Perception of pain associated with intraoral radiography in pediatric patients was evaluated through statistical comparisons of data obtained using the Wong-Baker FACES Pain Raiting Scale (WBFPRS) and visual analog scale (VAS) scoring.A total of 75 pediatric patients aged 6–12 years were included in this study. Simulations of each of three radiological methods  were performed on 25 pediatric patients. Following the simulations, the meaning of each facial expression on the WBFPRS and the numbers on the VAS were explained to each child. For the comparison between groups, the homogeneity of the variances was tested with Levene’s test; because the variances were not homogeneous, Welch’s test was used. Tamhane’s T2 test was used because the homogeneity assumption was not provided to determine the source of the difference between the groups.p < 0.05). When the PSPL and CCD sensors were compared, a significant difference was observed for the WBFPRS (p < 0.05). It was found the highest level of pain scores when used the CCD sensor method than the analog film and PSPL methods (p < 0.05).When the conventional method was compared to the PSPL (photostimulable phosphor luminescence) method, no significant differences were noted in either the WBFPRS or VAS results (p >0.05). The results obtained from both of the scales were significantly different between the conventional method and the CCD sensor method (It is expected that digital radiographic techniques will be improved in the future and that their disadvantages will be eliminated, resulting in imaging devices that are more comfortable for pediatric patients. While early enamel lesions are likely to progress to the dentine, this process occurs relatively slowly over a period of at least 2 years. Early diagnosis of such enamel lesions allows timely intervention and helps to stop or reverse the progression of lesions . Dental After a patient is prepared for an intraoral radiographic scan, the exposure is adjusted, the oral cavity is examined, the film and roentgen tube are positioned, and finally, the radiograph is obtained . The chiChildren tend to become more capable of describing increases in pain with age and experience . While sThe present study evaluates perception of pain associated with intraoral radiography in pediatric patients through statistical comparisons of data obtained from the Wong-Baker FACES Pain Raiting Scale (WBFPRS) and VAS scoring.Approval for this study (71306642) was obtained from the Bezmialem Vakif University Rectorate Clinical Research Ethics Committee. A total of 75 pediatric patients aged 6–12 and their parents, who were referred to Bezmialem Vakif University Department of Pediatric Dentistry for examination and had no systemic disease, physical disability or intellectual disability, pain, acute infection or trauma were included in the study. The parents of the included children were given a detailed explanation of the purpose and methods of the planned clinical research study and provided verbal and written informed consent for participation in the study.Power analysis was performed, and the results of the power calculation considering the VAS variance revealed that the minimum sample size for each group was 25. This value was determined by projecting the power as 0.80, the mean difference as △ = 1, and the significance level as a = 0.05.In this study, three different intraoral radiographic methods were used: analog films , and CCD sensors  and phosphorus plates , with the latter two as the digital methods Fig. .Fig. 1SSimulations of each of these three radiological methods were performed on 25 pediatric patients. To avoid for formation of potential age clusters, these participants were randomly divided into simulation groups with equal numbers of patients aged 6–12. Because wearing lead aprons and thyroid protectives may also affect patient comfort, these items were avoided to ensure that the results were not affected during the simulations.Each simulation was performed at the same site for each participant by positioning the sensors to obtain periapical films of the right posterior teeth of the lower jaw and applying a bisector technique. To avoid any cross-infection, the sensors were placed in single-use plastic sheaths before each simulation. All scan simulations were performed by the same individual who used the same-sized films and sensors to ensure standardization. Size 0 films and sensors, which are appropriate for pediatric patients, were preferred in this study; the size of the CCD sensor was 33.6 × 23.4 × 14 mm, that of the analog film was 22 × 35 × 0.77 mm, and that of the PSPL sensor was 21 × 31 × 1 mm.In parallel to the exposure time, a simulation time of 10 s was selected.Following the simulation, the meaning of each facial expression according the WBFPRS and the numbers on the VAS Fig.  were expEach child was radiographed with only one imaging technique, and the pain perception of the patients against the radiographic technique was evaluated with two different scales.The statistical analyses were performed using SPSS 24.0  program. For the comparison between groups, the homogeneity of the variances was tested with Levene’s test; because the variances were not homogeneous, Welch’s test was used. Tamhane’s T2 test was used because the homogeneity assumption was not provided to determine the source of difference between the groups. The 0.05 significance level was used to test the significant differences between the average points of the groups.p > 0.05]. A total of 53.3% of the patients were females, and 46.7% were males. When patient comfort was considered, in the study groups, 64% of the female (F) participants were examined using the analog film, 60% using CCD, and 36% using PSPL. 64% of the male (M) participants were examined using the PSPL, 40% using CCD, and 36% using analog films.A total of 75 patients were included in the study, and the median age was 9 years. There was no statistically significant difference between the ages of the patients in the radiography method groups [FWelch = .107, The gender distribution was homogeneous in all groups, and there was no significant difference between male and female participants when comfort was compared using the three methods. The descriptive statistics of age, WBFPRS and VAS by subgroups and those for the total sample are shown in Table p < 0.05), and the methods were compared using Welch’s ANOVA test. According to the WBFPRS pain scores, there was a statistically significant difference between the radiographic method groups  (Table p < 0.05). The average differences showed that patients who were examined using the CCD sensor method had higher pain scores than those of patients examined using the analog film and PSPL methods.The WBFPRS pain scores obtained using the radiographic methods were initially compared by checking the homogeneity of variance by Levene’s test (F 2.72) = 7.535, .72 = 7.5p < 0.05), followed by Welch’s test. According to the VAS pain scores, there is a statistically significant difference between the radiographic method groups . Tamhane’s T2 test was applied to determine which groups contributed to the difference (Table p < 0.05). The average differences showed that patients who were examined using the CCD sensor method had higher pain scores than those of patients examined using the traditional method.To determine whether the VAS scores differed significantly according to the radiographic method groups, homogeneity of variance was checked by Levene’s test (F (2.72) = 5.726, The subjects with the CCD sensor complained more than did those examined using the conventional and PSPL methods. According to the results, the CCD sensor method was the most disruptive.During conventional and digital radiological imaging studies, patient comfort may be negatively affected depending on the physical characteristics of the sensors used. Although patient comfort affects the dose of radiation to which patients are exposed, as radiographic procedures need to be repeated when the results are not satisfactory, this topic has been investigated in only a limited number of studies –6, 18. TIn a study carried out by Wenzel et al. , patientIn another study, Gonçalves et al.  evaluateEven though the image quality achieved with digital radiography is similar to that achieved with conventional radiography, the digital system used is still an important factor. No previous study has investigated the use of digital radiography in children, and the advantages of these methods are undervalued due to their inherent disadvantages, such as the acceptability of phosphorus plaques or sensors by children.Dölekoğlu et al.  reportedIn general dental practice, the number of dentists who prefer using digital dental radiography continues to grow. In the past, the type and use of digital radiographic equipment has already been the subject of several studies in multiple countries. These studies have shown an increased availability of dental radiographic units throughout the years, with an exponential increase in digitalization. In a recent survey, 90% of the respondents in Belgium reported using digital intraoral radiography . In 2005The statistical analyses of the data collected in this study indicated that the level of patient comfort was not significantly different between the PSPL sensor and analog film, while the children reported the CCD sensor to be the most uncomfortable. When the radiographic techniques were compared, there was a significant difference between the analog film and the CCD sensor on both pain scales, whereas a significant difference was found between the PSPL and CCD sensors when compared on the WBFPRS only. According to a study on validating the VAS and WBFPRS pain scales in children, the WBFPRS has the potential to be an excellent measure of treatment effects in school-age children and adolescents . The resConsidering these results, we believe that the thickness of the CCD sensor constitutes a great disadvantage. However, there was no statistically significant difference between the PSPL sensor and analog film because of their similar size. All three methods were applied without using film holders; the film/sensor was placed in the mouth parallel to the long axis of the tooth and was held in the mouth by the patient’s finger. We considered the influence of the oral characteristics, such as mouth opening and palate width of the subjects, to be negligible because the randomization of the subjects yielded no significant differences in baseline oral health status and oral cavity structures between the groups. Because the simulation was performed on pediatric patients without using a film holder, we believe that comfort was more negatively affected, especially in the CCD sensor group, because of the rigidity of the sensor and the difficulty of stabilizing it in the mouth. Based on these findings, we suggest that the thickness and size of the sensor and the involvement of a cable are among the most important factors affecting patient comfort.According to the results of this study, the CCD sensor causes the most disturbance, and there is no significant difference in discomfort between using the PSPL method and using the analog film.Nevertheless, as conventional methods involve the use of bath solutions, prohibit any image adjustment and result in the loss of time, the use of PSPL as a digital method may be recommended for children. The patient-reported level of discomfort for this sensor appears to be mild, and the use of this sensor is associated with certain advantages, such as saving time, allowing adjustments to be made, reducing the radiation dose, and permitting measurements to be made on the images while also eliminating the need for chemical procedures and consequently minimizing environmental pollution. However, large-scale studies are required to evaluate the comfort associated with different radiographic methods in pediatric patients.


