There is currently no treatment for early/intermediate Age-related Macular Degeneration (AMD) but Eye Care Professionals (ECPs) are recommended to advise patients about modifiable lifestyle factors, including dietary changes, that can slow disease progression. The aim of this review was to understand advice currently given to patients with AMD by ECPs and to evaluate evidence regarding patient compliance. A systematic review was conducted of literature published in electronic databases: CINAHL, MEDLINE, PsycINFO, PyscARTICLES, EMBASE, AMED. Methods followed PRISMA guidelines (PROSPERO registration number: CRD42020223724). Twenty-four reports were eligible for inclusion, 12 focused on ECP experience, 7 on patient experience, and 6 on impact of advice (one paper reported on the ECP and patient experience). Studies reported that a substantial proportion of patients did not recall receiving lifestyle modification advice from their ECP . Practitioners were most likely to provide advice about nutritional supplements , and least likely about smoking , however supplements advised did not always comply with evidence-based guidelines. The main reason for patients not following lifestyle advice was lack of provision by the ECP . The review highlighted a need for more studies to understand patient preferences for receiving advice and research on ECP perceived barriers to advice provision.  Age related Macular Degeneration (AMD) is a progressive eye condition that leads to irreversible loss of central vision and it is the leading cause of visual impairment in developed countries ,2,3,4,5.On this basis, professional bodies advise Eye Care Practitioners (ECPs) to recommend lifestyle changes based on this evidence  to patients with AMD verbally and in written format and to recommend other services such as smoking cessation services to help patients make the changes. The recommendations for some professional bodies are shown in However, studies have demonstrated that these recommendations are not consistently followed ,36 and nThe review process was consistent with PRISMA guidelines ,39. The To be included in the review, the studies had to include people with any diagnosis of AMD and had to be an evaluation of the provision of lifestyle, smoking and nutritional advice by ECPs and/or the effectiveness of this advice in bringing about a change in behaviour.Studies were excluded if they were not published in English language; they focused on people at risk of AMD ; the full manuscript was not available or was only a published protocol, review, letter to Editors or news article; they focused on AMD with other associated systemic and ocular conditions; they evaluated a medical treatment for AMD or advice following cataract surgery; or if they were published prior to 2001—the year of publication of the original AREDS results paper .https://www.mendeley.com accessed on 20 September 2022). The data from the included studies was extracted and recorded in a data extraction table (see All of the records were assessed for eligibility by two authors (SD and TC) and any disagreements were resolved by consulting with the other two authors (AB and VVN). The records were organised, and duplicates were removed using Mendeley software v1.19.8  and 859 records were excluded. 73 reports were retrieved to be assessed for full text eligibility and 1 was not retrieved as it was an older version of a paper, already included, that had been reprinted. The 73 full texts were assessed by SD and TC. One study was taken to the other two authors (AB and FVN) who confirmed eligibility. Finally, 24 papers were included in the review. Of the 24 papers included in this review, 7 papers focused on the patient experience of lifestyle advice ,37 and tTwo studies which surveyed patients with AMD at a hospital clinic, both reported that a high proportion of patients had no recollection of receiving advice regarding dietary modification from their ECP ,37. BottFive studies investigated patient awareness of risk factors of AMD ,48,53,58Stevens et al. (2014) aimed to characterise AMD patients who seek the services of the Macular Society in the UK, and to determine the level and source of their knowledge about dietary recommendations for people with AMD . The MacPatient understanding of the risks associated with tobacco use and the potential benefit of smoking cessation was only investigated in one study . SurveysOverall, there is good evidence from these 5 studies ,48,53,58Twelve studies included in this review were based on practitioner reported experiences. Out of the 12 studies, seven papers related to diet, smoking and vitamin supplement advice, three focused solely on advice about vitamin supplements and 2 focused on smoking advice.Lawrenson and Evans (2013) surveyed 1468 UK based ECPs  about the lifestyle advice currently given to patients with AMD. Sixty-eight percent of the practitioners reported that they would always or usually provide dietary advice to patients with established AMD. Although 93% of practitioners recommended nutritional supplements to patients with AMD, for the majority the vitamins recommended did not comply with best evidence-based practice for nutritional supplementation in AMD, i.e., not based on AREDS guidelines ,26. WithDownie and Keller (2015) carried out an online survey of 379 optometrists in Australia and similarly found that only 47% of the optometrists reported routinely asking patients if they smoke, 62% reported counselling their patients with regard to diet and 91% of recommended nutritional supplements to patients with AMD . It was In another study evaluating only optometrists, Sahli et al. (2020) administered postal surveys to 42 optometrists to examine the lifestyle advice that optometrists offer, to whom such advice is offered and reasons for not offering advice . In contn = 323) and ophthalmologists (n = 48) in Sweden, reported that ophthalmologists were more likely to provide smoking cessation advice than optometrists [Downie and Keller  and Sahlmetrists . Lawrensmetrists . Howevermetrists . Both stmetrists . FurtherIn a larger sample specifically targeting ophthalmologists, Aslam et al. (2014) evaluated ophthalmologists’ opinion of, and use of, nutritional dietary supplements 10 years after the publication of the first Age-related Eye Disease Study (AREDS). This study surveyed 216 participants  from 7 different European countries  and found that, on average, information about the benefits of nutritional supplements was regularly given to patients with AMD by 67% of ophthalmologists . SixOther studies have been more specific in the aspects of nutritional advice evaluated. For example, Larson and Cocker (2009) investigated the perceptions, recommendations and educational or informational materials of licensed Wisconsin optometrists on lutein and zeaxanthin and eye health. Although the AREDS2 findings did not support the recommendation of lutein and zeaxanthin supplements to well-nourished individuals , there iSimilarly, although AREDS2 did not find a benefit to the inclusion of omega 3 supplements in the AREDS formula, there is still evidence from observational studies (adopted by most practitioner guidelines) that inclusion of dietary omega-3, for example in oily fish, is beneficial to slowing AMD progression ,70,71. ZTwo studies specifically assessed provision of advice on smoking cessation by practitioners ,55. CabaHaving identified that there are limitations in the provision of lifestyle advice to people with AMD, there has been some effort to explore barriers to this advice provision. Jalbert et al. (2020) surveyed 77 eye care professionals and reported that cost/funding, patient understanding/denial, discipline silos, access/availability of services and willingness to make lifestyle changes were the most commonly reported barrier for practitioners to administer effective AMD care . As a poTo summarise, practitioners seem to be more likely to give advice about diet and nutrition than smoking cessation advice, possibly in part because of concerns about a negative effect on the relationship between patient and practitioner of asking questions which might be perceived as being judgmental ,72. FiguSix studies included in this review examined the changes that patients with AMD made to their lifestyle following the receipt of lifestyle advice from their practitioners. Shah et al. (2013) asked the 92 AMD patients surveyed in their study about their compliance to the lifestyle advice they were given . AdherenWeaver and Beaumont (2015) aimed to understand lifestyle changes that patients make as a result of the way advice is given . They fon = 64 and n = 193, respectively). In the Hochstetler et al. (2010) study, participants were all recruited from the retina clinic of a single retinal specialist in the USA. Fifty-nine percent of the patients reported taking a vitamin supplement for AMD, with 71% of these being AREDS based. All of the participants taking supplements were recommended to do so by their retinal specialist. Seventy-five percent of the participants who did not take supplements said this was because it was never recommended to them [Six survey-based studies specifically