fusion surgery ,33, and The present study demonstrates that patients with depressive or anxious symptoms reported higher pain levels and more functional restrictions before and 12 months after PRI. However, patients with these confounders did show similar pain relief, functional improvement, or improvement of HrQoL. In conclusion, patients with chronic pain in degenerative lumbar disorders with accompanied depression or anxiety can expect to receive a similar gain in PRO compared to patients without depressive or anxious symptoms following PRI. In a general sense, if confirmed in a larger number of different approaches and clinical situations, it should be considered that depressed and anxious patients should not be excluded from the possibility of infiltrative interventions. Further, the outcome may be improved after identifying patients with psychosocial confounders by early education regarding the expected outcome, possibly early psychological intervention, and shifting the focus to multimodal therapy concepts.


Since the start of the 2019 coronavirus pandemic, interest in digital therapeutics (DTx) has increased. Temporomandibular disorder (TMD) fundamentally requires cognitive behavioral therapy (CBT), including physical self-regulation. An application that records TMD pain and parafunctional activities for CBT has recently been developed. However, evidence of the reduction of clinical symptoms in patients via repetitive software-driven CBT is lacking. The purpose of the present study was to evaluate the impact of applications that support CBT regarding the performance of CBT and the improvement of clinical symptoms in temporomandibular joint patients. From 20 October 2020 to 7 January 2021, we randomly assigned 41 participants diagnosed with TMD to control  and experimental  groups. We randomly assigned 41 participants diagnosed with TMD to control  and experimental  groups. Improvements regarding the number of tender points, mouth opening, visual analog scale score, pain level upon palpation, joint sound, and stress were compared between the two groups. Compared with the control group, the experimental group showed significant improvements in the number of tender points and degree of mouth opening. They also showed improvements in pain level, joint sound, and locking, although not statistically significantly, as compared with the control group. Thus, further studies with a greater sample size need to be conducted to confirm the findings. Nevertheless, our results showed that repetitive cognitive behavioral therapy using a smartphone application can be used as digital therapeutics for temporomandibular disorder patients. In recent years, medical and dental experts have endeavored to devise and promote various scientific tools, such as the development and verification of new biomarkers to replace pharmaceuticals and the development of quantifiable disease models . In addiTemporomandibular disorder (TMD) is a disease characterized by dysfunction of the temporomandibular joint (TMJ) and the musculoskeletal system of the head and neck. It has a prevalence rate of 10–15% of the general adult population, with most of the patients being female, aged 20–40 years. The prevalence rate among adolescents is approximately 27% ,7. BruxiTypically, most TMD patients visit medical experts when their disease is quite advanced. According to Choi et al., as a result of a follow-up study of patients who discontinued treatment without symptomatic improvement resulting from the initial conservative treatment, 36% of the patients required treatment as the disease became chronic . ConsequThe clinician’s goal for TMD patients is to restore the function of the patient’s TMJ and return the condition to normal by reducing the patient’s pain and parafunctional activities that burden the TMJ . These pTherefore, the purpose of this study was to evaluate the impact of early-stage digital health applications, incorporating the recognition of self-behaviors and repetitive CBT, on TMD patients in improving the clinical symptoms. The null hypothesis was that there is no significant difference in the improvement of symptoms, such as the degree of pain, degree of mouth opening, and TMJ sound in TMD patients after the use of application based on CBT.From 20 October 2020 to 7 January 2021, we evaluated patients who were diagnosed with TMD at Yonsei University Dental Hospital of Oral Medicine. We compared 20 patients who received conservative treatment, such as behavioral therapy, drug treatment, and physical therapy, with a smartphone application and 21 patients who received only conventional treatment. Two participants in the experimental group and one participant in the control group were excluded from this study due to voluntary treatment discontinuation. The number of tender points, degree of mouth opening, subjective pain level, pain level on palpation, joint sound, and stress were compared and analyzed. In this study, the control group and the experimental group were randomly assigned. Randomization is a process that provides each participant with the same chance of being assigned to the intervention or control group.This study was reviewed by the Clinical Research Ethics Committee at Yonsei University Dental Hospital (IRB No. 2–2020-0055). Interviews were conducted in an independent space to protect the privacy of the subjects. During the in-person interviews, the researchers explained to the patients: the purpose and background of the clinical study, information about smartphone application used in the clinical study, procedures or tests that the subjects will undergo in a clinical study that involves invasive methods to the patient’s body, requirements that the subjects must comply with, other treatment methods or types that the subject may choose, and the potential risks and benefits of these treatments, etc. After explaining the study, we obtained consent from subjects, and the data collected during the study were stored on a computer with limited access.Inclusion Criteria(1)Male and female participants between the ages of 12 and 65 years old(2)Participants diagnosed with the following by a specialist at the Department of Orofacial Pain and Oral Medicine at Yonsei University Dental Hospital: Myalgia, local myalgia, myofascial pain, myofascial pain with referral, Arthralgia(3)Willing and able to comply with the clinical trial protocol(4)Participants who understand the contents of the study sufficiently and have voluntarily signed the informed consent form(5)Participants who own a smartphone capable of running the application and are capable of using the applicationExclusion Criteria(1)Participants who are not diagnosed with temporomandibular disorders (TMD) according to the DC/TMD criteria(2)Participants with rare muscle diseases such as severe myasthenia gravis, Eaton-Lambert syndrome, and muscular dystrophy(3)Participants with severe metabolic disorders such as hypertension and diabetes(4)Participants diagnosed with neurological disorders (such as Parkinson’s disease or Alzheimer’s disease) or psychiatric disorders(5)Participants who are currently potentially taking skeletal muscle drugs, alcohol, or drugs from other institutions(6)Participants who are undergoing orthodontic treatment or are wearing other oral devices(7)Participants who withdraw their consent during the trial(8)Other participants deemed inappropriate by the study investigatorsIn this study, we used a smartphone application that focused on identifying pain and inputting pain levels. The application was designed by a specialist in oral medicine. The experimental group received informed consent in a separate space and received sufficient education on how to install and use the application. Each usage of our smartphone application would take approximately 5–10 min per day, and patients were encouraged to use it every day. The contents of our app were equally prepared based on the Management of Temporomandibular Disorders and Occlusion  and a Yonsei University Oral Medicine questionnaire, and the contents were confirmed to be safe to use. This was a minimum viable product (prototype) of Software as a Medical Device , which is aimed at a TMD DTx. The main functions are (1) Morning Record (morning condition record), (2) Bedtime Record (evening condition record), and (3) Record Pain Now . Data from The Record Pain Now function were entered into the calendar and could be checked at any time, and the highest pain score was marked in color on a Visual Analogue Scale (VAS) on the calendar so that the subjective pain score could be seen at a glance. This allowed the patient to grasp the trend of an increase or decrease in pain level .Types of records(1)-Sleep quality-Subjective symptoms of bruxism and clenching-Pain upon waking upMorning Record(2)-Pain site-Pain intensity-Pain levelRecord Pain Now(3)-Whether the patient managed to avoid acts that cause pain-Whether the patient controlled habitual use of the jaw-Whether jaw resting was implemented (‘N’ sound position)-Whether jaw health exercise was performedBedtime RecordPalpation was performed by a specialist with more than 7 years of experience in orofacial pain treatment. The strength of the force measured was 1 kg for muscles and 0.5 kg for joints, according to the Diagnostic Criteria for Temporomandibular Disorders. The following tender points were evaluated on each side: TMJ, 2 points ; deep masseter, 1 point; masseter, 3 points ; temporalis, 3 points ; sternocleidomastoid, 1 point; splenius capitis, 1 point; and trapezius, 2 points . Thus, 13 sites per side (26 sites on both sides) were measured. Discomfort during palpation was recorded, and the conditions before and after treatment were compared.Among the 26 tender points, the degree of pain evaluated by palpation of the chief complaint area was subdivided into levels of none, mild, moderate, and severe, which were compared before and after treatment .The maximum degree of mouth opening and the other conditions were measured using the distance between the incisors , and were compared before and after treatment .The overall pain levels according to subjective statements were recorded via a VAS on the day of examination, and the conditions before and after treatment were compared. The criteria for the VAS were 0 point for no pain, 5 points for moderate pain, and 10 points for the worst imaginable pain .Joint sounds from the TMJ were recorded and categorized into none, simple joint sounds (clicking), large joint