At any one time, one in every five Canadians has low back pain (LBP), and LBP is one of the most common health problems in primary care. Guidelines recommend that imaging not be routinely performed in patients presenting with LBP without signs or symptoms indicating a potential pathological cause. Yet imaging rates remain high for many patients who present without such indications. Inappropriate imaging can lead to inappropriate treatments, results in worse health outcomes and causes harm from unnecessary radiation. There is a need to understand the extent of, and factors contributing to, inappropriate imaging for LBP, and to develop effective strategies that target modifiable barriers and facilitators. The primary study objectives are to determine: 1) The rate of, and factors associated with, inappropriate lumbar spine imaging  for people with non-specific LBP presenting to primary care clinicians in Ontario; 2) The barriers and facilitators to reduce inappropriate imaging for LBP in primary care settings.The project will comprise an inception cohort study and a concurrent qualitative study. For the cohort study, we will recruit 175 primary care clinicians , and 3750 patients with a new episode of LBP who present to these clinicians. Clinicians will collect data in the clinic, and each participant will be tracked for 12 months using Ontario health administrative and self-reported data to measure diagnostic imaging use and other health outcomes. We will assess characteristics of the clinicians, patients and encounters to identify variables associated with inappropriate imaging. In the qualitative study we will conduct in-depth interviews with primary care clinicians and patients.This will be the first Canadian study to accurately document the extent of the overuse of imaging for LBP, and the first worldwide to include data from the main healthcare professions offering primary care for people with LBP. This study will provide robust information about rates of inappropriate imaging for LBP, along with factors associated with, and an understanding of, potential reasons for inappropriate imaging.The online version of this article (10.1186/s12891-019-2427-1) contains supplementary material, which is available to authorized users. Low back pain is the world’s leading cause of disability due to non-fatal health outcomes from diseases and injuries, and presents a major societal and individual burden , 2. Low For people with low back pain who seek care, the most common providers of choice are family practitioners, chiropractors and physiotherapists . HoweverFor patients presenting with low back pain to primary care providers, serious pathological cause is rare and up to 99% of people have “non-specific low back pain” . Non-speMultiple international clinical practice guidelines consistently recommend that diagnostic imaging tests are not routinely indicated for people presenting with non-specific low back pain because it can lead to inefficiencies and waste in the healthcare system –21. ImagDespite evidence of the overuse of imaging for low back pain in other high-income countries , 11, 16,To inform effective knowledge translation interventions relevant in Canada, we need to determine current clinician and patient beliefs. A recent systematic review of qualitative studies identified that clinicians lacked content knowledge of low back pain guidelines . The fewWe need a better estimate of the extent of inappropriate imaging for low back pain in Canadian primary care. We also need to obtain reliable information to inform the design of effective knowledge translation interventions to improve the quality of low back pain care. This project will provide new knowledge to inform the design of tailored strategies to reduce inappropriate imaging for low back pain. These interventions will have the potential to improve the use of healthcare resources and reduce harm to the vast number of people who seek care for low back pain in Canada.Our overall project goal is to inform the design of evidence-based and theoretically-informed knowledge translation strategies to reduce inappropriate imaging for people with low back pain in Ontario, targeting primary care clinicians, patients and the public. To achieve this goal, we will undertake a mixed methods study incorporating an inception cohort study (Study 1) and a qualitative study of primary care clinicians and patients (Study 2).To determine the rate of, and factors associated with, inappropriate lumbar spine imaging  for people with non-specific low back pain presenting to primary care clinicians in Ontario.To determine the barriers and facilitators to reducing inappropriate imaging for low back pain in primary care settings.3.To determine differences in rates of recommending imaging among types of primary care clinicians.4.To describe demographic characteristics and patterns of care for people with low back pain in primary care settings.Clinician participants (n = 175) will comprise 50 each from chiropractic and physiotherapy, and 75 from family medicine. We are recruiting more family medicine clinicians than the other professions because lower numbers of patients with low back pain attend family medicine than chiropractic and physiotherapy. Our partner organisations will promote study participation via their normal communication strategies to their clinician members. We will invite clinicians in community-based practices chosen randomly from the lists of all registered clinicians in Ontario. From the College of Physicians and Surgeons of Ontario we will select only family doctors. From the College of Physiotherapists of Ontario we will select only physiotherapists whose primary work site is primary care. From the College of Chiropractors of Ontario we will use the full list.We anticipate a 30% response rate based on our previous experience , 52, henWe will invite clinicians to participate using a modified tailored design method  by sendiRecruited clinicians will complete a baseline demographic questionnaire including: sex; age; training location; years in practice; and proximity of practice to imaging facility : Consecutive patients with low back pain will be invited to participate until up to 25 are recruited from each participating clinician. Research staff will visit each participating practice to train the practice staff and clinicians in the study procedures. To reduce possible selection bias, we will encourage practice staff at each location to follow a strategy suitable for their practice that maximises the chances of recruiting consecutive patients with low back pain. For clinicians in solo practice without reception staff, typical of some chiropractors and physiotherapists, clinicians will approach potential participants directly. For clinicians in circumstances where practice reception staff are likely to know in advance that a patient’s consultation is for low back pain, practice reception staff will be asked to inform every such patient about the study during the recruitment period and provide them with recruitment information to read in the waiting room. If the patient consents to participate, the practice staff will inform the clinician, who will then complete the enrolment process, including screening for participation.We are allowing 12 months for patient recruitment; that is, approximately two patients with low back pain recruited per month per clinician, which is feasible based on incidence rates of low back pain presentations in these settings , 54, 55.Rates of patient recruitment will be monitored via contact from the research team to clinicians and practice staff approximately every 2 weeks. We will ask participating clinicians to keep a de-identified list of patients whom they approached, and to indicate how many were ineligible and how many declined participation. To reduce the risk of selection bias, practice staff, clinicians and patients will only be told that this is an observational study on the current management of low back pain in primary care, and not that lumbar imaging is the main focus. There is a lower incidence of low back pain presentations in family medicine compared to chiropractic and physiotherapy, so patient recruitment in this setting will require more support .Clinician participants will be currently practising and providing care for patients with low back pain. Their practice must be a first point of contact for ambulatory care in Ontario, and they must be in good standing with their respective Ontario regulatory body. We will exclude family doctors who practice in academic family health teams due to the presence of residents rotating through these practices.Patient participants will be eligible if they are consulting participating clinicians for the first time for an episode of low back pain, with or without leg pain, and they have an Ontario Health Insurance Plan (OHIP) number. Patients will be included if they are aged ≥18 years old with a new episode, or acute exacerbation, of low back pain. This is defined as the current episode of pain preceded by at least four weeks without significant low back pain; we define significant low back pain when average pain intensity is scored as 3 or more on a scale of 0 to 10, and the pain interferes with daily activities. Pain will be in the region bound by the lower ribs and the lower gluteal fold, with or without pain referred beyond this region. Patients will be excluded if they are pregnant, or if they are unable to speak and read English. Where possible, practice staff will use a checklist to screen potential patients for eligibility  to determine if any imaging was undertaken  scan, ultrasound). Although plain x-ray, CT scan and/or MRI are most likely to be ordered for patients with low back pain, we will capture all related imaging to be comprehensive in the assessment of inappropriate imaging. ICES data will also capture whether a pathological condition develops , and surgery and emergency visits related to such a condition.Some imaging may not be captured by the administrative data. Approximately 12% of chiropractors take their own plain x-rays and this information will not be captured in ICES data ; completThe encounter, questionnaire and administrative data will be used to determine if any imaging ordered is inappropriate. We will apply a modified version of the American College of Radiology imaging appropriateness criteria for low back pain . If any Trained secondary coders will undertake independent double data entry of encounter forms into the study’s purpose built database. Encounter data will be coded using the International Classification of Primary Care (ICPC-2), adopted by the World Health Organization as a classification system for primary care , 62, andICES, funded by the Ontario Ministry of Health and Long Term Care, links encoded population-based health information at the patient level. The practice-level and patient questionnaire data collected by the study team will be migrated to ICES for linkage. Analysis will be conducted using the following ICES datasets: OHIP database for imaging fee codes; OHIP Claims Database; National Ambulatory Care Reporting System Database for emergency room visits; Canadian Institute for Health Information Database for hospitalisation and surgery; Ontario Cancer Registry.The study will be adequately powered to determine factors associated with imaging behaviour, including both clinician (e.g. profession) and patient (e.g. severity and duration of pain) characteristics. We will compare inappropriate imaging rates among professions, assuming base imaging rates across the professions range from 10 to 45% , 64, 65.Characteristics of clinicians, patients and encounters will be summarised using descriptive statistics. We will calculate imaging rates per 100 low back pain patients with 95% confidence intervals and we will determine imaging rates for each primary care profession. We will undertake multilevel logistic regression analysis to determine the effects of clinician- and patient-level factors on inappropriate imaging. Clinician-level factors assessed will include age, sex, profession type, location of clinician training, clinician years in practice, ownership of imaging facilities, knowledge of imaging guidelines, and time spent with patient. Patient-level factors measured at baseline will include age, sex, race/ethnicity, insurance status, living in a metropolitan area, beliefs about usefulness of imaging, education level, duration/severity of low back pain, and three month measurement of satisfaction with treatment and adverse events. Patients consulting each clinician will form a cluster and will be considered as the second level in the multilevel logistic regression. We will also conduct a marginal logistic regression analysis to investigate the effects of clinician- and patient-level factors on inappropriate imaging and estimate the association between inappropriate imaging and explanatory factors in the marginal model using Generalised Estimating Equations. The analysis will allow examination of differences in results from the two models and determine whether the conclusions depend unduly on the model assumptions.We will conduct semi-structured in-depth interviews with clinicians from each profession and their patients. Study 1 clinician and patient participants will be eligible to participate. We will purposefully approach individuals to provide a variety of views and perspectives, including patients who have, and who have not, been referred for imaging. Patients will be approached for an interview during the early stages of their management for low back pain so that their experience is recent. Clinicians will not be interviewed until after they complete their participation in Study 1 to avoid revealing the true nature of the