studied the initiation of vitamin supplement intake and dietary changes that patients with AMD made as a result of advice received. Chang et al. (2002) surveyed 108 patients with AMD recruited from a retinal specialist clinic in Canada . They fo to them . Parodi  to them . They re to them .These studies ,47,51,56Yu et al. (2014) also reported similar findings in a German cohort ,61. The In summary, there was minimal evidence regarding compliance of patients to advice regarding general dietary changes, with the majority of studies focusing on compliance to vitamin supplement recommendations. The proportion of patients taking vitamin supplements for AMD in the included studies varied widely between around 40% and 68% ,56,60,61Overall, the studies included in this review have highlighted significant limitations in lifestyle modification advice provided by ECPs to patients with AMD.This review highlights a number of key issues related to the patient experience or receiving life-style advice. Firstly, patient awareness of the risk factors for AMD in the included studies was poor. A review by Armstrong and Mousavi (2015) discussed the reported risk factors for AMD and highlighted that factors including smoking cessation, dietary changes, and regular use of dietary supplements should all be considered to reduce the lifetime risk of AMD and that ECP’s should work to increase patient knowledge of these risk factors . HoweverHowever, patient reported studies have some limitations. Firstly, patients may not want their clinician to know that they are not following advice, or may not want to make negative comments about their ECP, especially when they are surveyed in the clinics. Anonymising data may help with this, but patients may still have reservations. Secondly, there is a risk of selection bias, where participants who respond may be more motivated to take part. For example, Stevens et al. (2014) recruited patients from a voluntary sector patient support group, which may have preferentially included people who were more inclined to engage with the management of their condition . Thirdlyn = 1169) reported feeling satisfied overall with their diagnostic consultation overall (76% compared to 61% in 1999) [The overall experience of patients with AMD in the UK has been evaluated previously . The study compared patients’ experiences of AMD care in 1999 compared to 2013 after the publication of patient management guidelines from the Royal College of Ophthalmologists . A highein 1999) . Althougin 1999) ,76.n = 100 was 68%), while advice regarding nutritional supplements was given by between 67% and 93%  of ECPs surveyed [The studies reporting practitioner experience in providing lifestyle advice for AMD found that practitioners tended to be more confident at providing advice about diet and nutrition, especially nutritional supplementation, than regarding smoking cessation. This was suggested to be at least partially attributable to concerns about a negative patient response to questions about smoking ,72. Betwsurveyed ,49,55,57surveyed . There wsurveyed ,36, and surveyed ,26 recomsurveyed . HoweverResearch in other healthcare disciplines  indicates certain common barriers which may prevent implementation of advice regarding nutrition . One facAll of the studies relating to practitioner experience were questionnaire based, self-reported studies about practitioners’ opinions and practice behaviours. It can be argued that these studies can be biased by a desire for practitioners to appear in a positive light before their peers, and may not truly represent the views or behaviours of the ECP. Another potential issue is selection bias, whereby those individuals responding to a questionnaire may be those who are more engaged with research in this field and therefore more motivated with respect to providing patient lifestyle advice. However, these limitations mean that the self-reported lack of provision of dietary advice to people with AMD by one third of ECPs surveyed is likely to be a favourable representation of the true scale of advice provision.An important point to consider is that the studies that were reported recently (2020 and later) ,57,62,78This finding is not unique to ECPs. A survey of 3167 general practitioners from four Scandinavian countries reported that, of the 67% who responded, the majority did not explicitly ask the patient about their smoking history unless they displayed smoking related symptoms, and few practitioners signposted smoking cessation services . SimilarIt is of particular concern that practitioners included in this review were also not asking about smoking history. This is crucial not just with respect to advising on smoking cessation, but also because as there is strong evidence that beta carotene supplementation increases the risk of lung cancer in smokers . This meGiven the limitations in advice provided by ECPs with respect to lifestyle modification, further exploration of the barriers limiting advice provision would be valuable to identify ways in which these barriers might be addressed.Additionally, this literature review has identified a significant limitation in the current published evidence base. The published studies do not cover the behaviour of practitioners in all countries. In fact, all of the studies which met our inclusion criteria were based in Europe, Australia and the USA, so there is a real need for research investigating the behaviour of practitioners in areas in Asia, Africa, South America.In this review, the majority of studies reporting on compliance related to vitamin supplements. Overall, patients were taking the supplements they were recommended, but were unsure if they would help. Previous studies have shown that, when informing patients of new medication, it is important to inform them about what the medication is, how it will help and how long they should take it for as this improves compliance ,86. The Finally, despite the large amount of evidence showing the benefits of smoking cessation on AMD progression, with smokers having a 4-fold increased risk of progression and former smokers having a 3-fold risk , there wn = 100) allocated to the intervention group (n = 49) were given a leaflet and prompt card containing advice on diet and supplements, whilst participants in the control group (n = 51) were given a leaflet created by the UK College of Optometrists. All of the participants were followed up after 2 weeks, at which time there was evidence that participants in the intervention groups showed a larger increase in confidence that changing diet could slow progression of AMD, and were also more likely to make dietary changes. However, the follow up period of this study was short, and participants were not randomly allocated to the intervention group. Another study assessed the effectiveness of a telephone delivered intervention designed for giving dietary recommendations to people with AMD [n = 77) were given a 20 min phone call every month for 4 months where they would provide advice to patients, assess their diet, help them with goal setting and arranging follow up support. The participants in the control group (n = 78) were given general leaflets about AMD and were followed up briefly once a month. Participants were also given a follow up call 4 months after the study was completed. After the intervention, participants in the interventional group significantly improved their dietary intakes of green leafy vegetables compared to baseline, whilst the change in the control group was not statistically significant compared to baseline. Additionally, the intervention group made more overall dietary changes compared to the control group, with a significant difference being in the consumption of nuts (p = 0.04) [There has been research into ways of improving effectiveness of advice provision to people with AMD. Stevens, Cooke and Bartlett (2018) carried out an interventional study to see if a novel educational intervention can promote healthy eating and nutritional supplementation in people with AMD . The parwith AMD . Particiroup n =  were givIn conclusion, this review shows that the lifestyle advice given to patients varies and is not consistent amongst all practitioners. Practitioners appeared to be most confident in providing advice about nutritional supplements, and least confident with respect to smoking, however nutritional supplements advised did not always comply with evidence-based guidelines. There was evidence that patients were inclined to follow advice regarding supplements provided by ECPs, and the main reason stated for not following lifestyle modification advice was that it had not been provided by the ECP and because patients were not sure if following the advice would be useful. This highlights the potential scope for ECPs to bring about a change in patient behaviour through effective advice provision. The review highlighted a need for more patient centred studies to understand the best ways of providing advice to patients as well as research regarding how to overcome the ECP perceived barriers to effective lifestyle advice provision to facilitate the translation of research to positive outcomes.