sounds (popping), and complex joint sounds (crepitus), while the state of locking was recorded separately. A clinician’s auscultation and the patient’s subjective statement of joint sound improvement were recorded before and after treatment.We compared the scores calculated on a 5-step Likert scale for 10 questionnaires; detailed information can be found in Supplement 2 , and the statistical significance level was set at p-values for age, gender, and treatment duration between the two groups, there was no statistical difference. The average duration of treatment for both groups was 5.9 weeks. Their general characteristics are summarized in A total of 41 subjects were randomly assigned to an experimental group (20 persons) and a control group (21 persons). When considering the p < 0.001), an average increase of 3.5 mm in the degree of mouth opening (p = 0.002), and an average decrease of 3.3 points in the patients’ subjective VAS levels (p < 0.001). These differences were statistically significant. In the control group, there was a statistically significant difference regarding the decrease in the number of tender points  and the decrease in the patients’ subjective VAS levels , but there was no significant difference in terms of the increase in the degree of mouth opening or the decrease in stress. In addition, in the experimental group, the number of tender points (p = 0.008), mouth-opening degrees (p = 0.042), and VAS scores (p = 0.012) showed significantly greater effects than in the control group  were similar to those of previous studies on TMD prevalence, in which the mean age was 30–40 years, with a ratio of 1:3.3 for men to women ,19,20,21p < 0.001) while the control group showed a mean decrease of 1.8 tender points (p = 0.002). In both groups, the respective treatments showed significant improvements in the number of tender points. Compared with the control group, the experimental group showed a significant decrease in the number of tender points (p = 0.008). The mean VAS score (subjective pain level) decreased by 3.3 points in the experimental group (p < 0.001) and 1.5 points in the control group (p = 0.008). The experimental group showed a significant decrease in the mean VAS score as compared with the control group (p = 0.008). The main treatments for myalgia included drug treatments, such as cyclobenzaprine, metaxalone, methocarbamol, and baclofen, as well as non-drug treatment, such as patient education, exercise therapy, CBT, and physical therapy [The American Academy of Craniomandibular Disorders states that CBT is an important treatment for TMD . TMD sho therapy ,25. Agga therapy . These fp = 0.002). In contrast, the control group showed a mean increase of 1.0 mm in the degree of mouth opening (p = 0.072). Compared with the control group, the experimental group showed a significant increase in inter-incisal distance (p = 0.042). In general, patients who have inter-incisal distances of less than 35 mm are thought to have mouth-opening limitations, and clinical symptoms may include pain but patients may not feel pain. Mouth opening limitations may present acutely, such as in the form of a myospasm, but they are mostly observed in patients with chronic articular disc displacement (ADD) [The mean degree of mouth opening increased significantly by 3.5 mm in the experimental group (nt (ADD) . In our nt (ADD) . In a stnt (ADD) .However, in our study, stress did not differ significantly between the experimental and control groups. Stress caused by pain may have decreased by the improvement in temporomandibular pain; however, overall stress, as an external factor, did not change among the participants. As previously described, stress caused by external factors may be a key factor leading to TMD . Thus, uThe pain induced by palpation of the tender points labeled as areas of chief complaint was compared before and after treatment. In both the experimental and control groups, positive treatment effects were observed, with no significant differences in the improvements between the two groups. In the experimental group, approximately 45% of the participants showed severe pain before treatment. After conventional treatment, combined with application use, no participant complained of severe pain, and the rate of participants without pain increased significantly from 5% before treatment to 40% after treatment. Similarly, in the control group, the rate of participants without pain increased by 23.8%, and the rate of participants with severe pain decreased by 14.2% after treatment, suggesting that the conventional treatment had positive effects. However, the improvement of the pain after palpation was greater in the experimental group that used the application than in the control group. TMD pain is improved with consistent drug treatments, stretching and posture correction, CBT, physiotherapy, and occlusal stabilization splints ,30,31. OOverall, joint sound was improved after treatment. In the experimental group, one of the participants with popping sounds reported having clicking sounds after treatment, and three of those with clicking sounds no longer observed joint sounds following treatment. In particular, in one patient with a locking state, joint sound improved to a clicking sound after treatment, which implied encouraging treatment effects. To avoid having to use reduction to treat chronic locking in patients suffering from ADD, education, restricted use and movement range, occlusal splints, and manual manipulation are important. The main goal is to induce the joint to maintain a resting position for as long as possible . CBT usiLiu et al. reviewed five articles on randomized controlled trials (RCTs) and semi-RCTs of 323 studies on the effects of CBT on TMD. According to their report, the reviewed articles resulted in insufficient evidence to present a high grade of recommendation on CBT due to inconsistencies in the methods, such as control groups and follow-up periods. RCTs with more thorough designs were needed . On the The findings of this study suggested that participating in repetitive CBT by using a smartphone application can improve TMD symptoms. These results may support the development and effectiveness of DTx. Previously, although self-management education and repetitive CBT were noted to be important, there were no options for clinicians to educate and recommended behavioral control after the treatment at the clinics. In this study, partaking in CBT by using a digital application for more than 10 min a day, for 4–6 days a week over 5.9 weeks, helped to control and improve symptoms of TMD. The application is expected to undergo updates focusing on determining professional treatment timing through self-inspection, repetitive learning, and understanding (with remote support), and would present information through data accumulation and analysis. Thus, such an application may be a promising means of DTx for the management and treatment of TMD.However, some limitations must be considered in the interpretation of this study’s findings. The limited sample size and limited CBT, using only patient records, present challenges in validating the effects of the intervention. Follow-up studies must include a larger sample size and a long-term follow-up period. Additionally, with a larger cohort, the experimental group could be subdivided by diagnosis for a detailed analysis of the effects.This study investigated the effects of a smartphone application that helps individuals voluntarily and repeatedly perform CBT for improving clinical symptoms of TMD. Based on the limitations and findings of this study, the following conclusions were drawn. The use of an application supporting CBT showed a positive effect in terms of reducing pain, increasing the degree of mouth opening, and improving joint sounds in patients with TMD, when used in conjunction with conventional treatment methods. These results imply that CBT conducted by using digital applications may be an effective DTx with clinical therapeutic effects for TMD patients. To validate the role of the application as a DTx, the function of the application must be expanded in terms of CBT and it must be tested on larger sample sizes for a longer period of time to demonstrate clinical effectiveness.


Objectives: Rheumatoid arthritis (RA) has been defined by the American College of Rheumatology in 1987 as a chronic inflammatory disease characterised by joint swelling, joint tenderness, and destruction of synovial joints leading to severe disability and premature mortality. There is a paucity of literature assessing corticomotor excitability in RA patients. This study aimed to assess the effect of motor imagery on corticomotor excitability and pain status in RA patients. The specific objectives were to study the effect of motor imagery on corticomotor excitability and pain status in RA patients. We also wanted to compare the corticomotor excitability between RA patients with healthy controls. The correlation between the measures of corticomotor excitability and pain status in RA patients has also been done.Methods: The study was designed as a pilot clinical trial with a case-control design. Forty participants were recruited for the study. Twenty RA patients were recruited from the Department of Rheumatology and Department of Physical Medicine and Rehabilitation (PMR), AIIMS, New Delhi, and 20 healthy controls. Testing was performed at the Pain Research & rTMS Lab, Department of Physiology, AIIMS, New Delhi. The study was approved by the Institute Ethics Committee, AIIMS New Delhi, and registered in the Clinical Trials Registry-India (CTRI). For the subjective assessment of pain, the visual analogue scale (VAS), Short-Form McGill Pain Questionnaire, WHO-Quality of Life Brief questionnaire (WHO-QOL-BREF), and Rheumatoid Arthritis Pain Scale were used. For the objective assessment of pain, hot and cold pain thresholds were assessed using thermo-tactile quantitative sensory testing (QST) using the method of limits and corticomotor excitability using a transcranial magnetic stimulation device. All participants were also asked to perform motor imagery tasks which consisted of a metronome-paced thumb opposition paradigm. Results: The resting motor threshold (RMT) decreased significantly after motor imagery when compared to the mental calculation group. The amplitude of motor evoked potential (MEP) and QST parameter value was comparable in both the groups before and after motor imagery and mental calculation. RMT was