study to them.Our target sample size will be 30–45 clinicians (10–15 from each profession) and 30 patients (10 who consult each profession). Recruitment and sampling will cease once our data analysis has produced a stable set of findings and emergent codes no longer arise during data collection and analysis  .Semi-structured interviews will be conducted over the telephone by a project staff member. Interview questions will be informed by the Theoretical Domains Framework (TDF) to systematically identify barriers and facilitators to practising in accordance with best practice recommendations, focussing on the use of inappropriate imaging , 70. IntFor clinician interviews, we will ask general questions about how they manage patients with a new episode of low back pain. We will ask about their knowledge of low back pain evidence-based guidelines to gain insight into the factors that hinder, or facilitate, clinical behaviour that is in accordance with the guidelines . For cliWe will undertake content and thematic analysis of interview transcripts and both the manifest and latent content will be examined . Both clOur project Advisory Committee comprises all investigators and representatives of the partner organisations. Partner organisations include the Ontario Physiotherapy Association, the Ontario Chiropractic Association and the Ontario College of Family Physicians. The committee meets at least twice each year over the project duration to advise on all aspects of the project.This will be the first Canadian study to document the extent of the overuse of imaging for low back pain, and the first worldwide to include data from all relevant professions offering primary care for people with low back pain and who can refer for imaging. The outputs will be robust information about rates of inappropriate imaging for low back pain, along with predictors and reasons why inappropriate imaging is occurring. The study will also reveal differences in rates of recommending imaging among types of clinicians, and describe demographics and patterns of care for people with low back pain in primary care settings. Using both quantitative and qualitative results, knowledge translation strategies will be developed to address the issue of inappropriate imaging in these professions. Working with our project partners, the knowledge translation strategies will aim to be relevant, feasible and acceptable for each profession and the general public.Additional file 1:Data collection forms. (DOCX 331 kb)


The autonomic response to pain might discriminate among consciousness disorders. Therefore, aim of this study was to describe differences between minimally conscious state (MCS) and unresponsive wakefulness syndrome (UWS) patients in their autonomic response to a nociceptive stimulus. ECG, respiration, finger blood pressure (BP) and total peripheral resistances (TPR) were continuously recorded before, during and after a standardized noxious stimulus in 20 adult brain-injured patients, 14 in UWS and 6 in MCS. Occurrence of fast autonomic responses synchronous with the stimulus was detected by visual inspection of the tracings; short-term (<20 s) and long-term (between 20s and 50 s from the stimulus) responses were evaluated by beat-by-beat quantitative analysis. The noxious stimulus elicited fast responses in both groups, but only MCS patients showed a significant short-term response in TPR and long-term response in HR. Thus, short- and long-term cardiovascular responses to pain might integrate neuro-behavioural assessments to discriminate between MCS and UWS. In the healthy individual, the cardio-respiratory autonomic response to pain induces an acute and transient increase in heart rate (HR), blood pressure (BP) and ventilation . Such reTherefore, it is conceivable that the evaluation of the autonomic response to pain may give objective information for discriminating states with different alterations of consciousness that follow brain damages, in particular, distinguishing between unresponsive wakefulness syndrome  and minimally conscious state  . Such diIn this context, response to a painful stimulus might help improving the diagnostic accuracy in discriminating between MCS and UWS. Actually, it has been reported that the areas of the so-called pain matrix are less activated by a noxious stimulus in UWS than in MCS patients, and that MCS patients, unlike UWS ones, preserve the functional connectivity between the primary somatosensory cortex and fronto-parietal associative cortices, suggesting a less impaired capacity of pain perception in MCS patients .Surprisingly, the evaluation of pain response has been judged of minor importance in the clinical assessment of consciousness disorders , probablAim of this study is therefore to describe differences between MCS and UWS patients in their autonomic and behavioural reactions to a standardized nociceptive stimulus, in this way evaluating the feasibility of discriminating between states of consciousness from the response to pain. This will be done considering patients classified in UWS or MCS according to the validated Coma Recovery Scale-Revised (CRS-r), and by The study was approved by the ethics committee of Fondazione Don C. Gnocchi, and all clinical investigations have been conducted according to the principles expressed in the Declaration of Helsinki. Due to the clinical condition of the patients, they completely lacked the capacity to provide any consent to the study. Therefore, the informed consent was obtained by the legal surrogate of each enrolled patient.Twenty patients with severe brain injuries  consecutively admitted to our “long-term care unit”  were enrolled. The aetiology was post-anoxic (n = 9), vascular of ischaemic (n = 4) and haemorrhagic (n = 2) origin, traumatic (n = 4), and post-encephalitic (n = 1). Fourteen patients (70%) were currently treated with β-blocking agents . All patients did not need assisted ventilation but one, who was assisted by nocturnal mechanical ventilation only.Some days before the administration of the nociceptive stimulus, a neuropsychologist executed a behavioural evaluation to each patient, administering the CRS-r , to clin2 saturation , systolic BP (SBP) and diastolic BP (DBP) (standard mercury sphygmomanometer) were measured. None of the subjects showed clinical sign of autonomic disease, like HR>120 bpm, SBP>160 mmHg, hypo/hyperthermia, sweating excess, cutaneous rushes.Data acquisition was performed in the morning, between 8:00 and 10:00 AM, in non-fasting state. First, all patients underwent a physical examination by an expert neurologist, during which a 12-lead standard ECG  was executed, and axillary body temperature, blood O5 lead. BP, ECG and ventilatory signals were digitized by the analog I/O system of the Finometer Pro device, at 200 Hz sampling frequency. Recordings were performed with the patients in recumbent position. Ten minutes after the start of the recording, a nociceptive stimulus was applied to the hand not instrumented by the Finometer cuff. The noxious stimulus consisted in a constant pressure produced by a load of 3.5 kg, applied for about 5 s on one fingernail bed by a validated Newton-meter . The recording continued for at least two minutes after the application of the stimulus.Then, all patients were instrumented by a thoracic belt, connected to a piezo-resistive respiratory transducer  to monitor rib cage movements. Arterial BP at the finger artery was recorded by applying a finger cuff around the middle finger of a hand . ECG was continuously monitored by a VDuring the delivery of the noxious stimulus an expert neuropsychologist administered the validated Nociception Coma Scale (NCS). NCS scoData were stored in a protected database for offline analysis. Finger arterial BP was processed with the Beatscope software  that reconstructed the BP wave at the level of the brachial artery and calculated SBP, DBP, HR, stroke volume (SV) and total peripheral resistances (TPR) on a beat-by-beat base. The R-R interval (RRI) was derived beat by beat from the ECG.Two independent observers, both blinded to the consciousness status of the patient, visually inspected the recorded signals off-line to identify the presence of a fast autonomic response, synchronous with the delivery of the stimulus see . PatientShort-term changes induced by the noxious stimulus were assessed by comparing the average values of SBP, DBP, HR, SV and TPR time series calculated over three consecutive, non-overlapping data windows of 10-s , with the second one (“stimulus”) starting synchronous with the delivery of the noxious pressure. Given the duration of 10 seconds, the “stimulus” data window completely covers the 5-s period of stimulus administration. Increments from the reference period to respectively the stimulus period and the short-term response period  were quat = 0 (time range: from -30 s to +50 s). To quantify the long-term autonomic response, the response period was defined between +20 s and +50 s after the stimulus, in this way following the short-term response period without overlapping, and the reference period was the data segment of equal length immediately preceding the stimulus. The long-term autonomic response was quantified as increment from the reference to the response period  with within-factor Time  and between-factor State (MCS or UWS) was performed on HR, SV, SBP, DBP and TPR, with Newman-Keuls post-hoc analysis.To assess changes due to the long-term autonomic response to pain, mixed ANOVA was performed considering Time  and State as factors, with Newman-Keuls post-hoc analysis. The hypothesis of Gaussian distribution was preliminary verified in baseline by the Kolmogorov-Smirnov test for each cardiovascular parameter .The associations between NCS scores and short/long-term autonomic responses to the noxious stimulus were assessed by linear correlation. The significance level was set at p<0.05 and analyses were performed with Statistica 7.1 .Based on preliminary CRS-r scores, 6 patients were diagnosed in MCS and 14 in UWS. Recordings in 2 UWS and 1 MCS patients were discarded from subsequent analysis because muscle hypertonia and uncontrolled movements did not allow applying properly the noxious stimulus or obtaining finger BP recordings of sufficiently good quality for the analysis.The histogram of NCS scores evaluated in the remaining 17 patients revealed a statistically different distribution of the behavioral responses to pain between groups . IndividAbout half of the patients (47%) elicited a fast autonomic reaction to the pain stimulus and were classified as “responders”. Percentage of responders was slightly higher in the MCS  than in the UWS group (41.7 ± 14.2%) but the difference was not significant (p = 0.62). Visual inspection of ventilatory movements showed the occurrence of periodic breathing see  in 5 outSince periodic breathing induces synchronous oscillations in RRI, SBP and DBP that alter importantly the dynamics of cardiovascular time series, patients with periodic breathing were excluded from the following analyses. The reasons for the exclusion are clear looking at The analysis of the autonomic response within 20 s from the application of the stimulus identified as statistically significant the factor time for TPR, SBP and DBP. However, the interaction between time and state was significant for TPR only .Post-hoc analysis showed that the noxious stimulus increased TPR from the reference to the short-term response condition in the MCS group only . MoreoveTime and the interaction between Time and Status as significant for HR only  identified the factor  HR only , suggest HR only . IndividThe time courses of SBP, DBP, SV and TPR did not evidence any trend that might differentiate the MCS and UWS groups , Table 25 for TPR (as short-term response), or of at least 1 bpm for HR (as long-term response), separately for MCS and UWS patients.Correlations between NCS scores and autonomic responses to pain are shown only for the autonomic variables where a significant interaction between time and state  indicateThe main finding of this study is that the autonomic cardiovascular response to a nociceptive stimulus appears characterized by a short-term response  and a long-term response , both of them somehow differently activated by pain in MCS and UWS patients.In our MCS patients, the short-term autonomic response parallels the typical cardiovascular response to acute pain, since we found a significant increase in BP and in TPR in the short-term response vs. the stimulus condition, and a tendency to increase for HR and SV . In factHowever, the finding that the percentage of patients showing a fast response to the nociceptive stimulus does not differ significantly between MCS and UWS groups would suggest that the lower neural centers (likely those responsible for the fast response) preserve their functions similarly in the two groups of brain-injured patients. These results are in agreement with those of previous studies reporting that the autonomic changes in HR, BP and respiratory movements were not reliable indicators of response to nociception in individuals with severe brain damage .Considering the response over a longer time scale, i.e., ten of seconds from the stimulus application, the picture substantially changes and we found a significant interaction for HR only. In fact, the HR level increased significantly about half a minute after the application of the painful stimulus, and then remained higher than baseline for tens of seconds, but in the MCS group only. The substantial lack of a long-term HR response in UWS patients probably reflects an extension of brain damage at higher levels compared to MCS patients. Indeed, magnetic resonance imaging studies showed that the central response to pain requires the integrity