Persistent pain can lead to incapacitation requiring long-term pharmacological treatment. Up to 82% of chronic kidney disease (CKD) patients undergoing hemodialysis (HD) have chronic pain and most do not respond to usual medication. Advances in non-pharmacological treatments are necessary to promote pain relief without side effects and to restore functionality. Transcranial direct current stimulation (tDCS) promises to be a novel, cost-efficient, non-pharmacological treatment for CKD patients with chronic pain. In this study, we hypothesize that tDCS could improve pain, depression, functionality, and quality of life in patients with CKD undergoing HD.We describe a single-center, parallel-design, double blind randomized, sham-controlled trial. Forty-five subjects with CKD undergoing HD will be randomized to a motor cortex (M1), a dorso lateral prefrontal cortex (DLPFC), or a sham group. A total of ten sessions will be administered to participants over 4 weeks using a monophasic continuous current with an intensity of 2 mA for 20 min. Participants will be evaluated at baseline, immediately after the tenth session, and at 1 week and 4 weeks of follow-up after the intervention. Pain, depression, functionality, and quality of life will be evaluated.The results from this study will provide initial clinical evidence on the efficacy and safety of tDCS in patients with CKD undergoing HD.ensaiosclinicos.gov.br), 1111–1216-0137. Registered on 20 June 2018.Brazilian Clinical Trials Registry/Registro Brasileiro de Ensaios Clínicos ( A complete physical and mood assessment is critical to provide an appropriate treatment plan for chronic kidney disease (CKD) . ManagemChronic pain in CKD patients has been considered a genuine neurologic disturbance, and it co-occurs generally with many pain syndromes in the context of suffering throughout the lifetime , 5. StudPain is a major cause of depression, disturbed sleep patterns, impaired dialysis adequacy (if unable to endure full sessions), and likeliness of withdrawal from dialysis . SeveralIn addition to medical therapies, adjunctive non-pharmacologic interventions must be considered whenever applicable for pain in CKD patients undergoing dialysis. Suboptimal pain control is associated with poor QoL, depression, and possibly long-term survival. Nonetheless, adequate medical pain control remains a challenge due to the potential for drug-induced complications and abuse and dependence. Clinicians and the research community should promote pain management in CKD patients undergoing dialysis as a clinical and research priority to improve their QoL and pain-related disability.Recent studies have shown that novel neuromodulating techniques can have pain-relieving effects in the treatment of chronic pain –11. StudtDCS emerges as a simple potential tool to improve QoL and functionality and shed light on the role of brain reorganization in pain function. For CKD patients with chronic pain, tDCS may represent an important cost-efficient, non-pharmacological treatment for a large number of patients with permanent chronic pain, depression, and disability. We currently have no evidence from randomized controlled clinical trials on the use of tDCS to treat pain and depression in CKD patients undergoing HD.The primary objective of the current study is to evaluate the effects of anodal tDCS over M1 and DLPFC on pain in CKD patients undergoing HD. The secondary outcomes are to assess its impact on depression, anxiety, physical performance, and QoL.This protocol is presented in accordance with the SPIRIT Initiative 2013 , registration number U1111–1216-0137; June 20, 2018. Data will be stored at Motricity Lab—Federal University of Rio Grande do Norte and will be archived with the principal investigator for 5 years and then destroyed. Possible changes to the protocol will be communicated to the local Ethics Committee, ReBec, and participants. Documents will not be made public without the permission of the participants and resulting publications will not identify the subjects.This study will be conducted at the Federal University of Rio Grande do Norte, Natal, Brazil and registered with the Brazilian Clinical Trials Registry ReBec  for > 3 months, (4-h session); (3) pain related with a score of more than 4 (range of scores from 1 to 10) in a visual analog scale (VAS) for > 3 months; (4) have physical capacity to do physical evaluation and be capable of consenting to treatment and understanding study explanations and questionnaires; and (5) provide informed consent.Patients will be included if they fulfill the following inclusion criteria: (1) male or female aged 18 to 75 years; (2) undergoing HD with ESRD (CKD 5DPatients with any of the following criteria will be excluded from the study: (1) electrical implants in the body; (2) a history of epilepsy or convulsion; (3) clinically contraindicated to receive tDCS, such as having metal embedded in their scalp or brain; (4) psychiatric illness; (5) pregnant women; and (6) signs of severe disease and/or indication of hospitalization, including hemodynamic instability, infection, acute myocardial infarction, and stroke.According to Brkovic et al. , end staDialysis patients report significantly more bodily pain, lower vitality, poorer general health, physical, mental, and social dysfunction, and limitations in their ability to work and participate in activities . To measSample size was estimated based on statistical considerations for a parallel trial and on previous studies that have paired noninvasive stimulation with chronic pain syndromes , 10, 15.Eligible and consenting patients will be randomized using the order of entry into the study and a previous computer-generated randomization list, using random blocks of six patients  to minimize the risk of unbalanced group sizes. A research assistant external to the study will generate the allocation sequence. Each participant will be equally likely to belong to any one of the groups. Opaque envelopes will be used to conceal allocations. Participants and researchers involved in the assessments and interventions will be blind to group allocation throughout the trial.Patients and evaluating researchers will be blinded. To ensure patient blinding, the electrodes of the sham group will be placed in the same position as for active groups. The anodal electrode will be placed over the motor cortex and the cathodal over the contralateral supraorbital area, according to placement procedures described below. Usually when the current initiates, patients report itching or a tingling sensation under the electrodes for 2 or 3 minutes. This method of sham intervention is therefore designed to provide an initial period of tingling so that similar sensations are perceived as during active tDCS . For theA total of ten sessions lasting 20 min each will be administered to participants over Monday/Wednesday/Friday or Tuesday/Thursday/Saturday (three sessions per week) by a trained physician at the Instituto do Rim Fig. . The tDC2 square sponge immersed in saline solution (150 mMols of NaCl diluted in water Milli-Q). For stimulation, a gradual current ramp-up and ramp-down with 30-s duration will be used. Electrodes attached to the scalp will be supported by an elastic band. The electrodes (anode and cathode) will be connected to a battery-powered (9 v) stimulator with current verified by a precision digital multimeter  with standard error of ±1.5%.During the baseline period, patients will be randomized at a ratio of 1:1:1 to receive sham tDCS (sham group), active tDCS of the primary motor cortex (M1 group), or active tDCS of the left DLPFC (DLPFC group). The M1 was chosen because studies show that stimulation of this area is associated with pain improvement , 15, 16.For ethical reasons, no changes will be made to HD routines (days and the place of sessions), clinical care , and previous prescription of painkillers or other medication.This study will follow the outcome measures used in studies of multiday repetitive tDCS applied to the M1 or DLPFC to treat chronic pain and depression .Data will be collected following assessments at baseline (week 2), immediately after the tenth day of intervention (week 6), and at 7- and 10-week follow-ups Fig. . All evaThe primary endpoint of the trial is pain assessed using the VAS pain score and McGill Pain Questionnaire (MPQ). Secondary outcome measures include depression anxiety, physical performance, and quality of life (QoL).The pain VAS is a unidimensional measure of pain intensity, which has been widely used in diverse adult populations . The paiThe MPQ is a multidimensional pain questionnaire designed to measure the sensory, affective, and evaluative aspects of pain and pain intensity in adults with chronic pain , 19. TheDepression levels will be assessed using the Beck Depression Inventory (BDI), a self-reporting tool of 21 questions relating to cognitive symptoms and attitudes . For eacThe severity of anxiety symptoms will be measured using the Hamilton Anxiety Scale (HAS) . The HASStrength of the lower limbs will be evaluated by the 30-s chair stand test. A chair 43 cm high, with backrest, without armrest and a stopwatch will be used. Participants will be instructed to keep their arms crossed on their chest and to sit with their backs resting on the backrest. When the signal is given, the participant will stand up and return to the starting position as fast as possible in 30 s. The score corresponds to the number of times that the person is able to perform the complete movement in 30 s.The arm curl test measures upper body strength and thus may contribute to aerobic fitness and arm muscle endurance. The 30-s arm curl test measures upper-body muscle function and is assessed by the number of arm curl repetitions performed with a 2-kg dumbbell during 30 s.To assess the flexibility of the lower limbs (posterior thigh muscles), a sit and reach test will be performed. A chair 43 cm high and 50 cm of backrest will be used. During the test, participants will be instructed to sit on the edge of the chair with feet flat on the floor, knees and ankles at 90° flexion; then the dominant or painful leg will be stretched (hip and knee) with the calcaneus supported on the floor and with the ankle flexed at 90°. With overlapping hands and middle fingers on the same level, participants try to get as close as possible to their toes and hold that position for 2 s in three attempts, to get the arithmetic mean. A negative score will be recorded if the middle fingers do not reach the toes, and a score will be positive if the middle fingers were above the toes. Flexibility of the upper limbs will be performed using the scratch flexibility test. Participants will be instructed to pass one hand (dominant or more painful) over the shoulder to assess flexibility of the shoulder in flexion, abduction, and external rotation and to try to reach the other hand to assess extension, adduction, and internal rotation on the center of the back. Three replicates will be made to obtain the arithmetic mean of the results. The measurements will be made using a ruler, and the scores are considered negative if there is any distance between the middle fingers, and positive if the middle fingers overlap.Timed Up and Go (TUG) test will be used to measure, in seconds, the time taken to stand up from a standard chair, walk 3 m, turn, walk back to the chair, and sit down. A chair with armrests and a seating depth of 44–47 cm is recommended . Those wThe Kidney Disease Quality of Life—Short Form (KDQOL-SF) will be used to assess the QOL. This questionnaire is a specific instrument to evaluate patients on dialysis, applicable to all types of dialysis .A total score for each physical test will be described by means and standard deviations. A total score of variables and all subscales will be compared within and between groups.Statistical analyses will use SPSS  and Graph Pad Prism 5. Clinical and sociodemographic characteristics  will be described by means and standard deviations for continuous numeric parameters, and by frequency tables with 95% confidence intervals for categorical parameters. Chi-squared test will compare the distributions of categorical variables. Kruskal-Wallis