found to be significantly higher whereas MEP values were found to be significantly lower in RA compared to controls.Conclusion: We conclude that patients suffering from RA have decreased corticomotor excitability compared to controls. Motor imagery was effective in improving corticomotor excitability in these patients and can be used as rehabilitation in RA to relieve their pain. Rheumatoid arthritis (RA) has been defined by the American College of Rheumatology in 1987 as a chronic inflammatory disease characterised by joint swelling, joint tenderness, and destruction of synovial joints leading to severe disability and premature mortality . An RA pThe study was designed as a pilot clinical trial with a case-control design. Forty participants were recruited for the study; 20 RA patients were recruited from the Department of Rheumatology and Department of Physical Medicine and Rehabilitation (PMR), AIIMS, New Delhi, and 20 were healthy controls. Not a priori sample size calculation could be done due to a lack of comparable studies. Testing was performed at the Pain Research & rTMS Lab, Department of Physiology, AIIMS, New Delhi. The study was approved by the Institute Ethics committee, AIIMS New Delhi (Ref. No. IECPG-98/28.02.2019) and registered in the Clinical Trials Registry-India (CTRI) (REF/2019/05/025648 (B)). The inclusion criteria were RA patients with pain  for more than half the number of days in the past six weeks and having >6/10 score in the scoring system for RA given by the American College of Rheumatology. The right-handed patients were included. The participants of the control group were age- and gender-matched, pain-free healthy volunteers. The age group for both sets of subjects was 18-65 years . The exclusion criteria were patients with known contraindications to TMS including metal implants in the head , known skull defects, facial tattoos, concussion within the last six months, history of epilepsy or seizures, a pacemaker or artificial heart valve, intracardiac lines, history of unexplained recurring headaches, and current pregnancy. Participants with a neurological condition, psychogenic/psychosomatic pain, a history of chronic pain other than RA, and cardiovascular and respiratory disorders were excluded. Participants who had a history of substance abuse were also excluded. For the subjective assessment of pain, VAS, Short-Form McGill Pain Questionnaire (MPQ-SF), WHO-Quality of Life Brief questionnaire (WHO-QOL-BREF), and Rheumatoid Arthritis Pain Scale were used. For the objective assessment of pain, hot and cold pain thresholds were assessed using thermo-tactile quantitative sensory testing (QST) using the method of limits and corticomotor excitability using a TMS device. All participants were also asked to perform an MI task, which consisted of a metronome-paced thumb opposition paradigm. Statistical analysisData were entered into MS Excel and analysed by SPSS 25.0 software for Windows . The data obtained were screened for normality to decide the appropriate tests. The various statistical tests used for analysis are elaborated in the Results section.The demographic details of the participants are mentioned Table . RA patiRMT was found to be significantly higher whereas MEP values were found to be significantly lower in RA patients compared to healthy controls. RMT and subjective pain rating were not significantly correlated in RA patients. RMT decreased significantly after motor imagery when compared to that in the mental calculation group. The amplitude of MEP was comparable in both the groups before and after MI and mental calculation. Quantitative sensory testing (QST) parameters were comparable in both groups before and after MI and mental calculation.RA is a chronic inflammatory disease characterised by the destruction of synovial joints leading to severe disability and premature mortality . CorticoIn our study, we observed decreased amplitude of MEP whereas increased RMT in RA patients compared to healthy controls suggesting lower corticomotor excitability in RA patients Figures , 3. Our We did not find any improvement in corticomotor excitability parameters in the mental calculation group Figure . This coRA patients reported moderate to severe pain on the numerical pain rating scale (VAS score = 5.5) Table . The WHOIn the present study, a high MPQ-SF score value = 26.35) was observed, suggesting the extreme nature of pain in RA patients Table . The var.35 was oIn our study, we used responses to thermal stimuli as an objective parameter for the assessment of pain status. We found WDT and CDT to be comparable after MI in RA patients. The hot and cold pain thresholds  at baseline were higher in RA patients compared to healthy controls which is similar to another study  Figures, 5. AfteThus, we conclude that MI improves corticomotor excitability when used regularly for an extended duration. We propose that MI should be used as a rehabilitation intervention for RA patients.Limitations and future directionsThe present study was conducted with a limited number of patients, and we believe that a larger sample size would have provided better insights into the role of MI in pain relief in RA patients. The duration of MI may be increased for better pain relief. Also, the use of techniques such as fMRI could have elicited the actual brain areas activated during MI and mental calculation.We conclude that patients suffering from RA have decreased corticomotor excitability compared to age- and gender-matched healthy controls. MI was effective in improving corticomotor excitability in these patients. Hence, MI can be used as a rehabilitation intervention for RA, which can relieve RA patients from their pain and motor deficits.


Postherpetic neuralgia (PHN) is a refractory neuropathic pain condition in which new treatment options are being developed. Repetitive transcranial magnetic stimulation (rTMS) may have the potential to reduce pain sensations in patients with postherpetic neuralgia.This study investigated the efficacy on postherpetic neuralgia by stimulating two potential targets, the motor cortex (M1) and the dorsolateral prefrontal cortex (DLPFC).This is a double-blind, randomised, sham-controlled study. Potential participants were recruited from Hangzhou First People’s Hospital. Patients were randomly assigned to either the M1, DLPFC or Sham group. Patients received ten daily sessions of 10-Hz rTMS in 2 consecutive weeks. The primary outcome measure was visual analogue scale (VAS) assessed at baseline, first week of treatment (week 1), post-treatment (week 2), 1-week (week 4), 1-month (week 6) and 3-month (week 14) follow-up.p < 0.005), as well as to the DLPFC stimulation . In addition to pain, sleep disturbance was significantly improved and relieved by targeting either the M1 or the DLPFC . Moreover, pain sensations following M1 stimulation uniquely predicted improvement in sleep quality.Of sixty patients enrolled, 51 received treatment and completed all outcome assessments. M1 stimulation resulted in a larger analgesia during and after treatment compared to the Sham (week 2 – week 14, M1 rTMS is superior to DLPFC stimulation in treating PHN with excellent pain response and long-term analgesia. Meanwhile, M1 and DLPFC stimulation were equally effective in improving sleep quality in PHN.https://www.chictr.org.cn/, identifier ChiCTR2100051963. Postherpetic neuralgia (PHN) is a typical neuropathic pain condition affecting the lesioned skin regions following the healing of skin rashes . PostherTranscranial magnetic stimulation (TMS) is a safe and noninvasive form of brain stimulation. Repetitive TMS (rTMS) is capable of inducing neuroplastic changes which has been proposed for the treatment of neuropathic pain . Only twIn addition to the M1, the dorsolateral prefrontal cortex (DLPFC) has been increasingly used as an alternative target in the management of neuropathic pain . The anaOverall, the clinical efficacy of motor cortex rTMS on postherpetic neuralgia needs to be re-evaluated and independently investigated given the refractory nature of pain and its adverse influence on quality of life. We have also presented the first investigation of DLPFC stimulation in postherpetic neuralgia. Clinical effects were systematically assessed, including not only pain sensations but anxiety, depression and sleep quality. It is hypothesised that M1-rTMS would be particularly effective in reducing pain sensations, and the DLPFC stimulation would have a unique effect on emotional distress.d = 0.59). Results indicated that 51 participants would ensure 95% statistical power. A total of sixty patients were enrolled considering potential dropout rates (~10%)  .Potential participants were recruited from the Affiliated Hangzhou First People’s Hospital. The inclusion criteria were: (1) IASP diagnosis of postherpetic neuralgia ; (2) at The exclusion criteria were: (1) contradictions to TMS treatment , such asWe conducted a double-blind, randomised, sham-controlled trial registered in the Chinese Clinical Trials registry (ChiCTR-IOR-14005304). Patients were randomly assigned to either M1, DLPFC or Sham group according to a centrally stratified computer-generated randomisation protocol. Patients received ten daily sessions in 2 consecutive weeks delivered by a trained staff (HW). Clinical assessments were performed at baseline, after first week of treatment (week 1), post treatment (week 2), 2 weeks (week 4), 1 month (week 6) and 3 months (week 14) follow-up. All assessments were performed by a single trained and blinded staff member (YH). All participants voluntarily participated in this study and signed an informed consent before the treatment. Ethical approval was obtained from the Ethics Committee of Hangzhou First People’s Hospital (IIT-20220301-0039). This study was conducted in accordance with the Code of Ethics of the World Medical Association (Declaration of Helsinki).Each session started with the assessment of resting motor threshold (RMT), using a figure-eight coil connected to an RT-50 stimulation system  delivering single pulses to the hand region of the M1 at 0.2 Hz. RMT was determined by the minimum intensity to evoke motor-evoked potentials (MEPs) >0.05 mV in 5/10 trials and re-examined in each session. Each rTMS session delivered 3,000 pulses at 10 Hz with 5-s trains and 25-s intervals at 100% RMT .rTMS was delivered either to the contralateral M1, the left DLPFC or a Sham condition. The M1 and DLPFC was located using the hotspot and Beam F3 methodology, respectively . The M1 The outcome measures were reported according to the IMMPACT recommendations for chronic pain clinical trials . The priSafety assessments were performed at each treatment and follow-up session. Headache and scalp discomfort were considered as mild side effects which were most common in rTMS treatment . PotentiIntent to-treat (ITT) analysis was set to include all randomised patients. Multiple imputation algorithm was initially performed, which is a highly recommended methodology in dealing with missing data .