Results: Provocation of the familiar headache occurred at the posterior arches C1 in 92%, and at one of the articular pillars of C2 in 65.3% of cases. At one of the rectus capitis major muscles, the familiar headache was provoked in 84.6% of cases; at one of the oblique capitis inferior muscles, the familiar headache was provoked in 76.9% of cases. The applied mean pressure ranged from 0.82 to 1.2 kg/cm2. Maintaining the pressure reduced headache pain intensity significantly between the start and end of each of the three consecutive trials (p < 0.04). This reduction occurred faster in the third application than in the first application (p = 0.03). Conclusion: Manual pressure at upper cervical segments provokes familiar referred migraine headaches, with low manual pressure. Maintaining the pressure reduces the referred head pain significantly, indicating modulation of central nociceptive transmission.Background: Manual pressure in the upper cervical spine is used to provoke and reduce the familiar migraine headache. Information is scarce on the segmental levels, myofascial structure provocation, and reduction occurrences. The required dosage  has not been objectified yet. Methods: Prospective observational study. Thirty patients with migraine were examined interictally. Manual pressure was applied at four sites: the posterior arch of C1, the articular pillar of C2, the rectus capitis posterior major muscle, and the obliquus capitis inferior muscle, bilaterally. On sites where the familiar headache was provoked, the pressure was sustained to induce pain reduction (three repetitions). Provocation of familiar headache (yes/no), headache intensity , time to obtain a reduction of the headache (seconds), and applied pressure (g/cm A migraine is a common primary headache type with an estimated global prevalence of 15.3% ,3. BesidReferred pain to the head can be provoked by pressure or stretches on cervical myofascial structures, such as muscles, ligaments, and joints. Provocation of headaches by techniques using a combination of movement and manual pressure on upper cervical myofascial structures may distinguish patients with migraine from healthy controls ,15,16. RAlthough provocation and reduction of referred head pain can be used to assess and treat patients with headaches, information about the applied pressure during these tests and the relevance of these specific tests is missing.Our study explores if familiar headaches can be provoked and reduced by manual pressure at the upper cervical spine in patients with migraine. The pressure to obtain this provocation as well as the reduction of referred pain have not been objectified as yet. Therefore, we measure the applied pressure and the immediate effects on referred pain to the head during the application of these techniques in patients with migraine. This information is mandatory to gain further insight into the underlying pathophysiological mechanisms and to verify if a change in the applied pressure does not cause the observed decrease. The objectives of this study were to determine whether manual pressure can provoke referred pain to the head in migraine, verify if sustained manual pressure can reduce referred pain to the head, and constantly monitor the amount of pressure.https://www.strobe-statement.org, accessed on 1 January 2022). A prospective observational study was conducted and reported according to the STROBE criteria for observational studies  by a general practitioner or neurologist .Patients were excluded in case of other headaches, medication overuse, rheumatoid disorder, chronic diseases , a recent history of neck/head trauma , anesthetic block in the past month, pregnancy, and symptoms of concomitant illness. Furthermore, migraine needed to be accompanied by neck pain; a good understanding of the Dutch language was required as all information, instructions, and questionnaires were in Dutch. Each patient was asked to keep a headache diary for four weeks to confirm the diagnosis and frequency of the migraine. Measurements were planned interictally, and patients were not allowed to take analgesics or muscle relaxants twenty-four hours before the examination.Measurements consisted of the completion of the headache diary (headache frequency and headache intensity), two questionnaires , the assessment of pressure pain thresholds (PPTs), and measurement of pressure during MPT.The headache diary was used to calculate the headache frequency (days/month) and mean headache intensity on a numerical pain rating scale (NPRS). The NPRS is a scale with 11-points, with 0 indicating no pain and 10 indicating intense pain (as intense as one could imagine) ,20; it wThe headache impact test 6 (HIT-6) measures the adverse impacts of headaches on social functioning, role functioning, vitality, cognitive functioning, and psychological distress; it also measures the severity of the headache pain. This questionnaire consists of six items that need to be answered on a five-point scale ranging from never to always. The total score varies between 36 and 78, with a higher score meaning a more significant impact. HIT-6 scores are divided into four severity levels; little or no impact (≤49), some impact (50–55), substantial impact (56–59), and severe impact (≥60). The HIT-6 is equally reliable  in patients with headaches and chronic migraine ,22.The central sensitization inventory (CSI) is also a self-reported scale designed to highlight the possible presence of a central sensitization syndrome. The first part, Part A, assesses 25 health-related symptoms common to central sensitization syndromes. Total scores range from 0 to 100, where a cut-off score of 40 provides a clinically relevant guide to assume the possible presence of a central sensitization syndrome . Part B 2 probe and are expressed in kPa/cm2. This algometer has excellent construct validity and high intra-rater reliability in people with migraine [The PPTs were assessed with the Somedic algometer with a 1 cmmigraine . This waThe participant had to push the button of a hand-held switch. Once the participant pushed the button, the recorded value on the display of the algometer was noted .The MPTs were performed by two musculoskeletal physiotherapists (W.D.H. and R.C.); each has over 20 years of experience in assessing and treating patients with cervical spine disorders. Four techniques were performed bilaterally. The first two techniques have been described by Watson et al. . The patThe third and fourth techniques were performed with the patient in a prone position and the cervical spine in a neutral position. Pressure with the thumb was applied deep toward the occiput to stretch the rectus capitis major muscle (the third technique). At a lower level, pressure with the thumb was applied toward the spinous process of C2 and attempted to stretch the obliquus capitis muscles (the fourth technique). Schematic representations of techniques 3 and 4 are presented in The outcome of these MPTs was defined as positive (yes/no) if provocation of the familiar headache occurred within 5 seconds. In all positive cases, the intensity of the provoked pain was registered via an NPRS.2) that were placed on the tip of the thumb . These sensors measure the applied pressure in kg/cm2. During the examination, a third assessor was in control of the software so that the examiner who performed the MPT was blinded to the outcome of the applied pressure. The third assessor also recorded the patient’s reported outcome of the MPT.During the MPT, the thumb pressure of the assessor was measured constantly using force-sensing resistor sensors  the familiar headache could be provoked. The outcomes of the MPTs being provocation of headache (yes/no) and corresponding headache intensity (NPRS score) were recorded. In the second step, the MPTs were performed and maintained for both the provocation and reduction of the referred pain to the head. The pressure was maintained until the NPRS score of the headache was reduced to <2/10 or after a maximum of 120 seconds. During the application of the MPTs, the NPRS scores were noted every 15 seconds and the applied pressure was registered constantly via the FSR sensors.Sufficient time was left between the two steps so there was no residual pain.p-values were given, and a graphical representation of the numbers. Consequently, no numerical data were available for a sample size calculation. Therefore, we doubled the sample size of the previous study and included 30 participants.A previous study included 15 participants . HoweverData were analyzed with the SPSS version 27 software .Descriptive data and headache characteristics were collected from all patients. The descriptive analysis was also performed for the outcomes of the MPT. The normality of quantitative data was assessed by means of the Kolmogorov–Smirnov test. Parametric tests were used for quantitative data with a normal distribution. Conversely, non-parametric tests were used for qualitative data and quantitative data without normal distribution.To study the reduction of the provoked headache, comparisons of NPRS scores before and after each trial were made via (paired samples T-test or) and across all three trials via a Friedman test. Changes in the time needed to obtain the reduction were analyzed via a Friedman test and consequent Mann–Whitney U tests. p-value < 0.05 was chosen as the level of significance.A 2-tailed A total of 30 patients with migraine, 3 men and 27 women, participated in this study. The characteristics of the patients are summarized in Familiar headaches were provoked in all 30 patients, but not at all sites. The number of locations provoking the familiar headaches ranged from 1 to all 8 locations .During this provocation, mean thumb pressures ranged from 0.81 to 1.2 kg/cm2 across all measurements.The reduction of headaches during three consecutive repetitions of MPT was measured via the headache intensity and the time needed for the reduction to occur.p < 0.001). At the start of each of the three consecutive repetitions, the provoked headache was always slightly less intense . The pain intensity at the end of the three consecutive repetitions did not differ between the three consecutive repetitions . These findings are visually represented in In 23 patients, changes in headache intensity were monitored at sites where the familiar headaches were reproduced. In 21 patients, there was a reduction in headache intensity up