of different brain areas and of their neuronal connections, besides the preserved function of peripheral sensory organs. The transport of the nociceptive information to the higher levels of the central nervous system occurs through multiple and parallel upward projections that lead the signal from the spinal cord to prosencephalon, mesencephalon, and cortex . The perA second explanation for the persistent increase in HR is that MCS patients  may develop an “alert” state in response to pain. Although indirectly, this may reveal a different sensitivity to nociception and therefore a different residual functionality of the central nervous system function in MCS and UWS patients.Finally, a third mechanism may have contributed to the long-term HR increase in MCS patients: a persistent increase in circulating catecholamines. Some studies demonstrated that catecholamines may increase excitability or sensitize nociceptors , therebyOur MCS patients also showed a more pronounced “behavioural” response to the pain stimulus, as quantified by the NCS score, compared to the UWS group. This finding supports the hypothesis that MCS patients have a less compromised capacity to perceive pain compared with UWS patients. This aspect of pain response in MCS state deserves therefore further neuro-hormonal and behavioural investigations.Interestingly, we found a significant correlation between the long-term increase in HR after the painful stimulus and the score of the behavioural response to the painful stimulus as provided by NCS. From a physiological viewpoint, the correlation suggests that the autonomic long-term response may involve the same complex brain processing centers devoted to "behavioral" responses to pain. This finding suggests that the HR long-term response could become the basis of an "automated" test for monitoring the patient’s consciousness status, simple to implement and relatively robust in terms of signal acquisition and processing. In fact, HR can be easily recorded, even on a beat-to-beat basis, for long periods of time, and currently available miniaturized devices can be safely used to this purpose. A test based on the HR response to pain might potentially provide information on the consciousness status similar to that scored by NCS, but in a less subjective way. Such a test could complement the NCS evaluation, providing a quantitative, long-term and operator-independent monitoring, without involving experienced testing staff.On the other hand, the short-term increase in TPR was not significantly correlated with the NCS score. In this case, the lack of correlation suggests the involvement of centers different from those producing a behavioral response, as those activated by vascular reflexes. This suggest the possibility that the information provided by the short-term vascular response to pain is independent from the information provided by NCS, and that a test based on TPR changes may effectively integrate the NCS score. Therefore, it is conceivable that a test integrating the NCS score with the short-term vascular autonomic response to pain may effectively improve the patients’ assessment.Such a test, based on the administration of a noxious stimulation, may have ethical implications that rise an important cost-benefit issue. It should be considered, however, that it may potentially provide relevant information in the face of a minimum painful stimulus. Furthermore, if its scientific validity will be confirmed by further studies, it could be used only occasionally in clinical practice, for instance to check the initial state of consciousness, being repeated only if the clinical conditions of the patient change.Finally, some limitations should be considered. First, the autonomic response to a pain stimulus could be altered by the use of β-blockers that may blunt the adrenergic response to nociception. Actually, comatose patients, especially those suffering from traumatic injuries, are often treated with β-blocking agents, which reduce mortality caused by catecholamine surges often occurring in such patients . HoweverSecond, the beat-by-beat BP response to the nociceptive stimuli could not be recorded with the finger cuff in patients in which a marked hypertonia of the upper limb muscles resulted in extreme flexion of the hand fingers. However, this is not a major limitation because our study points out that information for discriminating between MCS and UWS is also associated with the long-term response of HR.Third, periodic breathing induces HR changes that make difficult or even impossible to observe a reliable cardiorespiratory reaction to pain, suggesting that a test based on the autonomic response to pain cannot provide useful information for discriminating between MCS and UWS in this fraction of patients.S1 Table(DOCX)Click here for additional data file.S2 TableIndividual increments of the parameters HR, SBP, DBP, SV and TPR from “reference” to “stimulus” and to “response” conditions in the short-term analysis.(DOCX)Click here for additional data file.S3 TableIndividual increments of the parameters HR, SBP, DBP, SV and TPR from “reference” to “stimulus” and to “response” conditions in the long-term analysis.(DOCX)Click here for additional data file.


To retrospectively analyze the effects of our original combination therapy treatment on patients with nonodontogenic persistent dentoalveolar pain.  Twenty-one patients suffering from persistent dentoalveolar pain  participated in this study. They were treated with a therapy combination of jaw exercise and psychoeducation to reduce oral parafunctional activities every month. The intensity of pain in these subjects was evaluated using a numerical rating scale (NRS) before and after treatment.  The NRSs at the baseline ranged from 5 to 10 , from 0 to 10  at one month after treatment, from 0 to 10  at three months after treatment, and from 0 to 10  at the end of treatment. Pain intensity after treatment improved significantly.  There was a significant reduction in pain after our combination of therapies as nonpharmacological treatments, and therefore this treatment could be useful in the management of NPDP patients. Patients suffering from nonodontogenic persistent dentoalveolar pain (NPDP) continue to seek pain treatment from several doctors, not only dentists but also several kinds of medical practitioners. NPDP is known as idiopathic periodontalgia , phantomSeveral studies have shown that, in many cases of NPDP, the pain occurred after dental treatment, including endodontic treatment or surgical procedure , 9. HoweEffective treatments for NPDP have yet to be established. General treatments for NPDP are the pharmacological treatments used to treat neuropathic pain. However, these treatments are not actually always effective in alleviating NPDP, and some patients experience severe side effects , 16. FurRecently, there are many reports that therapies including exercise therapy, cognitive-behavioral therapy or progressive relaxation, and intensive interdisciplinary rehabilitation are moderately effective for chronic pain. Therefore, we tried to treat NPDP patients using our original combination therapy ) that was effective on craniocervical chronic pain in a previous study .The aim of this study was to retrospectively analyze the effects of treatment of our original combination therapy for patients with NPDP.Data were collected in a test battery using an iPad and through interviews conducted by a dentist. The same dentist treated the patients using our original combination therapy. The intensity of pain was rated by the patient using a Numerical Rating Scale (NRS), where 0 indicated no pain and 10 indicated the greatest pain possible. Patients were asked about the pain intensity at every visit, and inquiries about their pain condition were made by telephone call for the follow-up.All patients were referred from other hospitals to the Pain Center for treatment of NPDP. Treatment protocols used in the present report were based on institutional policy and clinical guidelines approved by the IRB of Aichi Medical University, and written consent was obtained from all patients (Reference number 13-083).(i) Nonodontogenic persistent dentoalveolar pain (NPDP)(ii) Pain duration more than 3 months(iii) Age >18 years  Inclusion criteria:(i) Clear case of odontogenic pain(ii) Rheumatic disease or general inflammatory condition(iii) Fibromyalgia(iv) Language difficulties and communication difficulties(v) Closed locking jaw  Exclusion criteria:Participants were the patients who visited the Multidisciplinary Pain Center (Pain Center) of Aichi Medical University from December 2010 to June 2012. Twenty-one patients were chosen as participants at first, but six patients dropped out during treatment. Nineteen patients were female and two were male, and their mean age was 55.7 ± 19.6 years. They were selected according to the following inclusion and exclusion criteria:The patients were administered our combination therapy under the supervision of a dentist (Makino) at our pain center at every visit. They were instructed to continue the exercises at home.After checking the medical history of each patient, we listened to the patient's complaints regarding NPDP and reconfirmed their pain. We confirmed that there was no clinical or radiographic evidence of relevant pathology in their pain and explained this to the patients.Patients were instructed to perform the jaw movement exercise at home. The exercise consists of ten sets of protrusion-retrusion (anterior-posterior) jaw movements, a lateral jaw movement with the right side, and then a lateral jaw movement on the left side. Protrusion-retrusion (anterior-posterior) jaw movements were performed while biting on a cotton roll with the front teeth. A lateral jaw movement with the right side was performed while biting on a cotton roll with the right canine, and then a lateral jaw movement on the left side was performed while biting on a cotton roll with the left canine. One set exercise: a cotton roll goes up from below to the occlusal plane at first, secondly, a cotton roll maintains position at the occlusal plane, and finally, a cotton roll goes down in each exercise. These exercises were performed once a day. It was important for the patients to concentrate on the jaw exercise while watching their jaws move in a small mirror and to move the jaw slowly. They were also advised to perform the exercise carefully so as not to induce pain .(1) Recognition of OPAs. We informed patients to understand that it was important to recognize both OPAs and the frequency of OPAs during the daytime. We advised them not to be obsessed with OPAs or attempt to avoid them, but just to recognize that it had occurred. In addition, our other instruction was that when they felt pain, they had to recognize what kind of OPAs they were doing and how frequently they were doing them.(2) Relaxation of Masticatory System Method. Patients were trained to relax their tongue, their masticatory muscles, and their jaw. This form of relaxation involved taking a breath with their mouth wide open and then closing the mouth and trying to relax the tongue and jaw, without allowing the teeth to clench together. They were instructed to perform this system of relaxation when they noticed their pain and OPAs . Pain intensity after treatment improved significantly (P < 0.01) (Wilcoxon test)  .One year later, we evaluated 11 patients by telephone call after the patient's last visit. Three patients out of 11 had no pain, seven patients had a recurrence of less pain, and one patient displayed no improvement. Ten patients took no medication, while one patient occasionally took medication. However, one patient took medication everyday with no improvement of pain .Generally, patients with NPDP are suffering from their pain for a long time because available treatments fail to provide adequate pain relief. However, this study found that our treatment significantly improved the pain intensity of NPDP and their QOL at follow-up. To date, therapeutic algorithm for NPDP  includesOur original therapy consists of exercise and psychoeducation that have become common therapies for chronic pain. Recently, there are many reports of moderately effective nonpharmacologic therapies for TMD , 22, andThe Hospital Anxiety  and Depression Scale  and Pain Catastrophizing Scale  of the participants in this study showed high score tendencies. Four out of the 6 subjects who dropped out in this study had mental diseases . Medical practitioners may need to be careful of mental conditions or mental diseases of NPDP patients.Based on the present results, we could generate a hypothesis about the onset mechanisms of NPDP. NPDP patients are iterating OPAs (clenching and tongue habit) pressure teeth or area where a tooth once resists. If these pressures continue, c-fibers on periodontal ligament space will keep receiving the stimulation at first, and wind-up phenomena will occur subsequently at the central nervous system. This could be why local anesthesia for NPDP patients leads to complete or incomplete pain relief, as seen on a previous study . And, moThere are several limitations to this study. First of all, the participants in this study were an undefined group having NPDP because correct diagnosis and pathophysiological mechanisms of NPDP have yet to be established. The number of participants in this study is small. The further studies of NPDP are needed but these studies are difficult because the population of NPDP patients is small.This study reported a significant reduction in pain after our own combination of therapies to improve jaw movement and psychoeducation to reduce OPAs as forms of nonpharmacological treatment. Therefore, this treatment could be useful in the management of NPDP patients.