χ2 tests. A series of tests were performed to check the assumptions of using a mixed design ANOVA. Specifically, Shapiro–Wilk test was performed to check the normality of the outcome measures in different combinations of our two factors. Levene’s test for homogeneity of variances and Mauchly’s Test of Sphericity were also performed. Results validated the use of mixed ANOVA (ps > 0.05).Data were analysed in SPSS . Demographic variables were initially examined with one-way ANOVA or p ≤ 0.05. χ2 tests were performed to compare the effects on patients’ evaluation of the treatment (PGIC), and bivariate correlation analyses were used to examine the associations between outcome measures. We also performed χ2 tests to examine the relationship between pain response and PGIC.Two-way mixed-design ANOVAs were then performed to examine the effects of treatment group , time and their interaction on the primary and secondary outcome measures. Post-hoc pairwise comparisons were Bonferroni corrected at According to the large neuropathic pain trial , we alson = 19) or not willing to participate in  or loss of follow-up . In the Sham group, five patients withdrew due to no clear effect  or loss of follow-up . All twenty patients in the M1 group were evaluated throughout. Data of twenty patients in each group were analysed with ITT methodology.A total of 105 patients were screened, of which 55 were excluded due to noting meeting the inclusion criteria .Demographic information is presented in F5.13, 146.19 = 8.93, p = 0.001, Post-hoc comparisons indicated that M1 stimulation resulted a larger analgesia during and/or after treatment compared to the Sham , as well as to the DLPFC condition . Both the DLPFC and Sham group resulted in smaller VAS compared to the baseline , but no group difference was observed between these two groups at any time , as well as to the DLPFC condition . Both the DLPFC and Sham group resulted in significant pain reduction compared to the baseline , but no group difference was observed between these two groups at any time  analyses revealed 2.5 and 2.5 for the M1 group at post-treatment and 3-month follow-up, respectively. Meanwhile, no patients reported a pain reduction over 50% in the DLPFC group and thus NNT was not calculated.F4.41, 125.72 = 13.46, p = 0.001, Post-hoc comparisons indicated that, compared to the Sham stimulation, both the M1  and DLPFC stimulation  significantly increased sleep quality during and after the treatment , mixed-design ANOVA revealed a significant interaction effect (reatment .p > 0.05), HAMA  or MMSE . M1 group also reported a higher response rate during the treatment  compared to the DLPFC stimulation , M1 stimulation resulted in larger response rates than the Sham group from post-treatment to all follow-up periods . No group difference was observed between the M1 and DLPFC group , both the M1 and DLPFC stimulation resulted in higher remission rates than the Sham group from 2-week to 3-months follow-up  indicated that more patients reported improvement in the M1 group than the Sham group at 3-month follow-up . When data were categorised based on “much to very much improved” .In the effects on patients’ evaluation of the treatment (PGIC), mproved” , no grouWeek1-PSQIweek4: correctedP = 0.030; VASWeek1-PSQIweek6: correctedP = 0.010; VASWeek1-PSQIweek14: correctedP = 0.005; VASWeek2-PSQIweek4:correctedP = 0.012; VASWeek2-PSQIweek6:correctedP = 0.004; VASWeek2-PSQIweek14:correctedP = 0.004; correctedP > 0.05).Bivariate correlation analyses corrected for multiple comparisons indicated that VAS scores during (week 1) and immediately after the treatment (week 2) were positively associated with sleep quality (i.e. PSQI) in all the follow-up periods in the M1 group  and/or mild scalp discomfort , but three groups showed no difference and the sensations dissolved within minutes or hours. Overall, the treatments were safe and well-tolerated by this treatment protocol .This double-blind, randomised, sham-controlled study was designed to investigate the analgesic efficacy of motor cortex- and DLPFC-rTMS in postherpetic neuralgia. Results indicated an excellent analgesic response following motor cortex rTMS with the effect being maintained up to 3 months. This analgesic effect was supplemented by improvement in patients’ global impression of change. In addition to pain, there was also a significant improvement and remission in sleep disturbance by targeting either the motor cortex or the DLPFC, although DLPFC stimulation was not superior to sham stimulation in reducing pain sensations. We further provided interesting findings on the dynamic relationships between pain and sleep quality following motor cortex rTMS, in which pain sensations uniquely predicted improvement in sleep quality. These treatment protocols were safe with a slight chance to experience mild headache or scalp discomfort.Our results indicated that motor cortex rTMS significantly reduced pain experience in postherpetic neuralgia, demonstrated by a consistent reduction in both VAS  and SF-MIt is also important to highlight that the response rate of pain was improved in our data compared to previous rTMS studies on postherpetic neuralgia. Previous studies reported a 40% response rate (average across different baseline pain groups) at the end of treatment . MeanwhiIn addition to pain sensations, our data also demonstrated significant benefits on sleep quality. Interestingly, both the M1 and DLPFC stimulation significantly improved sleep quality in patients with postherpetic neuralgia . More imWe also provided novel findings on the dynamic relationship between improvement in pain sensations and sleep quality following rTMS treatment. Specifically, pain sensations during and after M1 treatment were able to predict sleep quality in all the follow-up periods . MeanwhiPatients’ Global Impression of Change (PGIC) indicated that more patients reported improvement in the M1 group compared to sham stimulation at 3-month follow-up . When daIt is noted that there were no significant changes in anxiety, depression or cognition following either stimulation target . These rIt remains an open question the mechanisms driving the analgesic effects of motor cortex rTMS  have recently been demonstrated to increase treatment efficacy as well as to shorten treatment durations in depression , 2021. TIn conclusion, in this double-blind, randomised, sham-controlled trial, motor cortex rTMS is superior to DLPFC stimulation in treating postherpetic neuralgia with excellent pain response and long-term analgesia. Meanwhile, motor cortex and DLPFC stimulation were equally effective in improving sleep quality in postherpetic neuralgia. These findings bear direct clinical implications given the refractory pain and reduced quality of life in postherpetic neuralgia.The original contributions presented in the study are included in the article/The studies involving human participants were reviewed and approved by the Ethics Committee of Hangzhou First People’s Hospital (IIT-20220301-0039). The patients/participants provided their written informed consent to participate in this study.HW, YH, LY, and XC contributed to study design, data collection, data analysis and writing-up. JD, YY, and MH contributed to data analysis. All authors contributed to the article and approved the submitted version.XC was supported by the National Natural Science Foundation of China (4045F41120040), the Key Research and Development Programme of Zhejiang Province (2022C03038) and Hangzhou Municipal Health Commission (2021WJCY130).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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.https://www.frontiersin.org/articles/10.3389/fnins.2023.1158737/full#supplementary-materialThe Supplementary material for this article can be found online at: Click here for additional data file.


Background: The combination of ropivacaine and dexmedetomidine has been used as an epidural analgesic for inducing labor. However, there is limited data regarding the administration of epidural analgesia for labor maintenance, hence, this study aimed to determine the optimum concentration through dose-response curves of ropivacaine plus dexmedetomidine, which could be used along with the Programmed Intermittent Epidural Bolus (PIEB) technique.Methods: One hundred parturients were randomized into 4 groups who were administered four different doses of ropivacaine (dexmedetomidine at 0.4 μg mL−1): 0.04%, 0.06%, 0.08%, and 0.1%. The primary outcome that was determined included the proportion of patients experiencing breakthrough pain during their 1st stage of labor. Breakthrough pain was described as a visual analog scale [VAS] score of >30 mm, requiring supplemental epidural analgesia after the administration of at least one patient-controlled bolus. The effective concentration of analgesia that was used for labor maintenance in 50% (EC50) and 90% (EC90) of patients were calculated with the help of probit regression. Secondary outcomes included epidural block characteristics, side effects, neonatal outcomes, and patient satisfaction.Results: The results indicated that the proportion of patients without breakthrough pain was 45% (10/22), 55% (12/22), 67% (16/24), and 87% (20/23) for 0.04%, 0.06%, 0.08%, and 0.10% doses of the analgesic that were administered, respectively. The EC50 value was 0.051%  while the EC90 value was recorded to be 0.117% . Side effects were similar among groups.Conclusion: A ropivacaine dose of 0.117% can be used as epidural analgesia for maintaining the 1st stage of labor when it was combined with dexmedetomidine (0.4 μg mL−1) and the PIEB technique.Clinical Trial Register:https://www.chictr.org.cn/index.aspx, identifier ChiCTR2200059557 Epidural analgesia is regarded as the primary tool for managing labor pains owing to its effectiveness and popularity. Over the past decades, several modifications made in the use and administration of epidural labor analgesia have been investigated to achieve the best possible outcomes in patients. Despite considerable advancements, 25% of the patient still experience breakthrough pain  . The proSeveral studies have proposed the combined application of the programmed intermittent epidural bolus (PIEB) technique and the administration of analgesia for decreasing the breakthrough pain during labor in comparison to the continuous epidural infusion . TherefoRopivacaine with dexmedetomidine has been used in experimental trials for managing labor pains . AlthougAll experiments conducted in this study were approved by the Ethical Committee of Hangzhou City Lin-Ping District Maternal and Child Care Hospital, Hangzhou, China, (Chairperson Prof Ying-Hao Zhang) on March 23, 2022, (LLSC-KYKT-2022-0006-A). The clinical trial was registered in the Chinese Clinical Trial Register on May 4, 2022, before patient enrollment (ChiCTR2200059557). The patients enrolled in this study were asked to sign a written informed consent form. Finally, this study was initiated on June 1, 2022, and concluded on January 21, 2023.This is a single-center, double-blind, randomized, dose-finding study.