test and ANOVA will compare differences in final values between groups.The Shapiro-Wilk and Levene’s test will assess the normality of the distribution and homogeneity of variance of the data, respectively. Non-parametric tests will be used in case of non-normality distribution. Mauchly’s test of sphericity will be used to validate the correlation of the repeated measures and where the assumption of sphericity is violated, the Greenhouse-Geisser correction will be applied. The effects of stimulation on primary and secondary outcomes will be calculated using a mixed ANOVA model. The dependent variable will be the score of each outcome, and the independent fixed variables will be the time of treatment , the group of stimulation (active and sham), and the interaction term time vs group. Post-hoc comparisons will be carried out using Bonferroni correction for multiple comparisons.2 will be calculated as measures of effect size in the ANOVA results (main effects and interaction effects). Partial η2 will be used to calculate the effect size, where η2 = 0.01 will be considered small, η2 = 0.06 moderate, and η2 = 0.14 large effect. Statistical significance will be set at p value less than 0.05.Friedman test will be used for non-parametric data. Missing data will be treated by intention-to-treat analysis, taking into account the method of the last observation carried forward. Partial ηTo date, the use of conventional tDCS protocols in human trials  has not produced any reports of serious adverse effects or irreversible injury . AdverseA doctor will be on duty during tDCS sessions to handle any adverse events, including problems with dialysis. The researchers will communicate any important protocol modifications to relevant parties.The main strategy to improve adherence of patients is to perform tDCS during HD sessions and explain to participants the relevant contribution to the treatment of chronic pain, including the possibility of improving pain. There will also be flexible hours offered for receiving therapy according to the HD, as well as direct contact by telephone with participants confirming the evaluation dates and reinforcing treatment adherence.This is the first methodologically designed trial to evaluate the effect of tDCS in ESRD patients undergoing HD. Up to 82% of CKD patients undergoing HD have chronic pain associated with depression, anxiety, poorer QoL, and greater limitations in daily activities . PatienttDCS is a safe, effective, low-cost, and accessible method for treatment of chronic pain syndromes and it is a potential neuromodulatory technique to relieve pain and depression and increase functionality in ESRD patients undergoing HD.The protocol described in this paper is a randomized controlled trial designed to guide the development of a larger multicentre study to determine the safety, clinical viability, and patient acceptance of tDCS. The choice of a study design involving three sessions per week offers good conditions to use tDCS in real-world conditions. We assume that the design of the research study may not be accessible to all individuals with ESRD undergoing HD. There will be some clinical and social limitations to include patients in this trial, as it is expected that patients have low educational and income levels, and for these reasons, adherence could be impaired.If a positive effect is demonstrated in pain, mood states, and functionality, tDCS may represent an important alternative and complementary option for non-invasive brain stimulation for ESRD patients undergoing HD.Thus, new treatments supporting this strategy are required to improve the care of CKD patients undergoing HD suffering from chronic pain.Additional file 1. Standard Protocol Items: Recommendations for Interventional Trials (SPIRIT).Additional file 2. Informed consent form.


I analyze current neuroscientific research into the mechanisms of pain experience in patients with disorders of consciousness, and provide an explanation for why CMD patients likely can experience physical pain. I then do the same for physical pleasure. I conclude that providing these patients with pleasurable experiences, and avoiding subjecting them to pain, are viable means of promoting their well-being.Unresponsive wakefulness syndrome is a disorder of consciousness wherein a patient is awake, but completely non-responsive at the bedside. However, research has shown that a minority of these patients remain aware, and can demonstrate their awareness via functional neuroimaging; these patients are referred to as having ‘cognitive motor dissociation’ (CMD). Unfortunately, we have little insight into the subjective experiences of these patients, making it difficult to determine how best to promote their well-being. In this paper, I argue that the capacity to experience pain or pleasure (sentience) is a key component of well-being for these patients. While patients with unresponsive wakefulness syndrome are believed to be incapable of experiencing pain or pleasure, I argue that there is evidence to support the notion that CMD patients likely  A diagnAccurately diagnosing UWS/VS is highly challenging, with several studies indicating that nearly 43% of patients diagnosed as such show signs of awareness after repeated examination . Given tHowever, research over the last decade also indicates that a minority of patients who consistently show no evidence of voluntary behavioural response to stimuli at the bedside are nevertheless ‘covertly aware’ –5. UsingOne of the reasons that the discovery of awareness in these patients is important is because of its implications for their well-being. Well-being is concerned with prudential value, —of what is non-instrumentally, fundamentally good for a person— and encapsulates how well a person’s life is going for them. Different philosophical theories of well-being have different conceptions of what ultimately is prudentially valuable. However, it is a common feature of theories of well-being that they are concerned with what is good not impersonally, but for the person whose life it is . When weRecognizing their capacity for prudential interests is an important step to ensuring that the well-being of these patients is protected. However, it is not obvious what the prudential interests of these patients are. While successful completion of the mental imagery task illuminates some of their residual cognitive capacities, we are still left with questions about how these patients experience the world. Indeed, prior to the discovery of covert awareness, they were presumed to be incapable of any experience at all. Given their injuries, it seems likely that many of the things that make our lives go well as healthy adults will be inaccessible to them. Practically speaking, promoting the well-being of these patients must focus on prudential goods which are both valuable to them, and that they can realize. One place we might begin is with the experience of pleasure and pain. If CMD patients can experience pleasure and pain —if they are ‘sentient’— promoting their experience of this prudential good  could be an effective means of promoting their overall well-being. Yet, as we saw earlier, UWS/VS is defined by the absence of behavioural response to stimuli; even if a minority of patients diagnosed as UWS/VS are covertly aware, it is not clear that they can experience pleasure, or pain.In a philosophical context, the term ‘sentience’ is typically used in either a broad or narrow sense. An organism is sentient in the broader sense if it has the capacity for subjective experiences, when there is ‘something it is like’ to be that organism. Alternatively, an organism is sentient in the narrower sense when it has the capacity for subjective experiences of a certain affective quality, such as pain, pleasure, suffering, or enjoyment. Sentience in the narrower sense requires sentience in the broader sense, but not the converse. The purpose of this paper is to show that CMD patients are sentient in the narrower sense.Why begin by considering pleasure and pain, and not some other prudential interest? First, there is a consensus both within the philosophy of well-being, and, I would suggest, our common-sense intuitions, that pleasure and pain are critical components of well-being. The experience of pleasure tends to make us better off, and the experience of pain tends to make us worse off. While not impossible, it is hard to imagine a person’s life going very well if they are in constant pain, or have very few pleasant experiences.Second, focussing on the experiences of pleasure and pain makes sense from a pragmatic standpoint. Whereas there may be other prudential interests the satisfaction of which might promote patient well-being —such as the development of deep personal relationships, or the achievement of one’s goals— these are likely beyond the capacity of caregivers to satisfy. Conversely, if a patient is in pain, and can communicate this to a caregiver, concrete measures can be taken to reduce or eliminate the pain. Similarly, caregivers can provide pleasurable stimuli,  to promote patient well-being.Because pain and pleasure are subjective experiences, the only way we can verify that someone is having such an experience is via their self-report. For those patients in whom communication via mental imagery is not possible, then, we cannot directly verify their capacity for pain or pleasure. Nevertheless, as I argue in this paper, there is substantial empirical evidence to support the hypothesis that CMD patients are sentient in the narrow sense that is relevant to well-being. Moreover, even in the absence of conclusive evidence of sentience, I argue that we ought to treat CMD patients as if they are sentient. My argument will proceed as follows. In Part 1, I will argue that if CMD patients are sentient, then their interests in avoiding pain and experiencing pleasure matter morally. In Part 2, I will present evidence in support of the hypothesis that CMD patients can experience pain. In Part 3, I will do the same for pleasure. In Part 4, I will argue that even in the absence of certainty about the sentience of CMD patients, we ought to treat them as if they are sentient. Finally, in Part 5, I will discuss how caregivers might promote the well-being of these patients by promoting pleasure, and preventing pain.Suppose CMD patients are in fact sentient. How should this affect our treatment of them? One possible response is that we should do what we can to minimize any suffering they experience, including treating their physical pain, and making reasonable efforts to promote their pleasure. The reason for this is that sentient interests  matter morally; we have a reason to avoid frustrating these interests, and that reason exists simply in virtue of the harm frustrating these interests causes to the being that has them.my interest; their interests matter morally. Thus, insofar as CMD patients are sentient, their sentient interests matter morally. As a result, we have a reason to avoid causing these patients to suffer , and we would need sufficiently strong moral reasons opposing the alleviation of their suffering to justify failing to do so.I have an interest in avoiding suffering, because my suffering is bad or harmful for me; others have an interest in avoiding suffering, because their suffering is bad for them. If I take the badness of my suffering for me to be a reason for others not to cause me to suffer, the badness of others’ suffering for them must give me reason to avoid causing them to suffer. In other words, I cannot disregard their interest in avoiding suffering, just because it is not Debates about the treatment of patients with disorders of consciousness, including CMD patients, often place a great deal of weight on whether or not we should consider these patients to be ‘persons’  –18. Thes1In the next two sections, I will show that there is considerable empirical evidence to support the notion that CMD patients are sentient.The International Association for the Study of Pain (IASP) defines pain as: “an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage” . As reflobjects of perceptual experience, pains just are experiences themselves. And, unlike other