Pain is the subjective feeling of an individual, which affects the overall recovery of patients after cardiac surgery. Postoperative pain is the most inadequately managed symptom of cardiac surgery. Subsequently, there are many factors that can either hinder or facilitate pain management, including patients' beliefs, cultural values, physiological features, hospital policies, and healthcare providers' knowledge and beliefs. The purpose of this research was to identify factors associated with postoperative pain and its management, after cardiac surgery, among patients in a tertiary care hospital in Karachi, Pakistan. Quantitative correlational study design was employed to attain the study purpose. Data were collected from 136 adult cardiac surgery patients admitted in the Cardiothoracic Surgery (CTS) Department, of tertiary care hospital. A self-developed questionnaire tool was used to gather information from patients. Data was then analyzed on SPSS version 19. Mann-Whitney U, Kruskal Wallis, and Spearman tests were applied to find the associations between the pain levels and of the independent variables. The mean pain scores of the first, second, and third postoperative days were found to be 2.98, 2.96, and 2.98, respectively. The findings also showed that BMI and the types of surgery were significantly associated with postoperative pain. Patients' beliefs regarding drug dependency, fear of adverse effects, and postoperative physical activities were also associated with pain. Furthermore, the nurses' education level and reluctance in medication administration due to fear of adverse effects were found to be significant too. The study identified some of the important factors that were associated with postoperative pain. The results suggest the need for the enhancement of patients' education on drug dependency, adverse effects, and physical activity, before cardiac surgery. The nurses should be educated on pain management keeping the patients' culture and other perceptions of pain in mind. Cardiovascular diseases (CVD) are an area of major health problem worldwide . The burPain has been defined as the most important and inadequately managed symptom that affects the overall recovery of cardiac surgery patients , 9. The The pharmacological management of pain is carried out through the combination of different medications, such as opioids and nonopioids. Furthermore, there are many nonpharmacological methods which are used for the management of postoperative pain such as deep breathing, massaging, relaxing, and music therapy. However, despite using several pharmacological and nonpharmacological interventions, it has been identified that pain is inadequately managed after cardiac surgery , 13, 14.The prevalence of sternal incision pain from cardiac surgery has been reported to be around 20 to 50% during the first and second weeks following surgery and hospital discharge , 16. TheQuantitative correlational study design was used to assess the factors associated with postoperative pain among patients after cardiac surgery. The study was conducted at Cardiothoracic Surgery (CTS) department of the Aga Khan University Hospital (AKUH), Karachi, Pakistan. The AKUH is a tertiary care hospital with more than 600 inpatient beds.The study was conducted among patients admitted in the department of CTS from April to June 2016. The target population of this study included adult patients who had undergone any type of cardiac surgery, such as Coronary Artery Bypass Grafting (CABG), Valve Replacement/Repair Surgeries, and Congenital Heart Surgeries. Patients who followed the normal pathway of cardiac surgery were included in the study. The cardiac surgery pathway is the AKUH document used for the development of a clinical management plan, shows the fast track recovery goals for patients, and ensures the provision of ideal and systemic nursing actions to attain these goals with maximum efficiency. The format of a pathway provides the framework for the healthcare providers to focus on the step-by-step important components of care to be maintained on each postoperative day.Patients who were 18 years or older, followed the cardiac clinical normal pathway, and were ready for cardiac rehabilitation (3rd-4th postoperative day) were included in the study. Those patients who were unable to comprehend Urdu or English language and had altered conscious level and Glasgow Coma Scale (GCS) of less than 15 were excluded. In addition, those patients who were receiving intravenous opioids on the 3rd-4th postoperative day and had severe respiratory distress and hemodynamic instability were excluded from the study.The sample size was computed using the Open Epi Software version 3.03. In order to determine the factors associated with postoperative pain and its management, the variable of physical activity was considered. Keeping the confidence level at 95%, power at 80%, odds ratio (OR) as 0.25, and the frequency of pain among patients not rested (nonexposed) was taken into consideration. Finally, the sample size that emerged was 202 participants. This sample size was further inflated by 10% to wipe out the effects of errors, nonresponse, and missing data. Hence, the final sample size was taken as 223 participants.Data was collected by using a structured questionnaire; the questionnaire was self-developed and was divided into two sections. The demographic and clinical features were included in section A. The questions related to the factor of postoperative pain were included in Section B, and they consisted of 28 items in five categories, namely, patient's personal factors, sociodemographic factors, organizational  factors, communication factors, and postoperative factors. The questions of section B were based on Likert scale and were determined based on the literature review and input of experts. The patient's personal factors, such as belief in expressing pain, belief in opioids, fear of addiction, and side effects, were primarily taken from “Barrier Questionnaire II” (BQII), which has been used in previous study . Other cThe period of data collection was from April 2016 to June 2016. The score readings on pain were collected from the patients' charts for the 1st, 2nd, and 3rd POD, to assess the overall intensity of pain, and then participants were then asked to fill in the questionnaire. EpiData software version 3.1 was used for data entry, and questions with multiple answers were coded. Furthermore, double entry and data cleaning were also carried out by the expert.Data analysis was completed by using the statistical package for social sciences (SPSS) v.19 and STATA  v.12. Descriptive statistics were computed for the demographic data, and factors of the pain and pain management. The frequency and percentage were computed for all the categorical variables, and mean (±SD) was computed for all the continuous variables. The pain scores of each POD were assessed for the normality using Kolmogorov-Smirnov (K-S) goodness of fit test. The mean (±SD) was also computed for three days' pain scores. The Mann-Whitney U test was applied to all the variables having two categories along with some of the demographic, clinical, and other potential variables. Kruskal Wallis test was computed for demographic and clinical variables having more than two categories. Furthermore, Spearman's rank correlation coefficient was applied for determining the association between all the continuous variables. The p-value of less than 0.05 was considered as significant throughout the analysis.Formal approval of the study was taken from the Ethical Review Committee (ERC) of the Aga Khan University. All participants were approached and selected on a voluntary basis and they signed the informed consent form prior to the filling of the questionnaire. All the participants of the study were provided with detailed information regarding the purpose, risks, benefits of the study, and right of withdrawal. The confidentiality of participants' information was secured and soft data was saved on computers with password protection.The sociodemographic features of the cardiac surgery patients are presented in Some important clinical variables are shown in The pain levels of patients were noted from the bed-side flow sheets of the first, second, and third postoperative days (POD), which were assessed and recorded by the assigned nurses. The mean (±SD) pain levels on the first, second, and third PODs were 2.98 (±0.34), 2.96 (±0.36), and 2.98 (±0.48), respectively.The Mann-Whitney U, Kruskal Wallis, and Spearman test were applied to determine the relationship of pain scores with all the dependent variables, as shown in As shown in The results identified that the patients' beliefs were the important concerns of patients which are shown in Most of the patients  perceived that physical activity would increase their pain and 81.6% (n=111) believed that restricting physical activity was a good strategy to manage pain. The relationship of pain and postoperative physical activity showed a significantly high association with the pain levels of the second POD, as evident by the p-value of 0.001. However, the question related to activity restriction to manage pain was found to be insignificant , with each POD pain score.Sixty-three percent (n=86), of the participants, responded that they got adequate information on postoperative pain management during preoperative teaching. A small number of patients, 22.8% (n=31), perceived that hospital shave inadequate standards and policies about pain management. Furthermore, only 17.6% (n=24) of patients expressed that the process for carrying out the physician's order to give pain medication was time consuming. Related to the knowledge and practice of nurses about postoperative pain management, 49.3% (n=67) of the patients believed that nurses had limited knowledge and 40.4% (n=55) perceived that nurses were reluctant to give pain medication because they feared adverse effects. However, 24.3% (n=33) thought that the nurses' attitude and perceptions made them nervous about taking pain medication. Furthermore, 43.4% (n=59) reported that they had to wait for the pain medication because nurses were busy in other tasks.The results also showed that 21.3% (n=29) believed that nurses did not give priority to pain management during postoperative care. However, 88.2% (n=120) participants felt that the training of nurses needs to include more education on postoperative pain and management of pain. Nurses' reluctance to administer pain medication, due to fear of adverse effects, was significantly (0.027) associated with the pain scores of the second POD. Another factor, about the need for enhancing of nurses' education, was also statistically significant (0.037). However, most of the questions were found to be insignificant (not<0.05).The results also showed that the patients had misconceptions about the expression of pain. Almost 15.4% (n=21) expressed that it was difficult to tell the nurse about the pain. However, 89.7% (n=122) patients believed that frequent reporting of pain would give a negative impression of their personality, as shown in The study identified that BMI and the type of surgery impose a significant impact on postoperative pain scores, and pain scores in obese and overweight patients were higher than those with normal BMI. Similar association between BMI and pain have been also identified in other studies and argued that