−2, were allergic to ropivacaine or dexmedetomidine, had pregnancy-related issues , a history of opioid or other sedative use 4 h before analgesia administration, or known fetal abnormalities. Patients who experienced an unintended dural puncture and required emergency cesarean section delivery were excluded.We enrolled 100 nulliparous parturients based on the Physical Status II Classification System defined by the American Society of Anesthesiologists. The key inclusion criteria implemented in this study included singleton pregnancies at the gestational age of 37–42 weeks, with regular uterine contractions that occurred every 5 min, and those opting for neuraxial analgesia. The key exclusion criteria used in this study included patients who refused the use or presented contraindications to the use of neuraxial analgesia, had a body mass index (BMI) > 40 kg mPregnant women who opted for neuraxial analgesia were randomized into one of four groups based on the concentration of ropivacaine that they would be administered, i.e., 0.04%, 0.06%, 0.08%, and 0.1%. Randomization was achieved using a computationally-generated random number sheet . An assistant anesthesiologist, who was unblinded to the patients’ grouping and not involved in data collection, prepared the epidural solutions (ropivacaine plus dexmedetomidine) and marked the epidural infusion pumps as A, B, C, or D . All other study-related personnel were blinded to the grouping and infusion pumps.After entering the labor room, the patients were monitored using standard monitors . Additionally, the baseline heart rate and systolic blood pressure (SBP) values were recorded as the mean of three independent readings measured between uterine contractions. A 250 mL bolus of lactated Ringer’s solution, pre-warmed to 37°C, was initiated 20 min before placing the epidural catheter.−1). Patients, who had a pain score of ≤50% on the visual analog scale (VAS) from baseline within 20 min, were considered eligible to continue in the study. Patients who reported a VAS score of >50% from baseline received an 8 mL bolus of 1% lidocaine to determine whether the position of the epidural catheter was appropriate. If the VAS score remained >50% of baseline after 20 min of the rescued bolus, the procedure was regarded as a failure of epidural catheter placement, and the patient was excluded from this study. Thereafter, the epidural catheter was replaced.Epidural analgesia was administered in the left lateral decubitus position by applying the “loss of resistance to saline” technique using an 18-gauge Tuohy needle at the L3-4 vertebral interspace (ultrasound confirmed). A 19-gauge nylon multi-orifice epidural catheter-oriented cephalad was inserted 4–5 cm into the epidural space. Following aspiration, if blood and cerebrospinal fluid were absent in the epidural catheter, a test dose (3 mL) comprising lidocaine (1.5%) and epinephrine (15 μg) was administered. After 3 min, the patients were administered ropivacaine (10 mL bolus of 0.1% v/v concentration) with dexmedetomidine  that was programmed to administer a PIEB dose of 10 mL at an infusion rate of 500 mL h−1, which was initiated 1 h after the first loading bolus.Depending on the solution concentrations used in the study groups, the maintenance of labor with epidural analgesia was achieved using ropivacaine with dexmedetomidine at 0.4 μg mLPatients were allowed 5 mL boluses of patient-controlled epidural analgesia (PCEA) with a 10-min lockout interval. The patient was guided to press the PCEA button if she felt pain. If no pain relief was noted, clinicians administered a 10 mL bolus of 0.25% ropivacaine with 100 μg fentanyl according to the principles in our hospital. If pain persisted despite these boluses, it was considered a displacement of an epidural catheter. Thereafter, the patient could not participate in this study.Maternal demographic data, including age, weight, height, blood pressure, and gestational age were recorded. Obstetric characteristics, including cervical dilation at the time of neuraxial analgesia request, and duration of the first and the second stages of labor were recorded.The primary outcome of this study included the proportion of patients with breakthrough pain in the first stage of labor. Breakthrough pain was defined as a VAS >30 mm within 10 min after administering supplemental epidural analgesia and occurring after the administration of at least one PCEA bolus .The secondary outcomes included in this study were the epidural block characteristics (sensory level and motor block), side effects , neonatal outcomes , and patient satisfaction.The sensory block level was assessed using alcohol wipes by asking the patients whether they could sense the temperature, whereas motor block was assessed with the Bromage scale  . Calculations based on preliminary data showed that the proportions of patients without breakthrough pain were 0.45, 0.60, 0.75, and 0.90 receiving ropivacaine doses of 0.04%, 0.06%, 0.08%, and 0.1%, respectively. A sample size containing 76 individuals (19 in every group) was required to achieve 90% power for detecting a linear trend by means of a 2-sided Z test and a statistical significance value of 0.05. To allow for probable dropouts and to increase the power of the study, the sample size in this study was randomly increased to 25 individuals in every group (N = 100 in 4 groups). This would also enable us to take into consideration the probability that the true proportion of patients without breakthrough pain differed from the preliminary results noted in this study.Post-hoc Bonferroni pairwise comparisons were then performed to achieve significant results. Furthermore, the non-normally distributed data  were presented as the median and interquartile range (IQR) and assessed by means of the Kruskal–Wallis test, where Dunn’s tests were used for post hoc pairwise comparison. The chi-square test for trend and the Yates correction was used for assessing the categorical data when the expected number in one or more cells was ≤5.The data were statistically analyzed with the help of the Statistical Package for Social Sciences (SPSS) software for Windows ver. 22.0  and GraphPad Prism ver. 5.0 . Continuous data were tested for normality using the Kolmogorov–Smirnov test. The normally-distributed data  were presented as mean ± standard deviation (SD) and analyzed among different groups using the one-way analysis of variance (ANOVA) (or one-way ANOVA test for trendr) technique. p-value < 0.05 indicated the statistical significance level.The effective concentration for maintenance labor with epidural analgesia in 50% of the parturients (EC50) and 90% of the parturients (EC90) was calculated with the probit regression. A 2-sided Out of the 117 parturients who were initially screened for eligibility; 11 did not fulfill the inclusion criteria while 6 did not provide their informed consent. Hence, a total of 100 participants were recruited and randomized. Out of these 100 individuals, 9 patients were excluded from the final analysis as shown in p = 0.003) was observed that highlighted the relationship between the ropivacaine dose and the incidence of breakthrough pain. p = 0.702).The findings indicated that 55% (12/22), 45% (10/22), 33% (8/24), and 13% (3/23) of the patients who received ropivacaine doses of 0.04%, 0.06%, 0.08%, and 0.10%, respectively, displayed breakthrough pain . A signip = 0.022 and <0.001). No significant difference was observed in the Bromage score and sensory block levels across different groups . Patients who received 0.10% ropivacaine dose exhibited a higher patient satisfaction level compared to those receiving 0.04% and 0.06% doses.The patients across all the groups presented similar side effects . They shNeonatal outcomes, including umbilical arterial pH, 1- and 5-min Apgar scores, and fetal bradycardia have been presented in −1 dexmedetomidine was 0.051% , which caused no breakthrough pain during maintenance with epidural analgesia at the first stage of labor. The EC90 was 0.117% . An earlier study observed that the optimum dose of dexmedetomidine that could be used for epidural labor analgesia was 0.4 μg mL−1, hence, the same dose has been used in this study (In this study, the EC50 of ropivacaine with 0.4 μg mLis study .Our study is important since it validates the results presented in the earlier studies. In the past, This study also defines breakthrough pain. In direct contrast to other studies , breakth−1 dexmedetomidine for labor maintenance with epidural analgesia, it is important to remember that these results can be applied under the conditions used in this study. Factors affecting the results include differences in study protocols, statistical analyses, definitions of breakthrough pain, adjuvant drugs, doses of local analgesia, the use of epidural test doses, and the extent of cervical dilatation. Thus, we suggest that the use of epidural analgesia for labor management should be implemented according to the patient’s response to medication for providing a flexible regimen rather than a fixed one. Differences in the risk of hypotension, maternal fever, and breakthrough pain, indicate that it is important to provide individualized care for parturients opting for analgesia during labor.Although the findings of this study suggested that 0.117% was the optimum concentration of ropivacaine that could be combined with 0.4 μg mLOur study has several limitations that should be considered before implementing the results in clinical practice. Firstly, the generalizability of the results is limited due to strict inclusion criteria; hence, the results would vary in patients with obesity, shoulder dystocia, or other comorbidities or clinical factors. Secondly, as the EC90 value was outside the range of the study groups, further studies need to be performed using higher concentrations compared to those tested in this study. Thirdly, because the observational period was restricted to the first stage of labor, these results cannot be extrapolated to the 2nd stage of labor. Higher epidural analgesia doses may be needed for patients who are in the 2nd stage of labor. Fourth, because the PIEB interval was set to 60 min in this study, the EC50 and EC90 values might vary with the time interval. Further, we did not observe a direct clinical analgesic response at the EC90 value because it was outside the selected dose range. Thus, further studies are needed that focus on the EC90 value of epidural ropivacaine.−1 and a 60-min PIEB technique during the first stage of labor.To summarize, based on the findings of this study and after considering the study scenario, a ropivacaine dose of 0.117% has been recommended in this study for epidural analgesia when combined with dexmedetomidine 0.4 μg mL