to an NPRS of <2/10 at the end of the last repetition. The mean headache intensity decreased during the first repetition from 4.48 points ± 1.82 points at the start to 1.82 points ± 1.55 points at the end; during the second repetition from 4.05 points ± 1.84 points at the start to 1.23 points ± 1.51 points at the end; and during the third repetition from 3.71 points ± 1.99 points at the start to 1.02 points ± 1.23 points at the end. This reduction was significant , the second and the third , and between the first and the third . This is represented visually in With the three repetitions, the decrease in headache intensity occurred faster. A significant difference in time (seconds) was found between the first and second repetitions  of 9% in thumb pressure occurred. An example of a thumb pressure/time graph is presented in This study showed that a manual pressure with a low force can provoke referred pain to the head in patients with migraine in the interictal phase. Sustaining the MPT results in a reduction in the referred head pain. Repeating the MPT results in less intense pain provocation and a faster reduction in referred head pain.2. This is low compared to, e.g., the 4 kg/cm2 reference value in the tender point examination from The American College of Rheumatology’s diagnostic criteria for fibromyalgia [The provocation of referred head pain occurred even with low pressures. The maximum was only 1.78 kg/cmomyalgia . The facomyalgia  It is liOur MPTs are similar to those applied by Watson et al. ,17 and LA recent study found that patients with migraine where head pain could be provoked on palpation were more likely to improve after a physiotherapy intervention . This maProvocation of referred pain to the head was more frequent at higher cervical levels. The high percentage (93%) of provocation at C1 is in line with Watson and Drummond . CompariWe not only provoked the familiar head pain but reduced it by sustaining and repeating the MPTs three times. Similar to the study by Watson and Drummond, a significant reduction of the provoked pain intensity between the start and end of each trial occurred. Since all our participants had neck pain, it was not unlikely that the upper cervical region was already sensitive. Thus, even in an already sensitive starting position, the provoked referred pain can decrease. During the application of the MPTs, we monitored how many seconds it took to obtain this reduction. In the three consecutive trials, this reduction occurred faster. One could argue that during the MPT, the thumb pressure decreased, resulting in a less provocative stimulus. However, we registered a pressure variation of only 9%. Compared to the distribution of normative data from the pincer grip, this is a minimal variation . TherefoThe characteristic headache could be provoked on both sides. This can be explained by the side-shifting character of the migraine. In our sample, about half of the patients did not have dominant headache sides. The provocation of familiar headaches on both sides may imply that hyperexcitability at the level of the spinal dorsal horn of C1-2 is not restricted to one side. The dysfunctional activity of supraspinal descending inhibitory pathways may lead to hyperexcitability at multiple levels on both sides and may explain the occurrence of headaches and altered mechanosensitivity on both sides ,30,31,32During the provocation and reduction of the referred pain to the head, most patients experienced their characteristic headaches as during a migraine attack. Further, the referred pain to the head showed a pattern of referred pain that appeared to be identical to the characteristics of somatic referred pain, as explained by the hyperexcitability model described by Graven-Nielsen . AccordiThis provocation and reduction of referred pain may indicate modulation of central neural transmission of nociception. Sustained MPTs are supposed to affect the nociceptive modulating system by constant and repeated pressure on specific locations in the upper cervical region, and affecting the TCC through afferent pathways. The neurophysiological and behavioral backgrounds of the inhibitory effects of repetitive pain stimuli are described in different models, such as counterirritation and habituation ,34,35. ATo perform all measurements interictally, measuring moments were planned at least two days after the last migraine attack. Within the provided time frame of our study, we assessed the effects of the sustained MPTs in 23 patients. We received no information that the applied techniques provoked migraine.Our study has some limitations: All our patients suffered from migraine, diagnosed according to the ICHD III criteria for migraine by a neurologist or general practitioner, and neck pain. This reflects the characteristics of patients who asked for cervical spine treatment in daily practice . HoweverFuture studies are also needed to verify if the pressure in the upper cervical spine can provoke characteristic headaches in patients with migraine without concomitant neck pain. Although modulation of nociception at the trigeminal cervical complex appears to be involved in the provocation and reduction of referred head pain by MPT, more research is needed to understand and clarify the neurophysiological background of this phenomenon. Since some preventive medications can result in chronic neuromodulation, information on the intake of preventive medication should be collected and reported in future trials.We did not perform any visual, vestibular, or somatosensory measurements in our current study. In future studies, this could be useful to study the role of the vestibular nucleus complex in migraine symptomatology, such as in vestibular migraine . For insDue to the lack of numerical data, no a priori sample size calculation could be performed. Therefore, we opted for a convenience sample of 30 subjects, which is double the number of subjects in the study by Watson et al. . Since wWe only repeated the MPTs three times in one session, and can, consequently, only mention a short-duration effect. It is not yet known if more frequent repetitions of the MPTs in multiple sessions could have longer therapeutic effects. Further research is needed to determine if MPTs can be of value in treatment programs to reduce headaches in patients with migraine. At least one trial is currently ongoing .MPTs provoke referred pain to the head in patients with migraine. Provocation and reduction of referred pain were obtained, indicating modulation of central nociceptive transmission. The neurophysiological mechanism of provocation and the reduction of headaches by sustained MPT needs to be further elucidated.


The WOMAC positively correlated more strongly with PCS (rs = 0.512 p = 0.01) than with PainDETECT (rs = 0.329 p = 0.038). Neither PCS nor PainDETECT correlated with the LOS. Using multivariate regression analysis, a history of chronic pain medication use was found to predict early postoperative complications . There were no differences in the remaining secondary outcomes. Conclusions: Both PCS and PainDETECT were found to be poor predictors of postoperative pain, LOS and other immediate postoperative outcomes following TJA.Background: Both pain catastrophizing and neuropathic pain have been suggested as prospective risk factors for poor postoperative pain outcomes in total joint arthroplasty (TJA). Objective: We hypothesized that pain catastrophizers, as well as patients with pain characterized as neuropathic, would exhibit higher pain scores, higher early complication rates and longer lengths of stay following primary TJA. Methods: A prospective, observational study in a single academic institution included 100 patients with end-stage hip or knee osteoarthritis scheduled for TJA. In pre-surgery, measures of health status, socio-demographics, opioid use, neuropathic pain (PainDETECT), pain catastrophizing (PCS), pain at rest and pain during activity (WOMAC pain items) were collected. The primary outcome measure was the length of stay (LOS) and secondary measures were the discharge destinations, early postoperative complications, readmissions, visual analog scale (VAS) levels and distances walked during the hospital stay. Results: The prevalence of pain catastrophizing (PCS ≥ 30) and neuropathic pain (PainDETECT ≥ 19) was 45% and 20.4%, respectively. Preoperative PCS correlated positively with PainDETECT (rs = 0.501,  Total knee arthroplasty (TKA) and total hip arthroplasty (THA) are two surgical procedures with a steadily increasing demand; the number of each of these procedures is growing substantially each yearSurgical techniques and prostheses have improved in recent years, and outcomes after TKA and THA are constantly improving. However, some patients have a lower postoperative improvement in pain, physical function, and quality of life and report dissatisfaction with the outcomes of their TKA or THA ,2. The iOver the past few decades, the pain literature has extensively focused on the association between cognitive factors and pain processing. Of the cognitive coping measures, pain catastrophizing (the tendency to focus on and magnify pain sensations and feel helpless in the face of pain) has consistently been demonstrated to be highly predictive of higher levels of pain perception, psychological distress, impaired function, analgesic use and overuse, pain-related disability, and health service use in clinical and nonclinical samples  and was Another type of pain known to adversely affect quality of life is neuropathic pain . NeuropaThe primary objective of this prospective study was to examine the relationship between preoperative pain catastrophizing and neuropathic pain and the immediate outcomes following TJA, including postoperative pain, length of hospital stay (LOS), distance walked during the hospital stay, rate of readmission, discharge destination and early postoperative complications. We hypothesize that higher preoperative PCS and neuropathic pain scores will correlate with poor immediate outcomes as described above.A prospective, observational cohort study of patients undergoing primary total hip (THA) and knee arthroplasty (TKA) was conducted at a single academic institution from December 2015 to July 2016. The study protocol was approved by the respective center’s institutional review board and no funding was provided for this study. Patients were recruited from three participating