the surgery of obese patients is complex which causes injury to large tissue areas and prolongs the retraction period during surgery , 20. PaiIn addition, the fear of addiction and adverse effects of pain medication were found to be significant personal factors associated with high pain scores in the present study population. The element of fear of addiction was consistent with a previous study conducted which found that 78% of cardiac surgery patients believed that the use of opioid medication would certainly cause drug dependency . On the Likewise, postoperative physical activity was another factor that had a statistically significant association with pain scores. In the current study, majority (73.5 %) of patients believed that postoperative activities were painful. Similar to the current study, the patients from previous studies also considered postoperative physical activities as painful; specifically, the cardiac surgery patients experienced pain with coughing, positioning in bed, ambulation, and breathing exercise and endeavored to restrict their activity to manage pain, thereby increasing the risk of complication , 6, 24.Furthermore, in the current study, 40% of patients perceived that nurses are reluctant to give pain medication because of fear of adverse effects. Other studies also suggest that the nurses' attitude towards pain medication administration is a barrier to adequate pain management , 10. SimTo the best of the researchers' knowledge, this is the first study on this topic carried out in Pakistan. The questionnaire used in this study was found relevant because it was developed by analyzing the available literature on all the associated factors of pain and its management. The population of this study comprised all types of cardiac surgery patients, regardless of any specific type; therefore, this research could be replicated in other parts of the country as well. The data was collected by the principal investigator to reduce the chance of biases.The current study has some limitations; for example, the pain scores could be measured directly from the patients, during different activities, and at different time intervals. The anticipated sample size of the study could not be achieved because of time limitations. This might have affected the internal validity and power of the study. The study was limited to one setting; hence, this study has limited generalizability.The patients preparing for elective cardiac surgery should be encouraged to work on their weight reduction to minimize the risk of severe postoperative pain.Patients should be given adequate awareness with regards to the effects and side effects of opioid medication, to reduce their fears, and to promote compliance with pain medication, during hospitalization and after discharge.The preoperative education plan of a patient should include the significance of postoperative physical activities and the rehabilitation plan, in order to improve its effectiveness.Pain management should be incorporated as a separate unit in the nursing curriculum.Similar studies should be carried out in the private and public hospitals of the country on a larger scale, to improve the generalizability and to promote a better understanding of the phenomenon.Studies may be conducted to validate the precision of the tools employed in this research.Case-control or prospective cohort designs should be employed to identify the causal relationship between the variables. Furthermore, qualitative studies could be conducted to explore the phenomenon of pain management among healthcare providers and cardiac surgery patients in more depth.Overall, this study reported a mild postoperative pain score for the first, second, and third postoperative days, among the cardiac surgery patients. The study also highlighted some of the facilitating and hindering factors related to pain management. The findings suggest the need for enhancement in preoperative education of the patients, especially, giving importance to weight reduction, pain medication, and postoperative physical activities. Furthermore, the results also proposed the need for improvement in educating the nurses about postoperative pain management.


Gabapentinoids are increasingly used in preoperative premedication despite controversial results. The aim of our study was to evaluate the effects of preemptive use of gabapentin or pregabalin on postoperative shoulder pain and rehabilitation quality after laparoscopic cholecystectomy.  This is a clinical trial comparing the effects of a preoperative premedication with 600 mg of gabapentin or 150 mg of pregabalin versus placebo on postoperative pain and recovery quality after laparoscopic cholecystectomy. Premedication was taken 2 hours before the surgery beginning. Ninety patients were included and randomized into 3 groups . The anesthetic protocol was the same for all patients. Primary endpoint was the shoulder pain intensity at the 48th postoperative hour. Secondary endpoints were postoperative nausea and vomiting (PONV), sleep quality during the first night, and the onset time for the first standing position. p < 0.05). In gabapentinoids groups, the incidence of PONV was lower and the sleep quality during the first postoperative night was better with significant results. Mean Spiegel scores were 22.43 ± 1.45, 22.30 ± 1.44, and 17.17 ± 1.66, respectively, in pregabalin, gabapentin, and placebo groups (p < 0.05). The delay for the first standing position was 14.9 ± 4.9 hours in the pregabalin group, 9.7 ± 3.6 hours in the gabapentin group, and 21.6 ± 2.1 hours in the placebo group. No superiority was found between gabapentin and pregabalin.  During the first 48 postoperative hours, the gabapentin and pregabalin groups had significantly lower shoulder pain than the placebo group . Preemptive premedication with gabapentinoids can enhance postoperative rehabilitation quality after laparoscopic cholecystectomy by reducing postoperative shoulder pain, decreasing PONV incidence, and improving sleep quality during the first postoperative night. This trial is registered with  Laparoscopic cholecystectomy is one of the most widely performed surgeries in the world . Its posGabapentin and pregabalin are two drugs belonging to the gabapentinoids family. They are classically known as antiepileptic treatments. However, they have been used in other conditions such as neuropathic, diabetic, and postherpetic pain . They haPreemptive administration of gabapentinoids can reduce postoperative pain intensity even after laparoscopic surgery . It can The aim of this study was to evaluate the effects of preemptive use of gabapentin or pregabalin on postoperative shoulder pain and recovery parameters after laparoscopic cholecystectomy.ClinicalTrial.gov (NCT03241875).After obtaining institutional ethic committee approval and patients' informed consent, this randomized, double-blind clinical trial was conducted jointly between the anesthesia and the visceral surgery departments of Sahloul Teaching Hospital . This study was conducted between December 2016 and August 2017. This trial was registered with Patients aged 18–65 years, with American Society of Anesthesiologists (ASA) physical status 1 and 2, and scheduled for laparoscopic cholecystectomy under general anesthesia were enrolled in this study. Exclusion criteria were as follows: allergy to gabapentin or pregabalin, history of psychiatric disorders, chronic neuroleptic treatment, history of renal and/or hepatic disorders, pregnant and/or breastfeeding women, complicated lithiasis pathology, conversion to laparotomy, and perioperative complications .α risk at 0.05 and the study power at 80% and hoping a 30% decrease in shoulder pain intensity at the 48th hour postoperatively, the minimum sample size was estimated at 29 patients per group. Sample calculation was made by the software Epi Info 6.0.Fixing the Patients were randomized into 3 groups of 30 each. Patients of group 1 received 150 mg of pregabalin (2 capsules of 75 mg), those of group 2 received 600 mg of gabapentin (2 capsules of 300 mg), and those of group 3 received 2 capsules of placebo. Capsules were arranged in nontransparent and numbered envelopes. They were given to patients during preoperative visit to be taken 2 hours before arrival in the operating room. No other premedication was prescribed.µg/kg over one minute, and cisatracurium at the dose of 0.15 mg/kg. Anesthesia was maintained by isoflurane in a mixture of 50% oxygen and 50% air. Remifentanil doses and expired isoflurane concentrations were adjusted intraoperatively to maintain a hemodynamic profile  not exceeding ±20% from baseline. Cisatracurium was reinjected at the dose of 0.03 mg/kg depending on neuromuscular blockade monitoring. PONV risk was assessed by the Apfel score (a four-criteria score used to estimate the probability of experiencing PONV) and prevented by dexamethasone 8 mg and ondansetron 4 mg. Normal saline was used for intraoperative vascular loading at the dose of 4 ml/kg/h. Tidal volume was fixed at 6 ml/kg of ideal weight, and respiratory rate was adjusted to maintain EtCO2 between 30 and 35 mmHg.In the operating room, all patients had standard monitoring . Anesthesia induction was carried out by propofol at the dose of 3 mg/kg, remifentanil at the dose of 1 Postoperative analgesia was anticipated 30 minutes before the end of surgery by 1 g of paracetamol and 20 mg of nefopam. All patients were extubated in the operating room after complete decurarization. They were monitored in the post-anesthesia care unit for one hour and then transferred to the visceral surgery ward. Postoperative analgesia was performed with 1 g of paracetamol and 20 mg of nefopam given four times a day. Postoperative vomiting was managed by 4 mg of ondansetron.Primary endpoint was shoulder pain intensity at the 48th postoperative hour assessed by the Visual Analog Scale (VAS) ranging from 0 to 10. Secondary endpoints were PONV incidence, sleeping quality assessed by Spiegel Scale , and time for the first standing position.Statistical analysis was performed using SPSS software version 20.0 for windows . Categorical variables were expressed in percentages. Normal distribution of continuous variables was tested using the Kolmogorov–Smirnov test. They were expressed as means or medians according to their distribution.t-test was used to compare means of normally distributed variables, whereas the Mann–Whitney test was used for non-normally distributed ones. A value of p < 0.05 was considered to be statistically significant.Categorical variables were analyzed using chi-squared test. Student's This study enrolled 90 patients undergoing scheduled laparoscopic cholecystectomy. All of them were followed up until the end of the study. Demographic characteristics were comparable between all groups. Insufflation pressure and duration of surgery, anesthesia, and pneumoperitoneum were also comparable between the 3 groups .p=0.003). Postoperative shoulder pain occurred after the 6th postoperative hour in all cases. Its intensity at rest and at exertion was significantly lower in the gabapentinoids groups than in the control one. When comparing the pregabalin group to the gabapentin one according to postoperative shoulder pain intensity, no significant difference was found . Average Spiegel scales were 22.43 ± 1.45 in the pregabalin group, 22.30 ± 1.44 in the gabapentin group, and 17.17 ±1.66 in the