perceptual experiences, which are liable to error , the ‘true’ nature of pain just is the experience of it . Studies involving these patients have produced a great deal of evidence, both behavioural and through functional neuroimaging, to support the idea that they can experience pain . For exaThe results of these functional neuroimaging studies are confirmed using behavioural scales in MCS patients. The Nociception Coma Scale-Revised is used to assess nociception in non-communicative patients recovering from coma , by measuring behaviours believed to be indicative of nociception . It has The fact that MCS patients retain functional connectivity of the pain matrix is highly suggestive of a connection between the presence of awareness, and the ability to consciously experience pain. Because the functional integrity of the pain matrix  is good evidence of the experience of pain, and because conscious awareness appears to require a high degree of cortical integration  , 38, it A further concern is those patients in whom awareness has not been detected, but in whom we cannot be certain that awareness is absent. Indeed, it may be the case that a subset of patients who have not demonstrated covert awareness are nevertheless aware, and thus, may retain functional connectivity of the pain matrix. Moreover, given the high rate of misdiagnosis of patients in the vegetative state , it is nWhat exactly is pleasure? On a common-sense understanding, it is a feature of experience that makes those experiences good and attractive. In some cases, the experience or expectation of pleasure can motivate us to pursue certain rewards, or otherwise shape our behavior. As we saw earlier when considering pain, there is a rich philosophical literature concerning the nature of pleasure . I will Research in affective neuroscience suggests that the experience of pleasure consists of an interacting, yet distinguishable, set of processes, each with distinct underlying neurobiological mechanisms. As Berridge and Kringelbach describe, a pleasurable experience, or ‘reward’, consists of three components: ‘liking’, ‘wanting’, and ‘learning’ . ‘LikingIn most cases, ‘liking’ and ‘wanting’ work in tandem. However, these processes result from distinct brain mechanisms, and can be dissociated. For example, research has shown that rats with extensive damage to dopamine receptor neurons, or pharmacological dopamine blockade, fail to approach  sweet foods but nevertheless exhibit normal hedonic ‘liking’ reactions when the food is placed in their mouths . These rHow is this feeling of ‘liking’ produced in the brain? As Frijda argues, pleasure itself is not a sensation; rather, it is a ‘pleasantness gloss’ added to stimuli that the brain identifies as pleasant . Thus, bAs Berridge and Kringelbach argue, liking reactions to pleasure-inducing stimuli can be both conscious and non-conscious . At the Much of the work that has been done investigating how pleasure is generated in the brain has appealed to brain areas which generate objective ‘liking’ reactions, referred to as ‘hedonic hotspots’ . Using mWhile neurochemical activation of this network of hedonic hotspots can significantly amplify the experience of pleasure, only some of these hotspots are also necessary for maintaining normal hedonic levels of liking to pleasant sensations. In fact, normal liking reactions to pleasure are relatively difficult to abolish by any single event  . The moscauses of pleasure, other brain areas have been implicated in the coding of pleasure; activation in these areas is correlated with increases or decreases in pleasure, but not conclusively shown to be necessary or sufficient for pleasure. Neural coding of pleasure appears to occur in several brain sites, including the orbitofrontal cortex, anterior cingulate cortex, insular cortex, amygdala, nucleus accumbens, and ventral pallidum [In contrast to areas which are necessary or sufficient pallidum . Informapallidum . Activitpallidum .experience of pleasure. Pleasure is good because of how it feels, or because of our conscious attitudes with respect to pleasant things; it is unclear how we could enjoy the feeling of a non-conscious pleasure. Desire-satisfaction accounts of well-being argue that prudential value consists in having our desires satisfied. While non-conscious pleasures might be desirable because of how they color our other experiences, it is hard to see how they might be desirable in and of themselves. Similarly, objective-list views of well-being claim that certain goods are intrinsically valuable, independently of our attitudes towards them. While some objective-list theories hold that pleasure is an objective good, one would assume that this means pleasure that is subjectively experienced.Can non-conscious liking contribute to well-being? Given traditional philosophical accounts of well-being, the notion of a non-conscious pleasure is somewhat awkward. Hedonist accounts of well-being argue that pleasure is intrinsically good , but these accounts seem to imply the Nevertheless, even if non-conscious liking is not intrinsically valuable, it may still positively contribute to well-being. Indeed, non-conscious liking reactions can influence our behavior and motivations, while remaining undetected by the person having them. For example, Berridge and Winkeilman suggest that it is possible to generate an affective reaction, of which the individual is not consciously aware . In theiIn the case of CMD patients, non-conscious liking reactions may promote more positive moods, or help to mitigate the impact of negative moods or emotions, through the release of endogenous opioids. Endogenous opioids are involved in the non-conscious liking reactions to pleasant stimuli, and have been linked to an increase in pain tolerance when elicited by pleasant stimuli . SimilarOn the other hand, it seems uncontroversial that the conscious experience of pleasure would promote the well-being of CMD patients. In fact, it is somewhat surprising that there have been no studies investigating the capacity of these patients to experience pleasure. Perhaps this is because the experience of pain is thought to be more harmful to these patients’ well-being than the experience of pleasure is beneficial. In any case, if CMD patients can experience pleasure, providing them with pleasant experiences whenever possible seems an obvious way of promoting their well-being.In the previous section, I considered the potential contribution of non-conscious and conscious pleasure to the well-being of CMD patients. I now turn to the issue of whether CMD patients are capable of either the non-conscious or conscious aspects of pleasure. Given that much of this patient population is non-communicative, and thus, incapable of self-report, how can we determine their capacity for pleasure experience? We have seen that several brain areas —hedonic hotspots— are either necessary or sufficient for the causation of objective ‘liking’ reactions. Thus, if these brain areas remain functionally intact in CMD patients, this would provide evidence that these patients remain capable of generating hedonic liking reactions.There is evidence to suggest that this might be the case. Research investigating the relationship between clinical assessments of consciousness and underlying brain damage has shown that when compared to healthy volunteers, both traumatic and non-traumatic minimally conscious and vegetative patients show atrophy in the basal forebrain, which contains subcortical brain structures associated with pleasure causation, including the nucleus accumbens, and the ventral pallidum . HoweverAccordingly, if damage to the basal forebrain is not sufficient to abolish wakefulness in CMD patients, it may also be the case that the brain mechanisms underlying pleasure causation in the basal forebrain are preserved as well. This hypothesis is supported by research linking the circuit of the basal ganglia, thalamus, and frontal cortex in supporting awareness. Several studies have shown that disruptions to this network leads to severe deficits in awareness , 66, whiConversely, while the brain areas which cause non-conscious ‘liking’ reactions to pleasurable stimuli are concentrated in subcortical structures, those which appear to support the conscious experience of pleasure are primarily in the orbitofrontal cortex. Given the extensive cortical damage of many CMD patients, we might be skeptical about their preserved capacity for subjective pleasure experience.Firstly, although neuroimaging evidence clearly suggests that the orbitofrontal cortex codes for pleasure, it remains unclear if this area causes the consciousness of pleasure, more basic hedonic ‘liking’ reactions to pleasure, or whether it is a point of integration between non-conscious and conscious hedonic processing for decision making , 69. TheSecond, as Berridge and Kringelbach suggest, non-conscious ‘liking’ reactions “are ordinarily translated into conscious pleasure feelings by additional cognitive brain mechanisms that underlie subjective awareness” . Indeed,The default mode network is a set of brain areas —including the precuneus, bilateral temporo-parietal junctions, and medial prefrontal cortex— which has been found to be more active at rest than when subjects are preforming attention-demanding cognitive tasks. This network has been demonstrated to be involved in cognitive process like daydreaming, stimulus-independent thoughts, and self-related thoughts, and has been suggested as a network supporting consciousness , 74.In a study by Vanhaudenhuyse and colleagues, default mode network connectivity strength was found to be proportional to the level of consciousness of brain damaged patients  . While tGiven this relationship between connectivity of the default mode network and level of consciousness, we would expect that CMD patients would retain a degree of connectivity of the default mode network. If this is the case, it lends support to the idea that these patients may retain the capacity for the subjective experience of pleasure. Key regions of the frontal default mode network overlap with the brain areas implicated in the subjective experience of pleasure, such as the anterior cingulate and orbitofrontal cortices , 75. MorAs the above discussion shows, there is significant evidence to suggest that CMD patients can experience pain and pleasure. Acknowledging the fact that these individuals may still experience pains and pleasures of various kinds is critical to protecting their well-being; they are not simply ‘hedonically inert’, although they do not respond behaviourally to stimuli.Nevertheless, while I think that the evidence in support of sentience is strong, it is not decisive; it is possible (though I would argue unlikely) that CMD patients are not sentient. Taking this lack of certainty into account, I argue that we ought to treat CMD patients as if they are sentient, and thus, that we should treat their putative sentient interests as mattering morally. In doing so, I appeal to the idea of ‘precautionary reasoning’. Roughly, precautionary reasoning holds that when there is a lack of conclusive evidence for X, preventative measures against X may be justified, provided the consequences of X are sufficiently adverse . For exa2CMD patients can either be sentient, or not, and accordingly, their interests can either matter morally on those grounds, or fail to matter morally on those grounds. If they are sentient, it would be a large loss to mistakenly treat them as non-sentient (we would be harming them by failing to give their interests the consideration that they are owed), while it would be a large gain to correctly treat them as sentient (we would be giving their interests due consideration). Conversely, if a CMD patient were not sentient it would be a small gain to correctly treat them as non-sentient (we would avoid giving their interests greater consideration than we ought to), while it would be a small loss to mistakenly treat them as sentient (we would give their interests greater consideration than we ought to). In order to avoid the worst possible outcome (disregarding existing interests), and make possible the best possible outcome (regarding