surgeons’  patient populations after being evaluated at the Joint Replacement Center’s outpatient clinics. Candidates for TJA were screened for eligibility, and their informed consent was obtained. The data were collected using a standardized protocol. Preoperative data were collected within the six weeks before the TJA procedure, and follow-up data were collected during the hospital stay, 30 days and 90 days following surgery. The clinical data following discharge were gathered from the patients’ electronic medical records.The inclusion criteria required that the arthroplasty patients be older than 18 years, undergoing unilateral primary THA or TKA and able to comply with instructions. All patients undergoing revision surgery or trauma were excluded. We also excluded patients with a diagnosis of depression or active treatment with an antidepressant or anxiolytic, as well as patients with a musculoskeletal diagnosis that could potentially interfere with their interpretation of pain . Demographics were recorded preoperatively, and a Charlson comorbidity score was determined . The PaiPatients are asked to rate how often they experience each of the 13 thoughts when they are in pain ,15. ThouPainDETECT is a score system developed to discriminate between nociceptive and neuropathic pain and was previously shown to be a reliable discriminative tool to identify knee and hip osteoarthritis patients with a neuropathic pain profile . It usesThe Western Ontario and McMaster University Osteoarthritis Index (WOMAC) was used to assess clinical health status relevant to TKA outcomes. The WOMAC is an instrument that yields a total score and subscale scores for (1) Pain, (2) Stiffness, and (3) Physical Function . Higher The PCS, PainDETECT and WOMAC scores were obtained during the final preoperative visit, approximately 1–2 weeks prior to their scheduled surgery.All THA patients had spinal anesthesia and all TKA patients had spinal anesthesia with an adductor nerve block. All TJA patients received preoperative celecoxib , gabapentin and acetaminophen (1000 mg) as is standard care as part of the hospital’s orthopedics-anesthesia joint replacement center. Post-operatively, patients were placed on standing acetaminophen, gabapentin/pregabalin and celecoxib if not contraindicated, along with PRN oxycodone (2.5/5/10 mg) based on their VAS.All surgeries were performed by three high-volume arthroplasty surgeons at a single center. The surgery was performed under spinal anesthesia without the use of intrathecal narcotics. TKA procedures all used a medial parapatellar approach, using a cruciate-sacrificing total knee in all patients . A standard extramedullary guide was used for the proximal tibia cut, whereas intramedullary guides were used to facilitate the femoral cuts. The surgical approach for THA procedures was a posterior approach, which was used in all 40 cases. All THA procedures used a cementless construct ; 13 DePuy Pinnacle acetabular component and Summit stem ; and 9 Stryker Tritanium acetabular component and Stryker Accolade II cementless femoral stem ).The two primary outcome measures were the length of hospital stay and discharge destination. Secondary outcome measures included patient-reported postoperative pain at several time points as measured on a 0–10 visual analog scale (VAS), distance walked on POD1, maximal distance walked before discharge, early postoperative complications, and 30 and 90-day readmission rates. The primary pain outcome time point was postoperative VAS at 4 weeks.The sample size was chosen to be 100 patients based on the clinical volume of the study and the surgeons’ expectation of a 10% follow-up loss. A post-hoc analysis showed that 90 patients would more than adequately power a comparison between PCS subgroups, assuming a 2:1 ratio of catastrophizers to non-catastrophizers with an alpha of 0.05 to 80% power. Continuous variables were analyzed using a paired Student’s t-test after testing for normality and equal variance. Categorical analysis was conducted with chi-square and Fisher’s exact test where appropriate. A P value of less than or equal to 0.05 was treated as statistically significant.p < 0.10 after univariate analysis was included in a multivariate regression model. All analyses were performed using SPSS . A complete case analysis was performed to account for missing data.Multivariable regression analyses were implemented to investigate the possible predictors for the LOS, discharge destination, and early postoperative complications. Variables in the regression analysis included BMI, gender, age, type of surgery (THA/TKA), Charlson comorbidity, preoperative WOMAC, preoperative PCS and PainDETECT scores, postoperative VAS scores and distances walked on postoperative day (POD) 1, use of chronic pain medications and maximal distance walked before discharge. Potential predictive factors that reached a level of significance were p = 0.27). Likewise, the mean PainDETECT score did not differ significantly between THA and TKA patients and was 10.9 ± 7.7 and 11.8 ± 8.6, respectively (p = 0.6).During the study period, 100 patients agreed to participate in the study and completed the relevant scores following their initial evaluation. Complete clinical data were available for 93 patients who underwent elective TJAs (40 THAs and 53 TKAs). The sample’s mean age was 67 years (SD: 10.4) and 53% were men. The prevalence of pain catastrophizing (PCS ≥ 30) and neuropathic pain (PainDETECT ≥ 19) was 45% and 20.4%, respectively. The mean PCS did not differ between THA and TKA patients and was 24.3 ± 16 and 28.2 ± 17.6, respectively (p < 0.001), and the preoperative (day 0) VAS was significantly higher in pain catastrophizers . However, the VAS at POD1, POD2 and 4 weeks did not significantly differ between groups. Similarly, the distance walked on POD1, maximal distance walked during the hospital stay, the discharge destination, early postoperative complications and readmissions did not differ significantly between the groups. The LOS was longer for pain catastrophizers , although this difference was not statistically significant (p = 0.23).Pain catastrophizers had similar demographics and clinical characteristics to non-catastrophizers , except p < 0.001), and the preoperative VAS was 7.58 ± 2.2 compared to 4.76 ± 2.7 (p < 0.001), respectively.After analyzing the results for neuropathic pain using the threshold value of 19 on the PainDETECT scale, we found statistically significant differences in the preoperative WOMAC and preoperative (day 0) VAS between the two groups . The prep = 0.006). The LOS, maximal distance walked on POD1, early postoperative complications and readmission rates, and mean VAS on POD1 and POD2 did not vary significantly between the two groups. The maximal distance walked during the hospital stay was less in patients with neuropathic pain , although this was not significant statistically (p = 0.058). The existence of neuropathic pain did affect the discharge destination, with a significantly higher proportion of patients necessitating referral to rehabilitation than patients less likely to have neuropathic pain .The postoperative VAS at 4 weeks following the index procedure was significantly higher in patients with neuropathic pain compared to patients without such pain , bivariate regression, model fit p = 0.011).Another model  looking p < 0.001, Odds ratio −0.082 95% CI (−0.125 to −0.039)). PCS and PainDETECT were positively correlated with an rs = 0.501 (p = 0.001) on Spearman’s test. WOMAC was positively correlated more strongly with PCS (rs = 0.512 p = 0.01) than with PainDETECT (rs = 0.329 p = 0.038) on Spearman’s test.An ordinal regression analysis  was usedDespite the advances in surgical techniques, regional anesthesia, improved postoperative pain management with multimodal and preemptive analgesia, along with rapid rehabilitation protocols, there is still a significant proportion of dissatisfied patients despite undergoing a well-performed TJA procedure. Most studies dealing with patient dissatisfaction after TJA report either combined outcomes for patients undergoing both THA and TKA or report on outcomes specific to TKA ,2,18. InThe ability to pre-operatively identify patients who are less likely to improve following their surgery may be critical for optimal management, patient selection and well-organized service delivery. These essential data could act as an adjunct to clinical and radiographic data for surgeons and healthcare providers who refer patients for surgery. In addition, these data could help surgeons to counsel patients regarding what they may expect in terms of pain and function following surgery and could help the patient to set realistic expectations. Although the literature for psychological interventions  in conjunction with TKA and THA is still in its infancy , identifOur findings suggest that a notable proportion of end-stage knee and hip osteoarthritis patients who are considered potential candidates for arthroplasty procedures have pain with potential neuropathic features or catastrophizing pain. This finding is in line with a recent study by Power et al. who found an incidence of neuropathic pain reaching 19.4% in women with end-stage OA . They alThe LOS In the hospital for TJA has been declining in recent decades . PreoperPainDETECT differentiates between nociceptive and neuropathic pain and was previously found to be a reliable discriminative tool to identify knee and hip osteoarthritis patients with a neuropathic pain profile . An impoHowever, neither PainDETECT nor PCS remained significant predictors of discharge destination in a multivariate analysis.We acknowledge several limitations of the present study. First, we did not include evaluations of baseline mental health, which has been previously shown to affect various aspects of functional recovery after TJA . Second,In this prospective cohort study, we sought to determine whether PainDETECT and PCS could be used as predictors of postoperative pain and immediate outcomes following TJA. PCS was found to be of limited usefulness in predicting the immediate postoperative pain and outcomes following TJA. However, our findings suggest that a subset of patients with a substantial preoperative neuropathic pain component, detected with a PainDETECT equivalent of 19 or greater have higher pain levels at 4 weeks and are significantly more likely to be discharged to a skilled nursing facility.