control group. Sleeping quality was comparable between the pregabalin group and gabapentin group   .Dizziness was the unique type of side effects documented in the gabapentinoids groups . This adverse effect was reported only before anesthesia induction.Our results suggest that a premedication with a gabapentinoid  can reduce the intensity of postoperative shoulder pain after laparoscopic cholecystectomy. It can also reduce the incidence of PONV, shorten the time to the first standing position, and improve sleep quality during the first postoperative night. However, no superiority was found when comparing the two gabapentinoids.Gabapentin and pregabalin are known as antiepileptic drugs. However, they have other reported uses due to their analgesic and anxiolytic effects , 10, 11.Several studies have shown the effect of gabapentinoids use as anesthetic adjuvant in the reduction of postoperative pain and analgesic requirements , 13–17. Although a single preemptive administration was the most prescribed modality, other studies kept the treatment for 2 to 5 days postoperatively. The meta-analysis of Lam et al. including 74 protocols of pregabalin use in different surgeries did not found any significant difference in postoperative pain reduction when comparing a single preemptive administration to an extended postoperative administration. When comparing different gabapentinoids drugs especially for laparoscopic cholecystectomy, findings are in favour of pregabalin .Mishra et al. compared 150 mg of pregabalin to 900 mg of gabapentin in postoperative pain after laparoscopic cholecystectomy. Pain intensity and analgesic requirements were significantly lower in the pregabalin group at the expense of an increase in postoperative sedation .Although analgesic effects of gabapentinoids are well described in postoperative pain, few data are available about the postoperative shoulder pain which is particularly frequent in post-laparoscopic surgery. It has a mechanical mechanism, as it is related to residual gas in the peritoneal cavity and it occurs mainly after patients' mobilization. Valadan et al. conducted a clinical trial enrolling 40 patients scheduled for laparoscopic ovarian surgery. After premedication with 600 mg of gabapentin, a significant decrease in the intensity of postoperative shoulder pain at rest and at exertion was noted up to the 12th hour postoperatively . This anAnalgesic effects of gabapentinoids are due to their anxiolytic, antinociceptive, and opioid-like characteristics which are mainly explained by a central neural sensitization. Gabapentinoids have also an antihyperalgesic effect by their interaction with voltage-gated calcium channels of the spinal cord and the dorsal root ganglia . FinallyBy reducing postoperative pain, gabapentinoids seems to be interesting in inducing a quick postoperative rehabilitation allowing ambulatory practices after laparoscopic cholecystectomy.However, the high incidence of nausea and vomiting after laparoscopic procedures must be considered before patient discharge as it compromises the oral intake. Various pharmacological treatments are usually used in the operating room for antiemetic purpose. Dexamethasone–ondansetron association is the most prescribed medication. Recently, several studies have evaluated the antiemetic effects of gabapentinoids with controversial results.In a quantitative analysis of evidence from randomized controlled clinical trials, Achuthan et al. evaluated gabapentin prophylaxis for PONV in abdominal surgeries. Seventeen studies enrolling 1605 patients were analyzed. The incidence of nausea was reduced by 24% and the incidence of vomiting was reduced by 38% in the gabapentin group . Ho et aFinally, given analgesic and antiemetic properties of gabapentinoids, together with their sedative characteristics, an improvement in patients sleep quality especially during the first postoperative night was expected and evaluated in our study.Lunn et al. evaluated analgesic and sedative effects of perioperative gabapentin in a double-blind trial enrolling patients scheduled for total knee replacement. Assessed by the Nonrestorative Sleep Scale (NRSS), the quality of sleep was better in the gabapentin group during the first two postoperative nights .However, Eloy et al. found different results when they studied the effect of gabapentin on postoperative pain and sleep quality in patients undergoing total knee arthroplasty, total hip arthroplasty, or a hip fracture repair. Their findings indicate that gabapentin does not improve sleep quality assessed by the Pittsburg Sleep Quality Index. The small dose of gabapentin and the small study sample must be considered in results interpretation . AssessePreemptive premedication with 600 mg of gabapentin or 150 mg of pregabalin improves several parameters of postoperative rehabilitation after laparoscopic cholecystectomy. It reduces significantly the intensity of postoperative shoulder pain, decreases the incidence of PONV, improves the quality of sleep during the first night, and shortens the time to first standing position. However, some limitations should be considered such as the nonevaluation of analgesic requirements during the postoperative period and the absence of the pharmacoeconomic component in our study.Preemptive premedication with gabapentin or pregabalin before laparoscopic cholecystectomy can be interesting in postoperative rehabilitation allowing ambulatory practices. In fact, it can reduce postoperative shoulder pain and PONV incidence. It can also improve the sleep quality during the first postoperative night. However, the optimal doses of gabapentinoids and the duration of treatment are not yet well established.


Background: It is well-known that both inter- and intra-individual differences exist in the perception of pain; this is especially true in migraine, an elusive pain disorder of the head. Although electrophysiology and neuroimaging techniques have greatly contributed to a better understanding of the mechanisms involved in migraine during recent decades, the exact characteristics of pain threshold and pain intensity perception remain to be determined, and continue to be a matter of debate.Objective: The aim of this review is to provide a comprehensive overview of clinical, electrophysiological, and functional neuroimaging studies investigating changes during various phases of the so-called “migraine cycle” and in different migraine phenotypes, using pain threshold and pain intensity perception assessments.Methods: A systematic search for qualitative studies was conducted using search terms “migraine,” “pain,” “headache,” “temporal summation,” “quantitative sensory testing,” and “threshold,” alone and in combination (subject headings and keywords). The literature search was updated using the additional keywords “pain intensity,” and “neuroimaging” to identify full-text papers written in English and published in peer-reviewed journals, using PubMed and Google Scholar databases. In addition, we manually searched the reference lists of all research articles and review articles.Conclusion: Consistent data indicate that pain threshold is lower during the ictal phase than during the interictal phase of migraine or healthy controls in response to pressure, cold and heat stimuli. There is evidence for preictal sub-allodynia, whereas interictal results are conflicting due to either reduced or no observed difference in pain threshold. On the other hand, despite methodological limitations, converging observations support the concept that migraine attacks may be characterized by an increased pain intensity perception, which normalizes between episodes. Nevertheless, future studies are required to longitudinally evaluate a large group of patients before and after pharmacological and non-pharmacological interventions to investigate phases of the migraine cycle, clinical parameters of disease severity and chronic medication usage. Migraine is one of the most prevalent neurological disorder and consistently ranks fifth to eighth among the top causes of disability, worldwide . Ictal mNevertheless, during recent decades, electrophysiology and neuroimaging techniques have greatly contributed to the understanding of the mechanisms involved in this elusive painful disorder. Several neurochemical, functional and microstructural alterations across various subcortical-cortical cerebral areas have been described thus far –7. Howevper se appears to be vary greatly from person to person in the general population. However, there also exists intra-individual differences. Indeed, it is well-known that several factors, such as spontaneous neuronal fluctuations, attention, expectation of pain, cognitive and emotional states, sleep habits and stress, may influence pain perception  consists of delivering a series of discrete supra-threshold stimuli of varying intensity in random order . This meTo better understand migraine-related changes in pain processing, several authors have evaluated pain perception during different phases of the migraine cycle using pressure, electrical, and thermal (cold or heat) stimuli, single or repetitive pulses of varying frequencies delivered over cephalic, cervical, or extra-cephalic areas.The purpose of this review is to provide a comprehensive overview of the findings of clinical, electrophysiological and functional neuroimaging studies aimed to investigate changes in pain perception of migraine patients during the various phases of the so-called migraine cycle, using PT and PPI assessments.We initially searched the PubMed database to identify articles published up to December 2016. The search terms used were “migraine,” “pain,” “headache,” “temporal summation,” “quantitative sensory testing,” and “threshold,” alone and in combination. The literature search was updated using the additional keywords “pain intensity,” and “neuroimaging” to identify full-text papers written in English and published in peer-reviewed journals, using the PubMed and Google Scholar databases. In addition, we manually searched the reference lists of all research articles and review articles.Data were presented with the criteria of following the various phases of the migraine cycle, and the progression of migraine .Burstein and colleagues repeatedly measured PT both in the absence and during the course of moderate-to-severe migraine attacks in the same patients using bilateral heat, cold and pressure stimuli applied to the cephalic (forehead) and extra-cephalic (forearm) regions . In thisIn a 42 year old male affected by migraine with aura (MwA), Burstein and colleagues  further 2 laser stimulations, lowered basic PT and resulting increased cortical amplitudes during spontaneous or experimentally induced migraine attacks have been confirmed in the bilateral cephalic  and extra-cephalic areas (hand) ipsilateral to headache side compared to the interictal phase  has been demonstrated during the ictal phase compared with preictal and interictal phases in one migraine patient scanned daily for 30 days . In thisOverall, consistent data indicate that PT is lower during the ictal phase than both the interictal phase of migraine and in HC in response to pressure, cold, and heat stimuli applied over the cephalic (forehead) region on the usual headache side. The involvement of extracephalic territories (forearm or hand) ipsilateral and/or contralateral to the headache side depends