existing interests), we should treat CMD patients as if they are sentient.What makes the use of precautionary reasoning appropriate in this case is the strong empirical evidence cited in the previous two sections in favor of sentience in CMD patients. Indeed, each of the four possibilities mentioned above are not equally likely; it is more likely the case that CMD patients are sentient than that they are not. Thus, the most likely set of outcomes is the large benefit or the large loss, rather than the small benefit and small loss. Therefore, even if we remain uncertain about the sentience of CMD patients, the preponderance of evidence, in conjunction with precautionary reasoning, strongly supports treating CMD patients as sentient.A potential objection to applying precautionary reasoning to the sentience of CMD patients is that it ignores the potential costs of the outcome wherein a non-sentient patient is treated as sentient. Indeed, insofar as this unnecessary cost deprives other individuals of health-care resources, we might think that this is not merely a small loss, but a large one.any sort of treatment that might benefit them. Another patient may have a stronger claim to limited health-care resources in virtue of the fact that they have more interests at stake . My claim here is that the sentient interests of CMD patients give us reason to alleviate their suffering, simply in virtue of the fact that their suffering is harmful to them. We might have competing moral reasons against alleviating their suffering, which may be stronger in some cases . However, given the fact that the cost of alleviating the suffering of CMD patients (by minimizing pain and promoting pleasure in the ways I describe below) is unlikely to cause any significant harm or loss of benefit to others, there is no competing moral reason sufficient to override our obligation to alleviate the suffering of these patients.However, as I describe in Part 5, the kinds of interventions which could be useful in alleviating the potential suffering and promoting the well-being of CMD patients are not particularly burdensome; it is unlikely that the costs of providing these benefits would deprive other needy individuals of scarce health-care resources in any significant way. Indeed, it is important to bear in mind that taking the sentient interests of CMD patients into consideration does not entail that they are entitled to One complicating factor in alleviating the suffering of CMD patients is their inability to communicate the cause of their potential suffering. While it may be safe to assume that intense physical pain causes a patient to suffer, eliminating the source of suffering may cause the patient to suffer in other ways. For example, while administering a strong sedative may reduce the patient’s suffering caused by physical pain, it may cause greater suffering to the patient by reducing their level of awareness. However, it seems reasonable that when subjecting these patients to procedures known to cause physical pain, certain treatment measures  should be taken, because they are unlikely to cause additional suffering in the patient . FurtherThe practice of pain assessment and management of non-communicative patients with dementia, in long-term care facilities, may offer guidance. Pain assessment in this population presents many of the same challenges as in CMD patients  , 80. SevSimilarly, acknowledging a patient’s capacity for pleasure may influence how this patient is cared for. Knowing that a patient can experience pleasure may vindicate the efforts of caregivers to provide them with pleasant experiences, and engage with them in other ways, even when the patient’s ability to respond behaviourally is absent (or limited). For example, one patient who had been behaviourally non-responsive for 16 years, but was subsequently found to be covertly aware  regularlIf CMD patients are sentient, this ought to influence not only the stimuli they receive, but how these stimuli are provided. Numerous studies have shown that anticipating pain, or being anxious about pain, can exacerbate the pain experienced . SimilarIt is also well-established that the hedonic impact of a stimulus can be affected by factors like homeostatic balance; the pleasantness of a stimulus increases the more effective that stimulus is at restoring bodily homeostasis, while pain unpleasantness increases with greater perceived threat to homeostasis . ExcessiThe presence of covert awareness in some patients diagnosed as vegetative implies that these patients have prudential interests. Yet, given our nascent understanding of the subjective experiences of these individuals, we might wonder what sorts of things have prudential value for them. I argue that a natural starting point is the experience of pleasure and pain. While it may turn out to be the case that some CMD patients do not experience pleasure (or pain), this would not undermine the argument I set out to make in this paper. The potential harm of ignoring a patient’s capacity for pain is considerable, whereas the potential harm of mistakenly assuming a capacity for pain is low. Similarly, providing a patient with pleasant stimuli may improve their overall well-being if they are capable of pleasure; if they are not, it results in no significant harm to the patient. For these reasons, we ought to treat these patients as capable of sentience, provided we have some evidence to suggest that they are indeed sentient. I have provided such evidence in this paper. By acknowledging the capacity of these patients for pleasure and pain, and moreover, acting to minimize their experience of pain and promote their experience of pleasure (such as in the ways I describe in this paper), caregivers and family members of these individuals can make a positive step in helping them to live lives of at least decent quality.


Background. The aim of this study was to compare the postoperative pain intensity following the root canal preparation carried out with XP-endo Shaper , iRace  and Reciproc Blue  files.Methods. Mandibular molar teeth with asymtomatic necrotic pulps in 69 patients were randomly divided into three groups (n=23). The root canals were prepared using XPS, iRC or REC Blue instruments and obturated using the lateral condensation technique. The patients were asked to record their pain intensity at 24-, 48- and 72-hour and 1-week postoperative intervals on VAS. For intolerable pain after the procedure, ibuprofen (400 mg) was prescribed. Data were analyzed using chi-squared, Friedman, Kruskal–Wallis, and Mann–Whitney U tests.Results. The postoperative pain gradually decreased during the study period in all the groups (P<0.05). No statistically significant difference was found between iRC system and the two other systems at 12-, 24- 48-hour and 1-week intervals (P>0.05). When compared to XPS system, a higher level of postoperative pain was observed with REC Blue system at 24- and 48-hour intervals (P<0.05).Conclusion. The XPS group exhibited less postoperative pain than the REC Blue group at 24- and 48-hour intervals. iRC, XPS and REC Blue systems were found to be similar in terms of postoperative pain severity. It damages the periradicular tissues and might cause an acute inflammatory response. Depending on the level of damage in periapical tissues, the postoperative pain might be at high or lower levels.3One of the most frequently observed complications of root canal treatment is postoperative (post-op) pain. In the literature, there are studies reporting the prevalence of post-op pain after root canal treatment to vary between 3% and 58%.6 There is no consensus on which rotary and reciprocal system results in more extrusion and which one causes less.8 Despite the technological advancements, it was reported that different preparation methods and different file systems produced different levels of dentin extrusion.3 The factors such as file designs, tip diameter, taper and preparation method might affect the amount of apical extrusion.6The pain levels of the patients after the use of different preparation methods in root canal treatment have been examined in various studies.6 XP-Endo Shaper , continuous rotary single file system combining the MaxWire and Booster Tip technologies, was introduced recently. XPS files are in the martensitic phase at room temperature because of their aluminum content. Moreover, when placed into the canal at room temperature, they enter the austenitic phase (memorized shape). With an initial taper of 1%, the XPS file turns from a straight shape to a serpentine shape. This serpentine shape pushes out the envelope of movement and the files achieve a taper of 4%.9 iRace  system incorporates only 3 iRC NiTi rotary files in order to treat most of the cases. The files, for which an electrochemical surface polishing method is used, have a triangular cross-section and special anti-screw design. The file design allows prevention of the inward screwing effect and better control on the file progression.10 Reciproc Blue single file system , which operates based on the reciprocal motion and is an updated version of Reciproc  canal file, is now available on the market. REC Blue R25, R40 and R50 files are used for narrow, medium and wide canals, respectively. The REC Blue R25 (25/.08) files can be used in most of the cases. The geometry, size and design of REC Blue files are the same as those of Reciproc file system. REC Blue files are manufactured by using an innovative heat treatment method altering the molecular structure of the file. Specific S-shaped cross-section, variable taper, cutting angles and non-cutting tip of file increase the performance and efficiency.11Thanks to advances in production methods and metallurgy, as well as innovative concepts, it became possible to manufacture systems offering easier and faster instrumentation.13 In some clinical studies, it was determined that patients preferred and better tolerated root canal treatment completed in a single visit.14 The single-visit root canal treatment was safer in both vital and non-vital teeth in terms of endodontic flare-ups.13 In the literature, there is no study available to have compared the postoperative pain severity after using three different file systems. The aim of the present study was to compare postoperative pain levels after using XPS (continuous rotary single file system), iRC (continuous rotary multi-file system) and REC Blue (reciprocating single file system) in single-visit root canal treatment. The null hypothesis of the present study was that the instrumentation system used does not affect the severity of postoperative pain.There are various studies reporting that the root canal treatment of a tooth with asymptomatic necrotic pulp can be completed in a single session or multiple visits.The approval of the Ethics Committee of Mustafa Kemal University was obtained for the present randomized clinical trial (IRB No. 2017/190). All the subjects included in the present study signed informed consent forms about the treatment, risks and advantages. In addition, the subjects participated in the study on a voluntary basis. The sample size was determined by taking the results of a pilot study as basis. Based on the results of the pilot study, the final sample size was set at 69 (23 subjects in each group) for the α-value of 0.05 and study power of 80%.The participants were selected from the patients referring to the Endodontics Department of Mustafa Kemal University from September 2017 to February 2018. In the present study, 69 patients aged 21‒65 years, with no periapical pathology but first or second mandibular tooth with asymptomatic necrosis, were evaluated. After intraoral examinations, the demographic data of the patients and the locations of teeth were recorded. The pulp vitality and periradicular status of each tooth were determined using thermal and electric pulp tests, followed by palpation, percussion and periodontal charting. The clinical diagnosis of asymptomatic pulp necrosis was made based on the negative response to Green Endo-ice cold test and the electric pulp test. The diagnosis was supported because no bleeding was observed in the root canals after opening an access