This article examines the biological, genetic, and environmental aspects of fibromyalgia that may have an impact on its pathogenesis. Symptoms of fibromyalgia may be related to aberrations in the endogenous inhibition of pain as well as changes in the central processing of sensory input. Genetic research has revealed familial aggregation of fibromyalgia and other related disorders like major depressive disorder. Dysfunctional pain processing may also be influenced by exposure to physical or psychological stressors, abnormal biologic reactions in the autonomic nervous system, and neuroendocrine responses. With more research the pathophysiology of fibromyalgia will be better understood, leading to more logical and focused treatment options for fibromyalgia patients. The first description of fibromyalgia syndrome (FMS) is found in the nineteenth century. The term “fibrositis”, which Gowers first used in 1904, was in use until the 1970s and 1980s, when a central nervous system-related etiology was proposed . Then, iFMS is one of the most prevalent disorders that affects the muscles and is characterized by pain, stiffness, and soreness in the muscles, tendons, and joints. Fibromyalgia is in a family of disorders termed the affective spectrum disorders (ASD). ASDs frequently co-occur in both individuals and families and share physiologic abnormalities along with genetic risk factors that may be central to their etiology . The mosFMS commonly manifests in young or middle-aged females as chronic widespread pain, stiffness, fatigue, disrupted unrefreshing sleep, and cognitive difficulties. FMS often coexists with a number of other unexplained symptoms, anxiety and/or depression, and functional impairment of daily living activities. Fibromyalgia typically causes broad pain that affects both sides of the body with numerous “tender points”. Despite having incapacitating physical pain, FMS is not accompanied by tissue inflammation, tissue damage, or deformity .The volume and quality of research behind the pathophysiology of fibromyalgia continues to grow. However, there are still healthcare providers that believe that FMS is a mere construct of malingering or attention seeking. Some providers also think that FMS is a purely psychological condition compared to a physical disease. This manuscript will detail abundant research to contradict these outdated thought processes. Clinicians should be conversant with the symptoms and signs of fibromyalgia so they can make a timely diagnosis. In the US, the prevalence rate ranges from 6% to 15%, with women experiencing a five times higher frequency than men. The rate of new diagnoses in rheumatology clinics ranges from 10% to 20% compared to 2.1% to 5.7% in non-specialized settings . The symThe exact pathophysiological mechanism behind fibromyalgia remains undefined, though it is likely multifactorial in origin including abnormal cortical processing, reductions in inhibitory pain modulatory mechanisms and molecular changes to the pain pathway. What is clear however is that patients with fibromyalgia have increased sensitivity to a variety of stimuli, including mechanical and ischemic pressure, heat, and cold. Normally the source of sensory input (such as a nerve lesion) is discernible in both animal and human models of neuropathic pain, and pain sensitivity is decreased when the source is removed. It is unknown where fibromyalgia patients receive their unique sensory information ,10. BecaStudies have shown that compared to healthy controls, the stimulus intensity required to elicit a pain response in fibromyalgia patients is almost 50% lower ,11. ThisA systematic review in 2014 conducted by Cagnie et al. found 22 studies utilizing neuroimaging techniques to evaluate brain activity in patients with FMS. Within their review 8 articles utilized Voxel-based morphometry (VBM) to evaluate brain volume. They collectively found in those with FMS and moderate central sensitization VBM demonstrated physical reductions in gray matter mostly seen in the anterior cingulate cortex and prefrontal cortex, though global gray matter remained unchanged . There dThe ACC, periaqueductal grey and rostral ventromedial medulla appear to be large components of the descending pain processing pathway . The desWhen incoming A-delta and C-fibers synapse in the dorsal horn they normally release glutamate and substance P which initiates the ascending pain signal through the spinothalamic tract. Opioids normally bind to receptors most commonly mu-opioid receptor (MOR) located in neurons that synapse at this junction. At the spinal cord Opioids act on interneurons that synapse in the dorsal horn both pre and post-synaptically. When activated opioid receptors hyperpolarize ascending fibers and inhibit the release of glutamate and substance P presynaptically. This ultimately reduces the amount of pain signals reaching the brain. In addition, when the pathway is initiated Gaba is reduced in the periaquedutal gray which results in an increase in serotonergic and noradrenergic transmission in the ventromedial medulla thus reducing pain perception . It is hOther proposed mechanisms behind the development of hyperalgesia and allodynia involve microglial cells and the TLR4 receptor. Microglial cells are CNS macrophages or the main defense system of the brain and spinal cord. Normally in a quiescent state, they can become activated by triggers including cell death, peripheral inflammation, and infection. Once activated they undergo morphological changes and release numerous cytokines and other proinflammatory mediators . TLR4 isOther secondary mechanisms that could result in the symptoms experienced by those with FMS include reductions in neurotransmitters, alterations in hormone levels, genetics, and environmental triggers. Serotonin is especially important for regulating mood, depression, and anxiety. Those with FMS have been shown to have reductions in these neurotransmitters when compared to healthy controls. The alterations seen in the pain modulation pathway could account for these reductions in blood serum serotonin levels by reducing Gaba’s effects at the periaqueductal grey . Physiological stress can lead to symptoms such as fatigue, decreased work capacity and insomnia. Numerous studies have looked at anomalies of the hypothalamic-pituitary-adrenal (HPA) axis in relation to FMS. Collectively they have demonstrated a hyperactivity of the stress response, albeit the precise nature of these changes has not been clarified. For example, there was a significant relationship between cortisol levels and pain at awakening and an hour after awakening in FMS patients as compared to controls ,24. A sePatients with fibromyalgia frequently demonstrate abnormalities in the autonomic nervous system’s (ANS). In addition to reduced microcirculatory responses to aural stimulation, patients with fibromyalgia also displayed attenuated vasoconstriction responses to cold pressor activities . ThroughInnapropriate immune responses and specficially IgG immuoglobulin has demonstrated the ability to cause pain without obvious inflammation or nerve damage . This imSeveral functional neuroimaging techniques and studies demonstrate quantifiable changes in patients with FMS. One of the first functional neuroimaging techniques to be used to study FMS was the Single-photon-emission computed tomography (SPEC). This method provides a measurement of regional cerebral blood flow (rCBF), which reflects neural activity, throughout the brain following the injection of a radioactive tracer. There seems to be interest in the thalamus. Adigüzel et al. also suggested that the thalamus and basal ganglia are involved. After receiving amitriptyline treatment, he showed increases in rCBF in these areas . KwiatekSimilar to SPECT, positron emission tomography (PET) uses radioactive tracers, but it has higher temporal and spatial resolution. An example of PET utilization in FMS was performed by Wik et al. when he compared rCBF in 8 patients and controls at rest. Patients had greater rCBF in the retrosplenial cortex on both sides compared to controls, but less rCBF in the left frontal, temporal, parietal, and occipital cortices. This may indicate heightened sensitivity to subnoxious somatosensory signaling and an impairment of the typical cognitive processing of pain in fibromyalgia patients . PositroHarris et al. used radiolabeled opioid carfentanil in attempts to explain the endogenous opioid system’s apparent paradoxical hyperactivity. He demonstrated that fibromyalgia patients had significantly lower overall mu-opioid receptor binding potential. The areas most significantly involved were the left amygdale, right and left nucleus accumbens, and a tendency toward reduction was also observed in the right dorsal anterior cingulate cortex. These results might be the result of