mainly on the time that has passed since the beginning of the attack. PPI during continuous suprathreshold heat pain stimulation at the cephalic and extracephalic territories was significantly higher in patients in the ictal phase, than in those in the interictal phase or in HC. These changes in PT and PPI during the ictal phase are accompanied by a heightened cortical response and reorganization of brain areas devoted to nociception/antinociception.Although the abnormalities in the pain perception are more pronounced during migraine attacks, subtle changes may be present before and after the headache phase . The preictal phase occurs a couple of hours to days before the onset of a migraine attack, and is manifested by various symptoms such as fatigue, difficulty in concentrating, neck stiffness, increased sensitivity to light and sound, nausea, blurred vision, yawning, and pallor. The postictal phase usually lasts 24 h, and is frequently associated with mood changes, muscle weakness, physical exhaustion, and reduced appetite .Until now, few studies have directly or indirectly focused on PT in the preictal and postictal phases of the migraine cycle. Sand and colleagues  performeMoreover, in a study evaluating the relationship between PT and sleep quality in migraine, slow-wave sleep was negatively correlated with pressure PT, and slow bursts were negatively correlated with thermal PT, suggesting that sleep abnormalities might precipitate attacks and induce hyperalgesia .The fluctuations in pain processing of migraine patients depending on the time from attack onset has been further confirmed by Uglem et al. . They asOverall, during the preictal phase, at a time when premonitory symptoms may occur, patients tend to show only mildly significant lowered PT to heat and cold stimuli in the forehead, neck, and hand, mainly on the symptomatic side, compared to their own interictal phase or to HC. This condition was considered to be suggestive of preictal sub-allodynia and could be considered an early manifestation of (or a predisposing factor for) the development of the next attack. Some studies suggest that migraine patients experience fluctuations in pain processing depending on the distance from the attack, since PT decreases preictally approaching the next attack, while PT greatly decreased and PPI increased ictally.Several studies using different paradigms have investigated thermal, mechanical, or electrical PT in migraine patients in the interictal phase and compared them with HC. However, these studies have generated conflicting results, showing significant differences in PT between migraine patients and HC –28 or noFernández-de-las-Peñas et al. showed that pressure PTs in patients with strictly unilateral migraine was significantly lower in the cervical (upper trapezius muscle), but not cephalic areas of the symptomatic side compared to the non-symptomatic side or HC , 23. FurTaken together, these studies demonstrate great variability in results, likely due to a highly heterogeneous subject samples. For instance, studies included patients on prophylactic medication, or in some sub-analyses, intermixed  migraine patients , 27, 77.Using heat LEPs, the majority of studies did not report differences in laser PPI between migraine patients during the pain-free phase and HC , 59, 65,The absence of PPI differences between migraine patients during the pain-free phase and HC has been supported by robust behavioral data collected during event-related neuroimaging studies using noxious heat stimuli, although based on small heterogeneous migraine patient populations , 67, 72.A greater PPI in response to laser stimulation has been demonstrated in migraine patients compared to HC after capsaicin application, with less inhibition of laser evoked potential (LEP) amplitudes , 59. PPINeuroimaging studies in patients scanned during the migraine attacks either documented significant greater PPI than during the interictal phase , or no dCompared to HC, migraine patients are characterized by an increased blood oxygenation level dependent (BOLD)–response in brain areas involved in nociception/antinociception and neurocognitive aspects of pain processing  , 67, 70.Interestingly, spinal trigeminal nucleus activation appears to fluctuate during the migraine cycle, being slightly greater in the preictal state compared to HC and significantly enhanced compared to interictal scans. and decreased during an acute attack compared to both HC and preictal migraine patients .Russo and colleagues used fixed innocuous (41°C), moderate noxious (51°C), and severe noxious (53°C) heat stimuli over the innervation territory of the maxillary division of the trigeminal nerve delivered on the more affected head side in episodic migraine patients between attacks during MRI scans , 72. TheThere were no statistically significant correlations between PPI at any level of experimental stimuli nor BOLD-fMRI signal changes in migraine patients with or without experience of CA . FurtherMore recently, Russo and colleagues  used triOverall, the results obtained during the interictal period are conflicting, because either reduced or no differences in PT were observed. However, studies were mostly conducted using mechanical sensory testing, making it impossible to determine the contribution of the peripheral muscle  and central sensitization processes. Indeed, pressure PT was unrelated to the presence of overt interictal/ictal CA. Quantitative sensory testing and neuroimaging data support the concept that migraine patients may be characterized by a normal PPI, despite methodological limitations of the studies. Nonetheless, some authors detected increased PPI during concomitant sensitization-inducing stimulations (such as stimulus repetition and capsaicin application) in migraine patients between attacks compared to HC, especially when patients were tested closer to an attack or experienced higher attack frequency. Finally, neuroimaging studies reveal that, despite essentially normal PPI ratings, the migraine brain encodes and behaves differently to subjective PPI compared to HC, especially depending on patients' clinical features.Although migraine in children and the elderly may represent good models to test disease onset and progression, few studies have been dedicated to the assessment of the pain processing in childhood and elderly migraine patients. Nonetheless, research that has been done has also produced contradictory results.2 laser  as well as the thenar eminence of the non-dominant hand .2 laser evoked potential study, laser PT was significantly lower in children with migraine compared to HC at the hand level; however, no significant differences were observed in the trigeminal field , Perrotta and colleagues  found a Ferraro et al. studied PPI and LEP amplitudes in response to repetitive laser stimulations in CM and MOH (before and after successful treatment) patients as well as HC. They found that PPI and LEP amplitudes to laser stimuli demonstrated significantly delayed habituation in both patient groups, while after treatment, non-responders (true CM patients) showed lack of habituation compared to both HC and MOH patients. While in those MOH patients who showed a treatment response (true MOH patients), authors found normal habituation .In an intermixed group of chronic tension type headache and MOH patients, the duration of the chronic phase was associated with cutaneous PT reduction, while in the MOH only group, mean cutaneous PT values decreased with increasing daily drug intake . FinallyOverall, as for the interictal state, PT data obtained from migraine patients ranging from episodic to CM are inconclusive. However, some have documented lower PT in CM patients compared to HC and episodic migraine patients, almost exclusively using mechanical stimuli. Increased PPI ratings with reduced efficiency of supraspinal descending inhibition controls were documented in CM resulting from medication overuse, before and after drug detoxification. Nonetheless, the level of PT seems to be related to the severity of migraine and the daily drug intake level.Migraine is presently considered a disorder of the brain. Many independent research groups have observed that the brain of migraine patients abnormally processes all sensory information, with the exception of olfaction . These fHere, we have summarized clinical, neurophysiological, and neuroimaging studies that have assessed the perception of pain in the various phases of the migraine cycle. The studies performed during the spontaneous occurrence of a migraine attack have detected lower PTs and increased PPI during the ictal phase compared to both the interictal phase and HC in response to various type of sensory stimuli applied over the cephalic region on the usual headache side. The involvement of ipsilateral and/or contralateral extracephalic territories depends mainly on the time passed from the beginning of an attack. These time and spatial changes in pain processing and sensitivity can be interpreted as reflecting subtle manifestations of the sequential activation of the peripheral and central sensitization processes, sometimes clinically manifesting as CA.Contrary to what was observed during the ictal period, the results obtained during the interictal period are conflicting, as either reduced PT or no differences were observed. Moreover, PTs were unrelated to the presence of overt interictal/ictal CA, as well as the presence of CA was in any way related to PPI in response to different levels of stimulus intensity and induced only marginal changes in BOLD-fMRI signals. Despite these negative results, some studies show that migraine patients experience fluctuations in pain processing depending on the distance from the attack, as PT decreases preictally approaching the next attack, while PT greatly decreased and PPI increased ictally. Interestingly, a similar correlation with the number of days that had elapsed since the last attack was previously found in migraine with other sensory modalities, such as electrophysiology –94, psycAs for the interictal state, PT data compared from patients evolving from episodic to CM to both episodic migraine patients and HCs are conflicting and inconclusive. Instead, higher PPI ratings were documented solely in CM patients overusing acute medications before drug withdrawal compared to HCs. The latter results may be explained as abnormal modulation of pain processing at the spinal level due to a decrease in antinociceptive activity of the supraspinal structures in MOH patients. This hypothesis is supported by recent neuroimaging studies showing altered structural integrity and functional connectivity of descending pain modulatory areas, such as periaqueductal gray , 98–100,Quantitative sensory testing (chiefly using LEPs) and functional neuroimaging studies in response to noxious stimuli show evidence of plastic reorganization in brain areas anchored to the so-called salience network , in respFuture studies in this subject area in coming years should focus on the longitudinal investigation of a large group of patients before and after pharmacological and non-pharmacological interventions . This coAR and GC: review the literature, manuscript drafting, and revision; GT, AT, and FP: manuscript revision; MS and VP: clinical and neurophysiological studies revision to perform Tables 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.