cavity. The participants did not take any medication suppressing or changing pain perception such as antibiotics, narcotics, antidepressants and analgesics during the week before the procedure. Moreover, participants with periapical lesions, abscesses or cellulitis at the relevant tooth, those with a medical treatment history or those having undergone root canal treatment for the relevant tooth were excluded from the study. The study flowchart for inclusion in the present randomized controlled trial is shown in In this process, a dark-colored bag was used; 23 blue, 23 yellow and 23 green papers were prepared for 69 participants. The colored papers were put in the bag and the bag was closed. Before the procedure, a dental assistant in the clinic was asked to randomly choose a paper from the bag. The treatments were completed by using XPS file for green color, iRC file for yellow paper and REC Blue file for blue color. The patients were assigned to 3 groups according to the instrumentation system used. All the participants involved in the study were informed about the used systems prior to the treatment.A total of 7 patients were excluded from the study due to procedural errors and then another 7 patients were included in the study.15 After anesthesia, a standard access cavity was prepared in the mandibular teeth and the root canal orifices were found using #10 manual K-ﬁles (VDW). The teeth were isolated by using a rubber dam. The working length was set to 1 mm shorter than the apical foramen by using #10 K-file and an apex locator  and then confirmed with periapical radiography. The working length was repeatedly checked throughout the treatment procedure. One of the three file systems was used for shaping and cleaning the root canals in a single visit. Each file was used only in a single tooth.As in the similar studies carried out before, local anesthetic solution containing 1:100,000 epinephrine  and 4% articaine was used for the inferior alveolar nerve block.After determining the working length, the canal was shaped using #15 K-file (VDW). XPS (30/.01) files were used in continuous rotational movement with VDW Silver Reciproc endodontic motor at the speed and torque levels recommended by the manufacturer (800 rpm and 1 Ncm). 10 mL of 2.5% NaOCl was used in the root canals in total and the root canals were also irrigated with 17% EDTA before obturation.iRC files were operated in the rotational movement using the same endodontic motor in accordance with the recommendations of manufacturer (600 rpm at 1.5-Ncm torque). iRC systems were operated using a #15 file with 0.06 taper, #25 file with 0.04 taper and #30 file with 0.04 taper, respectively. After every file replacement, the root canals were irrigated using 2.0 mL of 2.5% NaOCl solution. 10 mL of 2.5% NaOCl was used in root canals in total and then the root canals were irrigated with 17% EDTA before obturation.The root canals were shaped at the working length by using #15 K-files (VDW). Then, REC Blue R25 (25/.08) files were used with the same endodontic motor in “Reciproc all” mode. The instrument was moved using a slow in-and-out pecking motion (not more than 3‒4 mm) with light apical pressure. 10 mL of 2.5% NaOCl was used in root canals in total and then the root canals were irrigated with 17% EDTA before obturation.After the preparation procedures, the root canals were dried using paper points and then obturated by using cold lateral compaction method in the same visit. After radiologically confirming the obturation, the teeth were restored using a resin-modified glass-ionomer and a nano-hybrid composite resin.Visual analog scale (VAS) was used for pain assessment. VAS consists of a line marked from 1 to 10 and the pain level is categorized as no pain (0), mild pain (1–3), moderate pain (4–6) and severe pain (7–10). The scale was given to the patient and the patients were instructed verbally and visually about how to fill the form. Then, the patients were asked to record their pain at 24-, 48- and 72-hour and 1-week postoperative intervals. For intolerable pain after the procedure, ibuprofen (400 mg) was prescribed. At 24-, 48- and 72-hour and 1-week postoperative intervals, a researcher with no information about the present study recalled the patients and the pain scores were recorded. Moreover, the use of analgesics by the patients was recorded, too.Data were analyzed with SPSS 21.0 . The normal distribution of data was examined with Shapiro-Wilk test. Friedman, Kruskal‒Wallis, and Mann‒Whitney U tests were used to compare the effects of different instrumentation systems on postoperative pain. Chi-squared test was used to compare the demographic data and use of analgesics.Sixty-nine patients were included in the present study. No patient died during the follow-up period. The demographic data  of patients are presented in 4 Among these factors, choosing a suitable preparation method and shaping the root canal are under the control of the physician. For this reason, severe postoperative pain might be prevented by shaping the root canal successfully, extruding the canal contents during the preparation procedure, and minimizing extrusion of this content over the periradicular tissues.Postoperative pain might occur because of factors such as age, sex, pulpal and periradicular factors, preoperative pain and the implemented method.16 Other factors that might influence the amount of extruded debris  were standardized in all the groups. Ibuprofen, which is the first analgesic option offered to the patients in many studies the relief of pain after the root canal treatment, was prescribed.In the present study, several criteria were implemented in eliminating the effects of different preoperative factors. Similar preoperative pain levels were achieved by including only asymptomatic teeth in the study. Since the preoperative periapical condition has a significant effect on postoperative pain, only teeth with necrotic pulps without any periapical pathology were included in the present study. The present study was carried out on the mandibular molar teeth. It has been reported that these teeth have the highest incidence of postoperative pain.17The scale should be easily understood by the patients and clearly interpreted by the researchers in order to determine the pain level of patients objectively. For this purpose, the VAS scale which is widely preferred in the literature was employed in the present study.18 Su et al14 reported that the incidence of pain after the single-visit endodontic treatment was less than that observed after the multiple-visit endodontic treatment. The apical extrusion of intracanal medications used in multiple-visit treatments, failure or leakage of temporary filling materials or the other factors that might affect pain might cause postoperative pain between visits. In the present study, the root canal treatments were completed in a single visit in order to minimize the effects of these factors.The single-visit endodontic treatments have become popular in recent years.The aim of this prospective, randomized controlled clinical trial was to compare the effects of three different root canal preparation systems on postoperative pain. For all the periods, the minimum level of postoperative pain was observed in the XPS group and the maximum level in the REC Blue group. For 24h and 48h periods, significantly higher levels of postoperative pain were observed in the REC Blue group when compared to the XPS group. For this reason, the null hypothesis of the present study was rejected.19 reported that the highest level of postoperative pain was observed in the early phase after root canal treatment. The postoperative pain incidence was reported to be 40% in the first 24 hours, to decrease significantly in the first 48 hours, and to be 11% or less on the 7th day. Similar results were also achieved in the present study.The severity of postoperative pain was observed to decrease gradually at all the time intervals, in which the pain measurement was performed after the root canal treatment. In a systematic review carried out in 2011, Pak and White21 Previous studies showed that one of the most important reasons for postoperative pain is the extrusion of debris in the canal from the tip of the root during chemomechanical preparation, and that this would cause peripheral sensitivity characterized by hyperalgesia and spontaneous pain.22 It was determined in the in vitro studies that, compared to the rotary file systems, the reciprocal file systems might cause higher amount of debris extrusion as a result of the reverse motion of instruments.7 During the rotary motion, the mechanical movement wave courses throughout the length of the working part of the instrument, minimizing the contact between the file and dentin. In this case, when compared to the reciprocal instruments, rotary files yield cleaner canals by ensuring lower amounts of debris accumulation.23 This was confirmed in the present study because the maximum postoperative pain was observed in the REC Blue reciprocal file group, whereas the minimum postoperative pain was found in the XPS rotary file group.It is very important to take the movement kinematics of file systems into consideration. Some studies showed that the postoperative pain level with the use of rotary file systems was significantly lower than that with the use of reciprocal single-file systems. The difference between the groups was attributed to extrusion of debris, occurring depending on the instrumentation method.24 Reaching to the working length by using higher number of instruments might cause more extrusion and postoperative pain. It can be thought that the higher level of postoperative pain observed with the iRC rotary file system when compared to XPS file system might be because of higher number of files, longer duration of preparation and possible increase in the amount of apical extrusion.Another point to consider is to compare the number of files required for preparing the root canals. When compared to REC Blue or XPS single file systems, more files are used in root canal preparation performed using multiple-file iRC rotary file system. Longer duration of contact with the root canal walls might result in the formation of higher amounts of debris and higher level of manipulation in the apical region.9 compared the amounts of debris extruded from the apex during the root canal instrumentation by using XPS, HyFlex EDM and REC Blue files. According to the results of the present study, the REC Blue files produced significantly higher amounts of extruded debris compared to the XPS files. This conclusion was supported because the level of postoperative pain in the REC Blue group was higher than that in the XPS group.In the present study, the files were tested in the XPS (30/.01), iRC (30/.04) and REC Blue groups (25/.08). Lower level of postoperative pain was achieved in the XPS group with smaller size and taper, whereas a higher level of postoperative pain was achieved in the REC Blue group with larger taper. The differences in sizes might affect the results of the study by causing different amounts of extruded debris. Uslu et al20 asserted that Reciproc file system caused more debris extrusion compared to OneShape, F360 and Mtwo file systems. Similarly, Lu et al25 reported that use of Reciproc instruments in retreatment procedures led to higher amount of debris extrusion compared to Mtwo R instrument. On the other hand, Üstün et al8 compared the ProTaper Next, Twisted File and WaveOne systems in terms of the amount of debris extrusion and reported that WaveOne system resulted in less debris than the two other systems did. Shokraneh et al6 compared postoperative pain levels after the use of three different instrumentation methods in mandibular molar teeth with necrotic pulps. They reported that the root canal treatments performed using WaveOne system created significantly lower levels of postoperative pain compared to the root canal treatments performed using ProTaper Universal rotary system and hand files, and they attributed this to the amount of infected debris extruded from the apex. Neelakantan et al22 reported that Reciproc file system resulted in lower levels of