receptor downregulation and occupancy by endogenous opioids released in response to persistent pain . Functional magnetic resonance imaging (fMRI), which has higher temporal and spatial resolution than SPECT or PET, is more accurate in both of these areas. In the first fibromyalgia fMRI study fMRI was performed while painful stimulation was applied to 16 patients and 16 controls. First, the stimulation pressure was the same for both groups, and then the intensity of stimulation for the controls was increased to produce a subjective level of pain comparable to that felt by the patients. Only when painful stimulation was present as a second condition did neural activation patterns resemble one another . These rThe descending inhibitory pain system’s function appears to be better understood through the use of functional magnetic resonance imaging. In a study by Jensen et al. fMRI was performed while individually calibrated painful pressure was applied to 16 patients and 16 controls. Affective or attentional brain regions, as well as those with sensory connections to the stimulated body area, did not exhibit any differences in activity. The rostral anterior cingulate cortex, a crucial part of the descending pain regulating system, interestingly displayed a diminished response to pain in these individuals . The funSmall fiber neuropathy (SFN) is a disease affecting the A-delta or C-fibers of the peripheral nervous system with a proximal, distal, or diffuse distriubtion. SFN typically manifests with pain, sensory disturbances, or autonomic dysfunction. Most SFNs are diagnosed with typical clinical features and a reduced intra-epidermal enrve fiber density via skin biopsy. SFN is brought on by a defect in glucose metabolism, immune dysregulation, gluten sensitivity and celiac disease, monoclonal gammopathy, vitamin deficiency, exposure to toxins, cancer, and unexplained causes ,43. Fibromylagia syndrom lacks clear defined abnormalities which hinders definitive testing, disease-modifying therapies, and the discovery of causes. One study performed by Oaklander et al. compared 27 FMS patients and 30 controls and found 41% of skin biopsies from subjects with fibromyalgia vs. 3% of biopsies from control subjects were diagnostic for SFPN sugesting that some patients with chronic pain labeled as fibromyalgia have unrecognized or concurrent SFPN . A similUceyler et al. examined the function and morphology of small nerve fibers in 25 fibromyalgia syndrome patients in this case–control study. Comprehensive neurological and neurophysiological evaluations were performed on the patients. Skin punch biopsies of the lower leg and upper thigh were used to measure intraepidermal nerve fiber density and regenerating intraepidermal nerve fibers, as well as to examine small fiber function using quantitative sensory testing and pain-related evoked potentials. These results were compared with a monopolar depression group and a separte healthy control group matched for age and gender. This study was the first to quantitatively show a reduction in intraepidermal innervation and regneration sparing myelinated nerve fibers along with an elevated cold and warm detection threshold indiciating functional impairment of A-delta and C-fibers . A meta-An extensive review by Meydan et al. covered the connection between non-coding RNA regulators and diabetic polyneuropathy and their possible connection to FMS. They elaborate on several candidate non-coding RNAs which regulate inflammation, pain-provoking, and metabolic syndrome pathways. Numerous non-coding RNAs were detailed. Although the connection may seem obscure, the authors voiced the importance of understanding the biological pathways involved in polyneuropathies . The role of genetics and FMS is not well defined however it is suggested that exposure of a genetically predisposed individual to a host of environmental stressors is presumed to lead to the development of FMS. FMS affects females more often then males in a 2:1 ratio . FMS is Hundreds of pain-regulated genes have been found, including those for catechol-O-methyltransferase, mu-opioid receptors, GTP cyclohydrolase 1, voltage-gated sodium channels, and GABA-nergic pathway proteins . SeveralA novel study evaluating genes in Smith et al. conducted the first large scale comparative genomic study on hundreds of individuals with FMS. They evaluated 496 patients with FMS paired with 348 pain free controls was performed in 2012. The Pain Research Panel gene array chip, which tests variations characterizing more than 350 genes known to be implicated in the biologic processes relevant to nociception, inflammation, and mood, was specifically used for genotyping. They found statistically significant diffefrences in three genes including GABRB3, TAAR1 and GBP1 when compared to controls . AlteratMC1R variants was associated with increased opioid analgesia [In a similar study of a Spanish population, there was a connection between FMS and the “high pain sensitivity” haplotype (ACCG) of the COMT gene. They also found that Inactivating the nalgesia . UnderstIn addition to a genetic predisposition, the environment may play a role in FMS development. Particularly, it has been demonstrated that early life experiences, such as physical trauma and psychosocial stressors. These early insults can affect gene expression and thereby influence the development of FMS ,61. ExpeIt has been shown that there is a bidirectional temporal association between depression and FMS, increasing the likelihood that the two will co-occur. The medial orbitofrontal cortex and cerebellum have shown altered gray and white matter morphometry in FMS patients, and the gray matter volume has been linked to the severity of depression and hyperalgesia . It is hLoggia and colleagues looked at the hypothesis of phycological stressors and their effect on pain scores for patients with FMS compared to healthy controls. They utilized unpleasant odors followed by application of a heat stimulus and measured the perceived unpleasantness. Their findings suggested that psychological and psychosocial stressors disproportionately worsened the perception of pain and discomfort in patients with FMS compared to the controls . A retrospective case–control study by Al-Allaf et al. gave a questionnaire to 288 individuals  to assess the prevalence of physical trauma prior to the onset of their respective symptoms. They found 53 (39%) of the FMS patients conveyed significant physical trauma within the six months preceding their FMS symptoms compared to 36 (24%) in the hospital control group . Widespread pain has been associated with numerous vitamin deficiencies, however, there is no clear efficacy in replacement therapies. Chronic pain and fibromyalgia have both been linked to thiamine (vitamin B1) deficiency. One case series took female patients with fibromyalgia and gave them high-dose oral thiamine (600–1800 mg/day) from which they experienced significant symptomatic improvements after 20 days of therapy . AlthougFibromyalgia patients frequently experience disordered sleeping, such as nonrestorative sleep, insomnia, early morning awakenings, and poor sleep quality. Patients with fibromyalgia also reported that their pain symptoms got worse after poor sleep quality . One metThe pathophysiology of fibromyalgia is influenced by abnormal pain signaling, genetic predispositions, abnormal neuroendocrine and autonomic system activity, environmental triggers, and sleep disturbances. The pathogenesis of fibromyalgia is not well understood, and the diagnosis remains clinical in practice. The enhanced pain sensitivity and persistence of widespread pain in people with fibromyalgia may be caused by changes in the central processing of sensory input and deficiencies in endogenous pain inhibition. Evidence of small fiber neuropathies in patients diagnosed with FMS indicate a connection between the two. Evaluation of SFN in FMS may enable better FMS classification and patient care direction resulting in better use of resources and outcomes. The recent recognition of SFN in a significant subgroup of patients with FMS reinforces the dysautonomia-neuropathic hypothesis and validates fibromyalgia pain. Oxidative stress, and maladaptive immune responses may have a significant impact on the severity of FMS. Although numerous genes abnormalities have been identified in FMS their direct correlation or significance is yet to be seen. These differences could suggest several subgroups if not different disease processes under the FMS diagnosis. FMS is apart of the affective spectrum disorders (ASD) which aligns with FMS’s pathogenesis. The development and validation of effective pharmacologic and behavioral treatments for these disorders will be aided by advances in our understanding of the pathophysiology of fibromyalgia and other types of ASDs.