Language barriers can negatively impact the quality of healthcare. In surgical patients, limited English proficiency (LEP) can lead to disparities in acute postoperative pain management. Interpreters are often used for communication with LEP patients to help alleviate these disparities. We aimed to investigate the impact of the need for language assistance services (LAS) in acute postoperative pain management in patients undergoing oncologic surgery. We retrospectively collected data on adult patients undergoing open abdominal oncologic surgery between March 2016 and August 2021. The need for LAS, patient demographics, treatment and clinical outcomes were obtained from the patient’s electronic medical record. The primary endpoint was pain intensity, while secondary endpoints included opioid use in PACU and regional anesthesia. Post-matching analysis (n = 590) demonstrated no significant difference in preoperative variables between patients needing LAS and those not needing LAS. The rate of regional use was slightly lower but not statistically significant in patients needing LAS. Patients needing LAS had significantly lower opioid consumption and reported lower pain intensity in PACU than subjects not requiring translation. In this study, LAS may have aided in the patient decision process regarding the acceptance of regional anesthesia. Although the need for LAS was associated with statistically significant lower pain intensity scores and a corresponding lesser opioid use than no LAS, the margin of differences, especially in pain intensity scores, may not be clinically significant. This may suggest that LAS allowed for better patient-provider communication and appropriate pain management.  In the United States, 8.6% of the population has limited English proficiency (LEP) and speaks English less than “very well” . LanguagPain is a multidimensional experience in which language proficiency is an important component of pain communication . AspectsInterpreters are often used for communication with LEP patients to help alleviate these disparities and have been perceived by patients to improve their pain assessment and treatment . HoweverIn this study, we aimed to investigate the impact of the need for language assistance services (LAS) in acute postoperative pain management for patients undergoing oncologic surgery. We hypothesized that patients with LEP would report significantly different pain scores compared to non-LEP subjects, which would be associated with differences in opioid use. Following Institutional Review Board approval (IRB#2021-0738), we retrospectively collected data for adult patients who underwent open abdominal oncological surgery between March 1, 2016 and August 1, 2021. We excluded patients whom a) had non-abdominal surgery, laparoscopic surgery, emergency surgery, outpatient surgery, b) were from surgical services that did not utilize regional analgesia, c) were classified as American Society of Anesthesiologists Physical Status > 3 and d) had abdominal plus additional surgical procedures. The need for LAS, patients’ demographics , comorbidities , preoperative coagulation labs and postoperative clinical outcomes were obtained from electronic medical records (EMR). LAS need is typically identified at the first encounter with providers at our institution by asking the patient if they wish to have an interpreter for medical communication. This “need” is subsequently visible in the patient’s EMR. Race and ethnicity were also self-reported by patients at the time of initial registration to establish care. All patients underwent general anesthesia according to routine care in our center. The primary endpoint of the study was pain intensity . Secondary endpoints included opioid use in PACU and the use of regional analgesia. p < 0.05 was considered statistically significant. Statistical software SAS 9.4  and Splus 8.2  was used for all the analyses.A prior sample size analysis was not performed. The chi-square test or Fisher’s exact test was used to evaluate the association between two categorical variables. Wilcoxon rank-sum test was used to compare location parameters of continuous distributions between patient groups. To adjust for selection bias in this observational study, we conducted a propensity score matching (PSM) analysis. We included the following prognostic covariates in the logistic model to estimate the propensity scores: age at surgery, BMI, gender, race, ASA (1/2 vs. 3), the status of anxiety or depression and preoperative use of opioids. The Greedy 5 -> 1 digit match algorithm was used to match the baseline covariates so that the two groups (no interpreter needed vs. interpreter needed) would have similar propensity scores. A multivariable logistic regression model was fitted to estimate the effects of important covariates on the highest or average PACU pain score using 3 (mild) or 7 (severe) as the cutoff points. A A total of 4791 patients were included from our database . Among tp < 0.0001). A diagnosis of anxiety or depression was significantly more frequent in patients in patients needing  translation services than those who were English proficient . Interestingly, the incidence of chronic opioid use was also slightly but significantly higher in patients needing (n = 100. 8.1%) translation services than those who were English proficient . Other demographic variables, including age, sex, ASA physical status, history of chronic pain, alcohol use and cigarette smoking, were not significantly different. The pre-matching analysis demonstrated that the association between the need for translator services and the patients’ race was statically significant. Asian and Hispanic/Latino patients  needed translation services in a higher proportion than Black/African American or White subjects  (p = 0.172) or post-matching (p = 0.9955) analysis (p = 0.021) and reported lower pain intensity during PACU stay  than subjects not requiring language translation. The difference in the percentage of mild average pain (average pain score ≥ 3) in PACU was not significant between the two groups (p = 0.056). Patients who needed LAS had a lower percentage of mild average pain in PACU (35% vs. 42.7%). In addition, the difference in the percentage of moderate average pain (average pain score ≥ 7) in PACU was not statistically significant between the two groups   . The neeanalysis . Patient= 0.593) . p = 0.06). Due to the limited number of patients with average PACU pain of 7 or higher, multivariable analysis was not performed. A multivariable logistic regression model was fitted to estimate the effects of important covariates on the status of average PACU pain of 3 or higher. After adjusting for age, BMI, gender, race, ASA physical status, platelet count, preoperative use of opioids, regional anesthesia and status of anxiety or depression in the model, the odds of having average PACU pain of 3 or higher is 40% higher for patients not needing LAS versus patients needing LAS (odds ratio (OR) = 1.40, 95%: 0.99, 1.99). The association between needed LAS and average PACU pain of 3 or higher was not significant (n = 49) of English-proficient patients and 60% of patients with LEP were treated with pain medications at the time of their worst pain [This is the first study investigating the association between LAS need and pain outcomes in patients undergoing major abdominal cancer surgery. Although the association did not reach statistical significance, we observed a 40% increase in pain (≥ 3) in patients with LAS needs compared to English-speaking patients. Proper postoperative pain assessment is integral to pain management since it can affect surgical outcomes . Languagrst pain . InteresTime and convenience are factors often cited as barriers to effectively utilizing LAS ,17. ThisOur study has limitations due to its retrospective nature and confounding from unknown variables that might have influenced the decision to prescribe opioids to both groups of patients. It is a single institution study at a cancer center, thereby inclusive of only institutionally specific variables such as, but not limited to, types of surgeries and types of regional anesthesia techniques utilized. The actual use of interpreters, whether via phone, videoconferencing or in-person, could also not be retrospectively determined. Lastly, cultural differences in the psychometrics of the numeric pain scale used in our patient assessments could have influenced reported scores. Further research can focus on how particular modes of LAS could be best utilized in efficient and precise postoperative pain assessment. Since different institutions have different hurdles in the proper utilization of LAS, education and quality improvement initiatives at the local level can help to improve appropriate pain assessment for this vulnerable population. Our study corroborates current literature on the need for LAS to overcome communication barriers in healthcare, potentially leading to an enhanced patient-centric experience and improved clinical outcomes in patients with LEP.