postoperative pain when compared to OneShape file system. However, Comparin et al18 reported that Mtwo and Reciproc file systems were found to be equivalent in terms of postoperative pain levels. The possible explanation for the differences between the opinions on this topic is that the amount of infected debris extruded depends on the motion, number, design and taper of files.26Previous studies have shown that reciprocal files result in higher levels of debris extrusion compared to rotary files. Burklein et alIt should be noted that the size, cross-section, number of files and kinematics of the instrumentation systems used are different from each other, and these differences might have affected the results of this study.The XPS group exhibited less postoperative pain than the REC Blue group at 24- and 48-hour intervals. iRC system and XPS and REC Blue systems were found to be similar in terms of postoperative pain severity.MA was responsible for conceptualization, data collection, formal analysis, funding acquisition, investigation, methodology, resources, software, supervision, validation, visualization, and writing the original draft and reviewing and editing the manuscript. PT was responsible for conceptualization, data collection, formal analysis, funding acquisition, investigation, methodology, project administration, resources, software, supervision, validation, and writing the original draft and reviewing and editing the manuscript. IIP was responsible for data collection, formal analysis, funding acquisition, investigation and methodology.The authors declare no conflict(s) of interest related to the publication of this work.The authors declare no conflict of interest to this studyThis study was financially supported by the Research Fund of Mustafa Kemal University (Project number 18.M.028).This study was approved by the Ethics Committee of Mustafa Kemal University.


To analyse the effect of the manual ischemic compression (IC) on the upper limb motor performance (MP) in patients with LTrPs. A quasiexperimental study was performed in twenty subjects allocated to either patients group with LTrPs  or healthy group with no symptoms . Subjective pain and linear MP (movement time and Fitts' Law) were assessed before and after a linear tapping task. Data were analysed with mixed factorial ANOVA for intergroup linear motor performance differences and dependent t-student test for intragroup pain differences.p < 0.05). After IC, the PG showed a significant decrease of pain (4.07 ± 1.91 p < 0.001). Furthermore, the movement time (15.70 ± 2.05 p < 0.001) and the Fitts' Law coefficient (0.80 ± 0.53 p < 0.001) were significantly reduced. However, one IC session did not allow the PG to get the same MP than the HG (p < 0.05). PG had a linear MP lower than the HG before treatment ( The results suggest the IC effectiveness on pain and MP impairment in subjects with LTrPs. However, the MP of these patients is only partially improved after the IC application. Myofascial syndrome is a clinical condition characterized by muscle pain related to Myofascial Trigger Points (MTrPs) . The MTrSeveral studies report alterations in muscle function of subjects with LTrPs, such as decreased shoulder muscle strength in both dominant and nondominant sides ; EMG actCommon tasks to analyse the upper limbs MP is the finger tapping task . This taMoreover, different manual therapy techniques are applied to subjects with MTrPs, in order to evaluate its effect on pain and functionality . ResultsA quasiexperimental study was performed in twenty subjects, aged between 20 and 47 years old . The subjects were allocated in a healthy group (HG) (n=10) or a patient group (PG) (n=10), after a clinical assessment performed by an experienced physical therapist.Subjects were invited to the experiment via email and by ads posted in the University. Before enrolment, all subjects signed an informed consent form to participate in the study, which complied with the ethical criteria established in the Helsinki Declaration (as revised in 2013) on research projects and was approved by the ethics committee of the Caen University.To be included in the PG, the individuals had to show: (i) a palpable taut band in at least two skeletal muscles, (ii) a hypersensitive tender spot, (iii) referred pain of the MTrP in response to compression, (iv) jump signs like (winces cry and/or withdraw), and (v) a local twitch response caused by the snapping palpation of the taut. LTrPs were considered positive if two or more criteria were identified . The indAn adapted version of the “Plate Tapping Test”, from the Eurofit Test Battery, was used to evaluate the upper limbs linear MP. The subjects were sitting at a comfortable distance from the table with their dominant hand setting on the border of the table in cubital deviation, such as the ring finger, the middle finger, and the index finger perfectly leaned on the target. The distance between the subject and the border of the table was adjusted according to the arm's length of each individual. Thus, the middle finger of the dominant hand leaned on the central line, which was aligned with the sternum. The participant's task was to stretch their dominant arm, without moving their trunk, in order to reach each target as fast as possible. The patients received instruction not to rotate the trunk maintaining the shoulders in contact with the backrest. Each participant executed two trials of twenty-five movements , after hearing the auditive signal “Go”. Trials were separated by 2 min interval. The average time of the twenty-five movements was used for the statistical analysis.Subjects had to express pain level by manipulating a slider on a scale. The VAS is a subjective measurement, which is used to quantify pain intensity felt by the individuals. This is a graduated scale used to gauge pain, from no pain (0) to maximum pain (10). The subject's task was to move a slider over a 0 to 10 cm graduated ruler. The reliability of the VAS was demonstrated by Jensen et al. .A physiotherapist expert in the MTrPs exploration performed an upper dominant limb physical examination. Four LTrPs were identified and evaluated on the following muscles: (i) middle trapezius, (ii) levator scapulae, (iii) infraspinous, and (iv) teres minor. These muscles were chosen because of their involvement in shoulder movements and LTrPs prevalence in healthy subjects .2 and a velocity pressure of 1 kg/cm2/s [Subjects were prone lying in a comfortable position, arms in abduction, and elbows in flexion and leaned on the table. This position ensured muscle fiber relaxation, facilitating MTrPs localization and evaluation . The poikg/cm2/s , 31. Thekg/cm2/s , 31. AllIn the same position as described in the MTrPs identification, the physiotherapist applied a manual pressure using his thumb on the LTrPs until reaching the PG subject's pain threshold. This threshold was identified by either an oral expression or a visible muscle contraction. Then the pressure had to be maintained during 30 s. If the patient expressed pain reduction before the 30 s, the pressure was gradually increased until reaching a new subjective pain threshold self-reported. If a patient experienced more pain during treatment, then pressure was decreased until attaining tolerable level. This IC technique was preferred because it reduces pain more efficiently than other manual therapies , 32. ForFitts' Law is a mathematical relationship that predicts the MT according to an index of difficulty (ID). Several studies have demonstrated that this equation is a universal empirical model for characterizing the human MP. Here, it is used as an advanced analysis to gauge the MTrPs impact on the correlation between speed and accuracy of the movement. The general formulation of the law is as follows:In ideal conditions, b is equal to zero and  can be sThe participants were asked about discomfort and pain perception in the upper limb. Before starting the experiment, all subjects were submitted to an MTrPs clinical examination and were allocated to PG or HG according to the presence of LTrPs. In order not to revive pain, the clinical examination was carefully performed. Then the first stage of the experiment consisted of the tapping task completion in both groups. Afterwards, the muscle pain perception in the PG was measured by VAS. Finally, the treatment with IC was applied on PG. This procedure was repeated 48 hours after treatment, without the IC application. This 48 hours' delay was determined considering that pain may persist 24 hours after the treatment . p < .05 was considered statistically significant.The statistical analysis was performed with SPSS, version 22.0. Values are presented as mean (M) and standard deviation (± SD). MP mean was calculated by averaging measures taken during the two repeated trials. Two separate mixed ANOVA were completed (2 Groups x 2 Measures) to compare mean differences between groups for the MT and the Fitts' Law analysis of the tapping test. Furthermore, a paired t-student analysis was performed in order to compare mean differences within PG for the subjective pain perception. A value ofFrom the twenty-eight subjects who met with the inclusion criteria and who voluntarily accepted to participate in the study, only twenty achieved the study. The losses of observation were caused by the fact that (i) three HG participants and two PG participants dropped out the study; (ii) the data of two subjects of the PG were lost due to error recording during the first evaluation; and (iii) one participant of the HG was excluded in order to have the same number of participants in each group .p = 0.001; 95% IC: 1.08 to 2.95) which suggests that the modification in the pain perception can be attributed to the IC treatment . The post hoc analysis shows a significant difference in the time required to complete the tapping test between the PG (17.67 ± 2.83s) and the HG (12.73±1.81 s) before IC  and after IC   , whereas no difference was reported in the HG   . In addito 0.74) . This reto 0.74) . p = 0.002) and after treatment . It means that the correlation between speed and accuracy in patients with LTrPs is different than the one predicted by Fitts' Law. This difference persists after treatment but tends to be reduced. The post hoc intragroup comparison before versus after treatment shows no difference in the HG . On the contrary, the same test performed on the PG shows a significant difference   . This reThe objective of this study was to analyse the effect of the musculoskeletal pain on MP in subjects with LTrPs. The results show that (i) pain resulting from LTrPs causes an alteration in the execution of the tapping task, and (ii) the IC treatment reduces pain and partially improves the upper limbs MP. The limitations of the study were that the therapist who administered both the intervention protocols and the evaluation could not be blinded. Also, the experimental conditions did not permit to test Fitts' Law with different indexes of complexity.The IC application significantly changed the values of the subjective pain perception registered in patients with LTrPs. The subjective pain was reduced 2.02 cm in the 48 hours that followed the treatment by IC. On one hand, this result is consistent with previous studies that demonstrated a significant pain reduction in patients with MTrPs and, consequently, the efficiency of the IC technique , 26, 33.The mechanism that permits the IC to reduce pain is based on a pressure that locally dilates the sarcomeres . This diThe study shows a MP alteration for executing tapping task in subjects with LTrPs. The average time to execute the movement was 4.94 s slower for the PG before treatment than for the HG. After the IC treatment, the difference was reduced to 3.08 s in average. The MT for the HG was maintained around the same value in the two sessions of evaluation, whereas this time significantly reduced in the PG after treatment (1.97 s). A study in patients with LTrPs did not find significant differences in arm movement measuring reaction time between LTrPs and control group . This suOn the other hand, these results confirm the hypothesis that a significant pain reduction improves the MP in subjects with LTrPs. This study is the first to demonstrate that the manual pain reduction is not enough to enable the patients to reach a normal MP, taking into account the fact that the PG cannot get the same performance than the HG. Two possible reasons may explain such an outcome. First, the pain reduction by the IC application does not permit a normal recovery of the muscle recruitment pattern. This interpretation is supported by studies that show an alteration of the muscle activation pattern in LTrPs subjects , 44. ProIn terms of clinical application, these findings suggest that the manual pain reduction would be insufficient and that it would have to be completed by a reeducation of the muscle activation sequence in order to totally recover the MP (time and accuracy). Thus, a possible therapeutic program for patients with LTrPs would be as follows: (i) reduction of pain, because it can impede the cortical neuroplastic changes associated with a novel motor-skill acquisition , (ii) inThe tapping task enables us to study the MP in terms of Fitts' Law, which consists of evaluating the MT according to the amplitude of this movement and the size of the targets . This laThis study constitutes the first comprehensive evaluation of the linear MP in patients with LTrPs. The main outcome is a demonstration of the limitation in the completion time to execute a linear movement in such patients. Other finding is the confirmation that the IC application is effective reducing pain. However, the short-term effect of the IC on pain perception is only partially reflected in terms of the MP recovery. Finally, this work suggests that an early detection of LTrPs could prevent the development of abnormal motor control, which may have consequences on the muscle activity and the emergence of ATrPs.