The aim of this randomized clinical trial was to evaluate and compare, duringthe first week of rapid maxillary expansion (RME), the impact caused by twotypes of appliances: Hyrax and Hybrid Hyrax. Forty-two patients who met the eligibility criteria  were selected andrandomly divided into two groups: TBB GROUP (tooth-bone-borne expander),treated with Hybrid Hyrax , and TB GROUP (tooth-borne expander), treated with Hyrax . Pain and discomfort were assessedin two times: after the first day of activation (T1) and four days after, bymeans of the numerical rate scale and the instrument MFIQ . Descriptive statistics and theMann-Whitney test were used for comparison between groups and between sexes.A 5% significance level was adopted. Both appliances had a negative impact, generating pain and discomfort, andreducing functional capacity. However, the scores obtained were of lowintensity and no significant differences were observed between the groups.Considering sexes, there were statistically significant differences, withthe female sex presenting higher scores for pain and functional limitation. Despite causing impact in pain and increase in the functional limitation,these changes were of low intensity, with no statistical difference betweenthe groups. Females were more sensitive to the impact caused by the RME. Thistechnique has proven effective in orthodontics, and is commonly used in clinicalpractice.-,Wilmes et al.-Patients undergoing RME with conventional appliances often report discomfort, pain,and even functional limitations.-,Several methods for measuring pain intensity have been described in the literature,and the pain numerical rate scale (NRS) has proven to be more appropriate due to theease of clinical application and patient understanding.Considering the importance of patients’ well-being, the present study aimed toevaluate and compare the impact of two types of maxillary expansion appliances(tooth-bone-borne and tooth-borne) with respect to pain, discomfort, andfunctional limitation during the first week of RME activation in growingpatients, by assessing pain (NRS) and functional limitation (MFIQ). Since theHybrid Hyrax is a new appliance, the literature on its symptomatology is scarce.Although this appliance has shown promising results, it involves a more invasivetechnique than traditional appliances, then it is necessary to understand morebroadly its impact. The null hypothesis tested was that there would be nodifference for the pain and discomfort impact between these appliances.This was a prospective randomized clinical trial that was approved by the EthicsCommittee on Human Research of University of São Paulo, School of Dentistry,under the protocol number: 3.311.813. This study was also registered in theREBEC clinical trials (RBR-48g9q6). The Consolidated Standards of ReportingTrials (CONSORT) statement and guidelines were followed.Patients aged 11-14 years, who visited the orthodontic clinic at University ofSão Paulo, School of Dentistry between January and July 2018, were screened foreligibility. Participants who met the eligibility criteria were invited toparticipate, and informed consent was obtained from all patients and theirparents or legal guardians. The inclusion criteria were as follows: age between11 and 14 years, transverse maxillary deficiency, bilateral or unilateralposterior crossbite, and the presence of maxillary first premolars and maxillaryfirst permanent molars. The exclusion criteria were: the presence of systemicdiseases, history of previous orthodontic treatment, presence of cleft lip andpalate, presence of congenital deformities, and agenesia or loss of permanentteeth. ,The Hybrid Hyrax appliance used in this study was supported by two mini-implantsinserted in the anterior region of the palate, posterior to the third palatalrugae, paramedian 2-3 mm from the palatal raphe, based on the appliance ofWilmes et al.Mini-implants  were inserted after local anesthesia using lidocaine.Further, a digital dental scan of the maxillary arch was performed using anintraoral scanner . The modelwas printed using a Form2 printer ,and the appliance was fabricated on the printed model , and in the following days, ¼turn twice a day (every 12 h) until correction of the maxillary deficiency andovercorrection of crossbite . No analgesics were prescribed; however, the patientswere allowed to use them at their discretion. None of the patients reportedusing analgesics.The pain NRS  was usedUsing the MFIQ,The primary outcome was the comparison between groups and sexes regarding painintensity, discomfort, and functional limitation during the first week of RMEactivation with the two appliances evaluated.The secondary outcome was the correlation between pain and MFIQ with age andskeletal maturation of the midpalatal suture.This study used the same sample as well as some statistical data of a previousrandomized clinical trial.No interim analysis was conducted, all data were analyzed after the study wascompleted.The sequence of 42 numbers corresponding to the patients (each numbercorresponding to a patient) was randomized into two groups using the excelRANDOM function.Double blinding was not possible due to the type of interventions administered. However, before the data assessment and statisticalanalysis, the questionnaires were identified with only a coded ID number, foranother examiner to compute the scores. Therefore, the examiner did not knowwhich patient the scores belonged to.The evaluated measurements were described according to groups, using means ±standard deviations, or medians and interquartile ranges, and the values beforeexpansion were compared between the groups using Student’s t-test orMann-Whitney U test. The sex of the patients was described according to groups,using absolute and relative frequencies; and the association between the groupswas determined using chi-square or Fisher’s exact tests.For the comparison of pain and functional limitation between the groups andbetween sexes, the Mann-Whitney U test was used.p-value of less than 5% (p< 0.05) wereconsidered statistically significant. Analyses were performed using IBM SPSS forWindows v. 20.0 .Spearman’s correlations were calculated between pain and MFIQ and the dataregarding the initial age and midpalatal suture maturation .Regarding the other initial characteristics, there were no statisticallysignificant differences between the groups.No statistically significant differences were found between the groups for any ofthe questions evaluated, regarding pain and discomfort, at T1 and T2 .Regarding the analysis of pain and discomfort, there was no statisticallysignificant difference between the groups .According to the intergroup comparison of MFIQ results, there was nostatistically significant difference between the groups in terms of functionalcapacity, feeding, and functional limitation . For theFinally, no significant correlations were found between pain and MFIQ and age andmaturity of the midpalatal suture at both T1 and T2 .-,Orthodontic patients frequently report pain and discomfort.Common methods to assess patients’ experiences of pain during treatment include theuse of pain scales. The visual analog scale and the NRS are the most commonlyused.,,,The assessment of pain score and the use of MFIQ instrument were performed after thefirst and fourth days of the first activation, since this is the time of greatestpatient discomfort during orthodontic treatment (first week).Both appliances caused pain  duringtAdditionally, in both groups, the intensity of pain was lower at T2. Pain during RMEis reportedly greater in the first activation, whereas in the study of Halicioğlu etal.,,,,Orthodontists know that with aging, bone maturation of the midpalatal sutureincreases.-The results showed that there were statistically significant differences betweensexes, considering the variables assessed by the MFIQ instrument , with thRegarding the MFIQ instrument, no statistically significant differences were foundbetween the groups at T1 and T2 in terms of the functional capacity, nutrition, andfunctional limitation. The medians obtained from the total score for functionallimitation in both groups were of low intensity. These results, reveal that thelimitation caused by both appliances was similar, as previously reported.A greater impact was noticed in both groups at T1 than at T2. This probably occurredbecause the participants begin to get accustomed to the appliance and to the changesthat occurred in their mouth. Despite this, the scores at T2 were lower in bothgroups, with no statistically significant difference between them, suggesting thatthe patients were adapted. Moreover, as the pain decreased concomitantly, thepatients’ activities became unaltered. ,,The equivalence between the symptomatology during RME and between the two evaluatedappliances is extremely important data for the literature, because both applianceswere well-tolerated by the patients. One should consider that the hybrid Hyraxgenerates a slightly higher cost, due to requiring intraoral scanning. However,considering the advantages observed in the reduction of side effects,The sample size calculation for this study was based on skeletal changes in thenasomaxillary region, and not on pain intensity or discomfort. The mini-implantsinsertion process can generate discomfort in the first hours after insertion, andfuture studies are necessary to evaluate and consider pain during mini-implantsplacement.No serious harm was observed other than pain and discomfort during RME.» Pain and functional limitation were common for patients in both groupsduring RME at both T1 (1 day after the start of activation) and T2 (4days after the first activation). The values obtained were of lowintensity, with no statistical difference between the groups. » There was no correlation between pain and functional limitation withage or skeletal maturation of the midpalatal suture.» Female patients experienced higher pain perception and functionallimitations during RME.


This experimental study aimed to assess pain sensitivity in low-frequency episodic migraine (LFEM), high-frequency episodic migraine (HFEM), and chronic migraine (CM) patients across the different phases of the migraine cycle.In this observational, experimental study, clinical characteristics (diary and time from the last/next headache attack), and quantitative sensory testing (QST) (wind-up pain ratio (WUR) and pressure pain threshold (PPT) from the trigeminal area and PPT from the cervical spine) was performed. LFEM, HFEM, and CM were assessed in each of the 4 migraine phases  and compared vs. each other’s (matched for the phase) and controls.A total of 56 controls, 105 LFEM, 74 HFEM, and 32 CM were included. No differences in QST parameters were observed between LFEM, HFEM, and CM in any of the phases.p = 0.001) and 2) lower cervical PPT (p = 0.001). No differences were observed between HFEM or CM and healthy controls. During the ictal phase and when comparing with controls the following were found: HFEM and CM had 1) lower trigeminal PPTs , 2) lower cervical PPT s , and 3) higher trigeminal WUR . No differences were observed between LFEM and healthy controls. During the preictal phase and when comparing with controls the following were found: 1) LFEM had lower cervical PPT (p = 0.007), 2) HFEM had lower trigeminal (p = 0.013) and 3) HFEM had lower cervical (p = .006) PPTs. During the postictal phase and when comparing with controls the following were found: 1) LFEM had lower cervical PPT (p = 0.003), 2) HFEM had lower trigeminal PPT (p = 0.005), and 3) and HFEM had lower cervical (p = 0.007) PPTs.During the interictal phase and when comparing with controls the following were found: 1) LFEM had lower trigeminal PPT (This study suggested that HFEM patients have a sensory profile matching CM better than LFEM. When assessing pain sensitivity in migraine populations, the phase with respects to headache attacks is of utmost importance and can explain the inconsistency in pain sensitivity data reported in the literature.The online version contains supplementary material available at 10.1007/s10072-023-06858-x. Migraine is a complex brain disorder characterized by cyclic changes in experimentally assessed pain sensitivity . MigrainQuantitative sensory testing (QST) has been used as a proxy to assess pain sensitivity and hence pain sensitization in patients with migraine . To the Thus, to fulfill this gap in the literature, this study aimed to 1) assess if pain sensitivity (QST) differed across LFEM, HFEM, and CM patients assessed during different phases of the migraine cycle, and 