The objectives were to evaluate the intensity of pain perceived 24 hours following insertion of fixed orthodontic appliance components i-e separators, bands and brackets.This cross-sectional study conducted at a Dental College in Karachi (July 2017-March 2018) investigated the amount of pain perceived during different stages of fixed orthodontic treatment. The inclusion criteria were healthy individuals without systemic disease, age 13-26 years, fixed orthodontic treatment candidates having healthy permanent first molars. The exclusion criteria were missing permanent first molars, patients requiring brass wire separators instead of elastomeric separators and molar tubes instead of bands, ongoing or previous periodontal disease and syndromic patients. Pain intensity was assessed in ninety eight patients using a Numeric Rating scale (NRS) at baseline (T0) before insertion, and 24 hours after insertion (T1) of a component. This procedure was repeated six times, twice each for separators, bands and brackets. Scoring was done on the NRS from 0 to 10 where 0 indicated no pain and 10 indicated worst pain possible.A significant difference in perceived pain was found between baseline and after 24 hours of placement of all components . Odds ratio indicated that males were at a greater risk to feel pain than females at baseline and after 24 hours of insertion of all components. Mann-Whitney U test showed that the most painful components at baseline were bands  and after 24 hours were brackets .Significant increase in pain was noted 24 hours after insertion of separators, bands and brackets. The most painful components were bands at baseline and brackets after 24 hours of insertion. There were no significant variations in pain perception based on age. However, males perceived higher pain than females both at baseline and after 24 hours. Pain due to orthodontic treatment is an important clinical problem which is generally overlooked by the dentists but is of considerable importance to the patients. Patients experience varying degree of pain and discomfort at the initial stages of fixed orthodontic treatment that negatively affects their compliance and co-operation and at times their willingness to continue the treatment.3Factors such as past pain experiences, present emotional state, stress, age, gender and cultural differences are believed to affect an individual’s pain perception.3Oliver and KnappmanVery few researches have compared the degree of pain perceived by the patients 24 hours after the placement of multiple fixed orthodontic treatment components. People belonging to a third world country face much more hardships as compared to the more developed countries and therefore the results of such studies if conducted in a third world country should markedly differ from the studies carried out in more developed parts of the world. Also we did not find any study conducted on Pakistani population gauging the intensity of pain perceived due to orthodontic treatment. This study will benefit the patients as they can be informed in advance regarding the level of pain that is likely to be experienced by them during treatment. In addition it will also help to improve the counseling skills at the clinician’s end. With this study we want to evaluate if there is any difference in pain perception among the different orthodontic components therefore our objectives were to evaluate the intensity of pain perceived by the patients after placement of separators bands and brackets, with identification of the most painful component, along with determination of variation in pain perception in different ages and genders.Our null hypothesis is that there would be no difference in pain perception for the different orthodontic components used during treatment, also there would be no variation between genders and ages in pain perception.This observational cross-sectional study was conducted at the Orthodontics Department of a Dental College in Karachi, Pakistan from July 2017 to March 2018. The study was approved by Ethical review board , previously placed bands for any restorative procedure, syndromic patients and patients who took painkillers before or in between the different steps of the study.*Np(1-p)]/ [(d2/Z21-α/2*(N-1)+p*(1-p)],keeping the population size 1000000, frequency at 90%,confidence limit 5%,confidence level at 90% and design effect as 1.Convenient consecutive sampling was used with age range of 13-26 years. The participants were grouped into 52 adolescents (13-19 years) and 46 young adults (20-26 years).The sample comprised of 98 patients .The sample size was calculated on the basis of study conducted by AldreesPatients were assessed with a self-administered proforma formulated using the Numeric Rating Scale (NRS). Scoring was done on the NRS from 0 to 10 where 0 indicated no pain and 10 indicated worst pain possible. The participants were instructed to encircle the numbers that they best believed represented the pain perceived by them at that time. The scoring on the NRS was first done at baseline (T0), before the fixed orthodontic appliance components were placed and the second time it was given to the participants to be filled by them 24hrs after insertion (T1) of the components. This procedure was repeated six times each for separators, bands and brackets and all the components used were from 3M Unitek. A period of one week was given in between the appointments and all the components were placed by a single operator in order to reduce operator bias.Patients were asked to avoid the use of analgesics and were instructed to note it in the forms if used. However, none of the patients used analgesics after 24 hours of insertion of all three components. All the patients were individually called by the researcher in order to remind them to record their entries as advised and it was made sure that the participants themselves rated NRS correctly after each step so that none of the forms got discarded. The forms were returned subsequently on the next appointment.In the first visit, operator placed the elastomeric separators inter-proximally between the permanent first molars  in all the four quadrants using separator plier. The appointment for banding of all permanent first molars was scheduled after one week of separator placement. Second molars were banded after the second form of bonding was received from the patients as these teeth were not included in the study. The bonding was done only on a single arch (Upper Arch) due to increased patient load in the OPD. Fixed appliance prescription of 0.022-slot was used and 0.012 NiTi wire was placed after bonding and secured with elastomeric o- rings in all the patients with and without crowding to maintain a similar standard. All the components were placed according to the manufacturer’s instructions and the entire procedure was performed by the same clinician in order to reduce operator bias. Out of the selected 98 patients, 58 patients had extractions in their treatment plans due to crowding. In those patients, the fixation of the brackets and grading on NRS was done two weeks after extractions so that any bias as a result of post extraction pain is eliminated.SPSS version 23 was used to analyze the data with level of significance set at <0.05.Wilcoxon Sign Rank Test was performed to find any significant differences in the intensity of pain perceived at baseline and 24 hours after insertion of different fixed orthodontic appliance components.Due to the unequal number of males and females in the study, which was due to higher number of female patients in our setting, Binary Logistic Regression Analysis was done to compare genders and age groups. Mann-Whitney U test was applied to compare the differences between independent component groups at baseline and after 24 hours following the insertion of orthodontic appliances in order to find out the most painful component at baseline and after 24 hours.After 24 hours all the components of fixed orthodontic treatment therapy were significantly painful . The results of Binary logistic Regression Analysis are shown in When the baseline mean pain scores of separators, bands and brackets were compared using Mann-Whitney U test; bands were found to be more painful at baseline whereas; after 24 hours of insertion, brackets were identified as the most painful component . Table-IIIIn this study pain was evaluated using the Numeric Rating Scale (NRS) which has been used in various studies, as a subjective method of measuring pain, and has been identified as an easy and a highly reliable tool to evaluate variations in pain intensity which is comparable with VAS.Our sample showed that patients with severe crowding showed more pain as compared to others after the separator placement. This could be due to the excessive pressure exerted by the separators when they were forced in between the tight interproximal contact points of the crowded arches. However Jones et al.22We found significant variations in pain intensities between the two genders, as males experienced more pain when compared to females, but Ngan et al.Our study had certain limitations. Participants from the out-patient orthodontics department of only one institution were selected as the study sample and shorter follow-up period of 24 hours was observed for each component.This study concluded that a significant increase in the intensity of perceived pain was noted after 24 hours of insertion of all fixed orthodontic treatment components including separators, bands and brackets. However bands were the most painful components at baseline, while after 24hours of placement, brackets were the most painful component. No statistically significant variation in pain perception was seen when comparing the two age groups. Thus the null hypothesis was accepted. Males showed higher pain perception after the placement of all three fixed orthodontic components both at baseline and after 24 hours when compared with females. Therefore, our null hypothesis was rejected in this regard.MJ conceived and designed this study, did data collection, manuscript writing, editing, compilation of results and drafting of the article, is also responsible for integrity of research.THQ critical revision and final approval of the version to be published.MFF did Statistical Analysis and interpretation of dataMJ takes the responsibility and is accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.


The transradial approach is generally associated with few complications. However, periprocedural pain is still a common issue, potentially related to sheath insertion and/or arterial spasm, and may result in conversion to femoral access. Radial artery occlusion (RAO) following the procedure is also a potential risk. We evaluate whether the design of the sheath has any impact on these variables. A total of 1,000 patients scheduled for radial CAG or PCI were randomized (1:1) to the use of a Slender or a Standard sheath during the procedure. Randomization was stratified according to chosen sheath size  and gender. A radial band was used to obtain hemostasis after the procedure, employing a rapid deflation technique. A reverse Barbeau test was performed to evaluate radial artery patency after removal of the radial band, and level of pain was assessed using a numeric rating scale (NRS). Use of the Slender sheath was associated with less pain during sheath insertion , whereas no difference was observed in pain during the procedure, radial procedural success rates, use of analgesics and sedatives during the procedure, and radial artery patency following the procedure. Rate of RAO was 1.5% with no difference between groups. The use of the hydrophilic coated Slender sheath during radial CAG or PCI was associated with less pain during sheath insertion, whereas no difference in other endpoints was observed. A rapid deflation technique was associated with RAO of only 1.5%. The transradial approach has become increasingly popular worldwide when performing coronary angiography (CAG) or percutaneous coronary intervention (PCI) because of fewer bleeding complications . There aThe purpose of the present study was to evaluate whether the use of the 10 cm Slender sheath affects pain, rate of conversion to the femoral access, use of analgesics or sedatives, and RAO following the procedure compared to the 10 cm Standard sheath when performing radial CAG or PCI.ACCESS-1 was a randomized, controlled, prospective open-label two-center trial in which 1,000 patients we enrolled between the 15th of December 2015 and the 12th of July 2016 at Aarhus University Hospital Skejby, Aarhus N, Denmark and at Viborg Hospital, Denmark . Only paInclusion and randomization were performed in the catheterization laboratory before the procedure.Patients were randomly assigned (1:1), by a computerized IT system according to chosen sheath size  and gender, to receive either a “Slender sheath” or a “Standard sheath” during radial CAG or PCI. Patients, investigators and clinicians were not masked to treatment allocation;however neither patients nor the nurses at the ward removing the TR-band and performing the reverse Barbeau test were told which treatment group the patients were randomized to.Subcutaneous injection of Xylocaine 20mg/ml was used as local anesthesia at the access site. The sheath was inserted and the patients were asked to state their maximal perceived pain during sheath insertion according to a numeric rating scale (NRS) going from 0 to 10. The scales express subjective feelings (pain) as a numerical representation. We ensured the patient respond was related to the procedure of sheath insertion and not potential chest pain. While the NRS scale was well-known to the clinical staff, for consistency and to limit noise all nurses were re-trained in its use prior to study start. The training also took place during meetings, held routinely at the cath lab, and also together with the staff just prior to a CAG/PCI procedure along the full inclusion period. Prior to the procedure, 5000 IU heparin and 0.25 mg nitroglycerine were injected through the sheath. If PCI was performed, additional heparin was administered if found indicated by the physician. After the procedure, the patients were asked to state the maximal pain they had perceived during the procedure and during sheath removal according to the NRS. Following the procedure, a radial artery compression device (TR band) was applied. After initial inflation with 15 ml air, the TR band was slowly deflated until bleeding was observed. Approximately 1 ml air was then re-inflated to achieve hemostasis. The total air-volume inflated and the time of TR band application were recorded. At the ward, the nurses were instructed to deflate the TR band by removing 25% of the total air volume every 15 minutes (Rapid deflation technique). If bleeding occurred, the TR band was re-inflated with the volume removed, and the procedure was repeated after an additional 15 minutes. The time of TR band removal (time of hemostasis) was registered. Following removal of the TR band, a reverse Barbeau test was performed by the nurses at the ward to evaluate radial artery patency by monitoring pulse oximetry findings on the thumb or index finger when compressing the ulnar artery. The four different patterns of the reverse Barbeau test are illustrated in All patients with reverse Barbeau D were scheduled for an outpatient visit after 1 month where the same physician would evaluate the radial artery patency with a reverse Barbeau test and do the arterial ultrasound examination.To ensure standardization of the fitting and removal of the TR Band, we introduced the concept of a “contact nurse”. In each department one or two nurses were trained in the study protocol and agreed to ensure that their colleagues had sufficient knowledge about the study and were trained in the practical handling of the TR band and performance of the Reverse Barbeau test, to ensure consistency with data, throughout the study. Furthermore all study nurses meet regularly in each department both before study execution and during the study period.The following primary endpoints were registered: (a) maximal pain (NRS) during sheath insertion, (b) maximal pain during the procedure (CAG or PCI) and during sheath removal (NRS), (c) proportion of patients converted to femoral access, (d) use of analgesics during the procedure (cumulated micrograms of fentanyl), (e) use of sedatives during the procedure (cumulated milligrams of midazolam), and (f) result of reverse Barbeau test after removal of the TR band.Secondary endpoints were (a) number of catheters used and (b) number of sheaths used.NCT02637843). All patients provided written informed consent.The study was approved by the regional scientific ethical committee (J.nr.1-10-72-282-15) and the national data protection agency (J.nr. 1-16-02-679-15). The study was registered at ClinicalTrials.Gov , while it is 3 ± 2 for the radial CAG [Data are analyzed according to the intention-to-treat principle. Continuous variables were presented as median  and comparisons were made using Mann-Whitney U test. Categorical variables were presented as proportions and compared using the Chi-square test. A p value <0.05 was considered statistically significant.Statistical analyses were performed using STATA 14.0. .A total of 1,000 patients scheduled for subacute or acute CAG or PCI were included in this study of whom 891 patients were included at the regional PCI center  and 109 patients at a satellite center performing only CAG  . BaselinThe primary and secondary endpoints are presented in Following removal of the TR band, 13 (1.5%) patients had a reverse Barbeau type D. . Eleven In the 45 patients who had Reverse Barbeau test performed by both a nurse and a physician, there was agreement in the classified reverse Barbeau type in 40 (89%). In four patients, the physician evaluated reverse Barbeau type B and the nurse reverse Barbeau type A. In one patient, the physician evaluated reverse Barbeau type A and the nurse reverse Barbeau type B.It is well established that transradial access is associated with fewer complications, especially in patients with acute coronary syndromes , 6, and NCT03626129).A second observation made in the present study was the extremely low rate of RAO in both groups, i.e., approximately 1.5% at discharge, with two-thirds even achieving patency at 1-month follow-up. This may be explained by the rapid deflation technique we deployed which aimed at removing the TR band as soon as possible. Notably, we did not install a fixed air volume, but instead deflated until bleeding occurred and then re-installed a volume of approximately 1 ml air. It seems logical that the optimal volume in the TR band varies from patient to patient, depending on how tight the TR-band is applied, and maybe the high rates of RAO observed in other studies can be explained by delayed initiation of deflation and inflation of fixed volumes . More usThe rather high rate of conversions to femoral access may be explained by the fact that, historically, our center has prioritized femoral access, and we had just gradually switched to radial access within the past three years before the current study was conducted, at a time when many fellows were in training. It is well known that success rate is dependent on operator volume . NeverthUse of a coated Slender sheath during radial CAG or PCI was associated with less pain during sheath insertion than use of a Standard sheath. No difference was observed in pain during the procedure, conversion to femoral access, use of analgesics, or radial artery patency following the procedure. A rapid deflation technique was associated with RAO of only 1.5%.