2) assess if pain sensitivity correlates with time from the headache attack and if this differed in LFEM, HFEM, and CM across the migraine cycle. We hypothesize that 1) HFEM patients would have a pain sensitivity profile matching CM more than LFEM, and 2) pain sensitivity would correlate with time from the headache attack in HFEM and CM, but not in LFEM.A better understanding of similarities and differences in pain sensitivity across the different migraine phases in migraine patients with different headache frequencies may help phenotyping patients and provide knowledge which at some stage may be utilized in individualized treatment approaches.This multicenter, cross-sectional, observational study was conducted in the Headache Center of Parma and Genova  and approved by the Ligurian (244/2018) and “Area Vasta Emilia-Nord”  regional ethic committee. All subjects signed an informed consent form and were assessed between April 2019 and February 2022.Patients on waiting lists to receive their first visit to the Headache Center were invited to participate in this study. Men and women aged between 18 and 65 with migraine for at least 3 months were included. Patients were excluded if they had: any other primary/secondary headache; less than 1 headache attack in four weeks; changes of headache characteristics, or onset of a “new” headache after COVID-19 infection/vaccination; any other neurologic, psychiatric, rheumatologic  or systemic pathology with medical diagnosis; history of head/neck trauma in the previous year; received cervical/head surgery; received manual therapy in the cervical spine, cervical anesthetic block, or botulin injection in the last 6 months; changed the prophylactic treatment in the last 3 months; were unable to speak and understand Italian; patients with headache attack modified by acute pharmacologic treatment in the previous 24 h who developed a headache in the 24 h after the assessment .Control participants were recruited specifically for this study. They were defined as healthy subjects with a maximum of two headache episodes per year that did not fulfill the criteria for migraine or any other primary headache type with no family history of migraine or other primary headaches. The inclusion criteria for the control subjects were the same as the criteria used for migraine patients.Low-frequency episodic migraine (LFEM): patients with less than 8 headache days in a month.High-frequency episodic migraine (HFEM): patients with 8 or more headache days in a monthChronic Migraine (CM): patients with 15 or more headache days in a month (at least 8 or more headache days had to fulfill the criteria for migraine)The first screening was made by telephone interview where patients were excluded if they presented any signs of red flags  or any eThen, the neurologist retrospectively assessed the diary and recorded the interval between the first assessment and the following headache attack. LFEM, HFEM, and CM patients were categorized according to the phase of the migraine cycle in which the first examination was performed , 18:Interictal phase: no headache attack occurred in the 48 h before or after the evaluation.Preictal phase: headache attack occurred in the 48 h after the evaluation.Ictal phase: headache attack during the evaluation.Postictal phase: headache attack occurred in the 48 h before the evaluation.LFEM and HFEM were categorized in:LFEM and HFEM patients with a headache attack that occurred in the 48 h after and in the 48 h before the evaluation were categorized both in the preictal and the postictal phases.Interictal phase: no headache during the evaluation.Ictal phase: headache attack during the evaluation.CM patients were categorized in:Due to the shorter period occurring between two consecutive migraine attacks in CM patients, it was not possible to identify a preictal and a postictal phase in this subgroup of patients.General and clinical characteristics were assessed for each patient. Patients used a daily updated diary recording the total use of drugs and the frequency, intensity, and duration of headache attacks Table .Table 1cPressure pain threshold (PPT): Pressure pain thresholds to hand-held algometry , probe area 1cm2, 30 kPa/s force increase were assessed over the trigeminal area , the upper cervical spine (sum of left and right articular pillars), and lower cervical spine (sum of left and right articular pillars). The lower the PPTs, the higher the sensitization. PPT has high reliability (test–retest reliability (TR-R) = 0.88; interobserver reliability (IO-R) = 0.84)[3.Wind-up ratio (WUR): the WUR assessed the temporal summation of mechanical pinprick pain (50.1 g pinprick) over the trigeminal area temporalis muscle). The subject gave a pain rating  for the first and last stimulus of 10 stimuli. The difference between the pain rating of the ten stimuli series and the pain rating of the first stimulus was calculated. The higher the WUR, the higher the sensitization. WUR exhibited good reliability  [ = 0.56) .) = 0.84).3.Wind-uQST was performed from distal pain-free areas first, then the cervical area, and finally the trigeminal area  . The folDetails of the QST assessment were previously presented , 18, 20.2: 0.20) with an alpha level of 0.008 and the desired power of 80% in a two-tail linear regression model with 6 predictors was 107. The sample size needed to achieve a medium/large effect size (f2: 0.20) with an alpha level of 0.017 and the desired power of 80% in a two-tail linear regression model with 6 predictors was 94. As multiple analyses were performed using different samples, we included a total of 267 subjects assuring that at least 107 subjects were included in the analysis that compared Controls, LFEM, HFEM, and CM , and at least 94 subjects were included in the analysis that compared Controls, LFEM, and HFEM . The sample size needed to achieve a large effect size (r: 0.50) with an alpha level of 0.05 and the desired power of 80% in a correlation analysis was 26. As the correlation analysis was performed in each migraine subgroup , at least 26 patients in each group were needed.Sample size calculation was performed using G*Power 3.1. The sample size needed to achieve a medium/large effect size (fAll data were presented as mean (standard deviation), median (interquartile range), or numbers (percentage). Data distribution was assessed using the Shapiro–Wilk test and non-normal data were transformed to fulfill normality assumption. A preplanned analysis was performed. For subjects included between August 2021 and February 2022, this was the primary analysis of these data. For subjects included between April 2019 and August 2021, this was a secondary analysis of these data and previous results were reported elsewhere, 20.To assess differences in QST values between LFEM, HFEM, CM, and controls, we performed a linear regression for each migraine phase using QST variables as the dependent variable and group as the predictor, while adjusting for possible confounders . LFEM, HFEM, and CM patients were assessed separately in each migraine phase  while in each model all the Controls were included. As multiple comparisons were performed, a Bonferroni-corrected p-value was adopted .p < 0.05.Then, to assess if the correlation between QST variables and time from the last or to the next headache attack differed in LFEM, HFEM, and CM, a Spearman correlations analysis was performed between QST results and time relative to the last or the next migraine attack in HFEM, LFEM, and CM  separately. When assessing the correlation between QST results and time relative to the last migraine attack, only LFEM and HFEM in the interictal, ictal, and postictal phase were analyzed. When assessing the correlation between QST results and time relative to the next migraine attack, only LFEM and HFEM in the interictal, ictal, and preictal phase were analyses. For all the correlation analyses, patients with a headache attack that occurred in the 48 h after and in the 48 h before the evaluation were excluded. The threshold accepted for the statistical significance of the correlation analyses was Patients with any missing data were excluded from the analysis. All tests of statistical significance were two-tailed and statistical analyses were performed using the SPSS software (version 24).After 779 subjects were initially recruited, 267 were included  , and lower-cervical (p = 0.001) PPTs, and no differences in upper-cervical PPT and in trigeminal WUR interictally   Fig. , Table 2p = 0.007 and p = 0.003, respectively), and lower-cervical  PPTs, and no differences in trigeminal PPT and trigeminal WUR  compared to controls   Fig. , Table 2p > 0.090; CM all, p > 0.103)  Fig. , Table 2p = 0.013 and p = 0.005, respectively), upper-cervical , and lower-cervical  PPTs, and no differences in trigeminal WUR  compared to controls , upper-cervical , and lower-cervical  PPTs, and higher trigeminal WUR  compared to controls  and WUR  and with lower-cervical PPT . No significant correlation was observed with upper-cervical PPT . The time to the next headache attack was significantly correlated with trigeminal PPT  and WUR . No significant correlation was observed with upper-cervical , and lower-cervical  PPTs , upper-cervical , and lower-cervical  PPTs and with trigeminal WUR  , the time from the last headache attack was significant correlated with trigeminal , upper-cervical , and lower-cervical  PPTs and with trigeminal WUR . , the time to the next headache attack was significant correlated with trigeminal  the trigeminocervical pain sensitivity was similar between LFEM and HFEM, with both groups showing significantly enhanced pain sensitivity of the trigeminocervical complex compared to healthy controls. These results suggested that the perictal phases act as transition phases. In LFEM patients, the transition would be from a status of “interictal enhanced sensitization” to “ictal normal sensitization”, while for HFEM from a status of “interictal normal sensitization” to “ictal enhanced sensitization”. As a significant negative correlation between increased trigeminocervical sensitization and time from the last or to the next headache attack was observed in HFEM but not in LFEM, this transition is more enhanced in HFEM than LFEM. These results could explain why studies including both groups showed a significant correlation between time to the next headache attack and pain sensitivity, 31, whiThe opposite pattern in cyclic changes in pain sensitivity observed between LFEM and HFEM could explain why studies that assessed differences across migraine phases in pain sensitivity pooling together LFEM and HFEM found heterogenous results , 33.Interestingly, HFEM showed a sensory profile similar to CM. Both groups had enhanced ictal sensitization of the trigeminocervical complex compared to healthy subjects that normalized in the interictal phase. They also showed a significant negative correlation between enhanced sensitization and time from the last or to the next headache attack. The similarity observed between these two subgroups could explain why studies comparing pain sensitization between episodic migraine and CM did not find significant differences , 35. TheThe population was recruited from specialized headache centers, and over half of the patients were excluded for age, concomitant pathologies, and concomitant diagnosis of other headache types. Thus, the external validity of these results should be interpreted with caution.The blindness of the assessor could not be maintained for the entire evaluation of every patient. QST in the trigeminal area was only assessed from one side to reduce the assessment duration, leading to a loss of blinding in patients with unilateral headache on the non-dominant side. However, the assessor would be blinded regarding the headache frequency and phase.Moreover, the present study did not allow to control for the interval from the beginning of the headache phase. As known the sensitization occurs within 1–2 h after the beginning of the headache phase , this coAnother limitation is that in this study no questionnaires to assess allodynia symptoms were used.Finally, as the study does not have a within-subjects design, comparison between different phases in each migraine subgroup should be interpreted with caution, and longitudinal studies with a within-subjects design must replicate these results Table The study showed that HFEM patients seem to have a QST profile matching CM better than LFEM, supporting the previous suggestion  to incluSupplementary file1 (DOC 91 KB) Below is the link to the electronic supplementary material.