Pain plays an important role in chronic ankle instability (CAI), and prolonged pain may be associated with ankle dysfunction and abnormal neuroplasticity.To investigate the differences in resting-state functional connectivity among the pain-related brain regions and the ankle motor-related brain regions between healthy controls and patients with CAI, and explore the relationship between patients' motor function and pain.A cross-database, cross-sectional study.This study included a UK Biobank dataset of 28 patients with ankle pain and 109 healthy controls and a validation dataset of 15 patients with CAI and 15 healthy controls. All participants underwent resting-state functional magnetic resonance imaging scanning, and the functional connectivity (FC) among the pain-related brain regions and the ankle motor-related brain regions were calculated and compared between groups. The correlations between the potentially different functional connectivity and the clinical questionnaires were also explored in patients with CAI.p = 0.005) and clinical validation dataset (p = 0.049), which was also significantly correlated with Tegner scores  in patients with CAI.The functional connection between the cingulate motor area and insula significantly differed between groups in both the UK Biobank (A reduced functional connection between the cingulate motor area and the insula was present in patients with CAI, which was also directly correlated with reduction in the level of patient physical activity. Lateral ankle sprain is one of the most common sports injuries , and further validation in patients with CAI enrolled from a sports medicine clinic. We hypothesized that there was an abnormal functional connection between the pain-brain region and the ankle-motor brain region in patients with CAI, which might also correlate with the clinical outcomes of the patients.The study was designed with two parts of cross-sectional analyses to explore the pain symptoms in patients with CAI. Ethical approval was granted for the UK Biobank data usage, and the present research was prospectively registered online (No. 62721). Validation for using the dataset and all study protocols was approved by the Institutional Review Board Huashan Hospital, Fudan University (No. 2016M-008). Informed consent was obtained, and the rights of all subjects were protected.http://www.ukbiobank.ac.uk/). Participants were included if they met the diagnosis based on the ICD10 disease diagnostic classification codes M25.57 Pain in joint (Ankle and foot), and M79.67 Pain in limb (Ankle and foot). Exclusion criteria included patients with painful symptoms due to other factors, joint instability beyond the ankle, no brain imaging, not right-handed, lack of demographic data, and other excluded diseases. Brain images were acquired after the diagnosis of their disease. The diagnosis code of chronic ankle pain and the excluded codes can be found in supplemental digital content  history of at least one significant ankle sprain, which occurred at least 12 months prior to the study, resulting in pain, swelling, and at least one interrupted day of normal physical activity; and (2) a score of < 24 on the Cumberland Ankle Instability Tool (CAIT) questionnaire . For the validation dataset, the Tegner Activity Rating Scale score and American Orthopedic Foot and Ankle Society Score (AOFAS) were measured prior to MRI scanning. The validation dataset MRI scanning was performed on a 7T scanner  equipped with a 1Tx/32Rx head coil . Subjects were reminded to lie still at rest, looking at a cross reflected on a projector without thinking about anything. First, a MPRAGE sequence was used to acquire high resolution 3D T1-weighted images : TR = 8.1 ms, TE = 3.7 ms; field of view = 256 × 256 mm; matrix = 256 × 256; inplane resolution = 1 × 1 mm; slice thickness = 1 mm; number of slices = 180. Second, fMRI data of resting-state were acquired with the following parameters: TR = 650 ms; TE = 30 ms; flip angle = 53°; field of view = 200 × 200 mm; acquisition matrix = 68 × 66; SENSE factor = 1.5; reconstructed in-plane resolution = 2.5 × 2.5; slice thickness = 3.5 mm; number of slices = 40; multi-band factor = 4. In total, 500 frames of data were collected, and the total time for the resting-state fMRI sessions was approximately 5.5 min.MRI data acquisition protocols of the UK Biobank are presented online  software of Matlab2014a was used, including slice timing and realign, normalization to Montreal Neurological Institute (MNI) template space (resampled to 2 mm isotropic), and smoothing . Participants with movement outlier were confirmed using mean frame-wise displacement (FD) >0.2 mm, which would be excluded from the analysis.www.neurosyntsh.org) . The volume of the ROI spheres was used to represent the total voxel size of this brain region, and the time series of BOLD signal under this ROI was extracted. The FCs calculated by the Fisher-z transformed Pearson correlation coefficients between the ankle motor-related and pain-related ROIs to identify neural differences in brain connectivity between ankle motor control and pain processing , supplementary motor area (SMA-proper), cingulate motor area (CMA), premotor cortex (PMC), secondary sensory cortex (SII), basal ganglia, and cerebellum . The thalamus was excluded because the coordinates of bilateral brain regions were not available  in patients with CAI, with the absolute values of correlation coefficients (r) classified as weak (0–0.4), moderate (0.4–0.7), or strong (0.7–1.0).The remainder of the statistical analyses were performed by Graphpad Prism Version 9.0. Data normality was tested using the Kolmogorov-Smirnov test. Chi2 tests, Mann Whitney U-tests, and independent two-sample p > 0.05).A total of 502,461 participants were screened from the UK Biobank Resource, of which 463,486 were removed because they had no brain imaging, 4,274 were removed because they were not right-handed, 8,753 were excluded for disease, 879 were removed because they had no demographic data. The remaining 25,069 participants were screened based on the ICD10 disease diagnostic classification. After the exclusion of major illnesses/ traumas, joint instability beyond the ankle, inclusion of ankle instability and selecting fMRI data quality, 28 participants were included in the chronic ankle pain group and 109 in the healthy control group for part 1, the detailed ICD10 codes and diagnosis are presented in p > 0.05). The CAI patients had significantly worse sports level (Tegner) and ankle function (AOFAS) (p < 0.001) when compared with healthy controls.In part 2, 16 CAI patients and 18 healthy controls were recruited, while four subjects were excluded due to excessive head motion, leaving 15 in each of the patient groups for further data analysis. The flowchart of participant selection in part 2 is also presented in p = 0.005), CMA and Putamen (p = 0.004), CMA and Rolandic Operculum (p = 0.004), SII and Putamen (p = 0.009). These ROIs were used in the validation study in part 2; only the CMA and Insula persisted in patients with CAI (p = 0.049) , as shown in r = 0.2738, p = 0.3234).A Heatmap of the t value of the between-group comparisons of the FCs between 9 ROIs of ankle activity and 159 ROIs of pain in the global brain is shown in = 0.049) . The FC The most important finding of this study was that FC between CMA and insula was reduced in patients with CAI and the degree of connectivity was positively correlated with impaired motor function. To our knowledge, this study is the first fMRI study to evaluate the neuroplasticity of pain processing and motor control in patients with CAI.The insula, a region involved in pain processing, is usually divided into partial subregions based on anatomy and connectivity  for the publication of any potentially identifiable images or data included in this article.YW carried out the study design, data collection, quality rating, statistical analysis, and manuscript writing. XXue carried out the study design, data collection, quality rating, statistical analysis, and manuscript reviewing. QL carried out the study design, data collection, quality rating, and manuscript reviewing. XXu carried out the study design and manuscript reviewing. YH carried out the study design, supervision of the literature search, data collection and quality rating, and manuscript reviewing. All authors have read, approved the final version of the manuscript, and agree with the order of presentation of the authors.


Common and frequent as acute pain is, it is often underestimated and undertreated in older people with dementia in nursing homes and inadequate pain management remains an issue.The study is designed to be a randomized, sham-controlled trial and is underway in nursing homes located in China. A total of 206 dementia patients are being recruited from nursing homes in Yinchuan, China. They are randomly allocated to an intervention or a controlled group in a 1:1 ratio. The intervention group will be treated with true APP therapy, while the other group will receive APP at sham point stimulation therapy. The patients will be assessed at baseline (T0), at 5 min during performing the intervention (T1), and at 5 min after completion of the intervention (T2). The primary outcome is the level of pain relief at T1 and T2. Physiological parameters, side effects and additional use of analgesics during the procedure, satisfaction from caregivers, and acceptance of patients are evaluated as secondary outcomes.The results of this study are expected to verify the analgesic effect of APP for acute pain in patients with mild dementia in nursing homes. It has the potential to prompt APP therapy to be implemented widely in dementia patients with acute pain in nursing homes.ChiCTR2100047932. Registered on 27 June 2021. Currently, patient recruitment is ongoing. Recruitment is expected to take place from December 2020 to December 2021.Chinese Clinical Trial Registry  For residents in the nursing home, dementia and pain have aroused great public concern and a lot of discussions in the global medical policy, research and education fields for many years . Pain isAcute pain is common and frequent, but it is often underestimated and undertreated in elderly people with dementia in nursing homes. Therefore, poor pain management in this population remains a problem . ComplicTherefore, it is important to seek non-drug therapies for controlling dementia patients with acute pain. Traditional Chinese medicine (TCM) theory holds that non-pharmacological methods, such as acupoint acupressure, acupuncture, massage, psychotherapy, and electroshock therapy, play a positive and important role in the treatment of acute pain. Non-pharmacological interventions have become the priority for patients with acute pain due to fewer side effects, non-invasive, and better safety . AccordiThis study is a multi-center and single-blind, randomized, sham-controlled clinical trial. It aims to compare and analyze the one-time analgesic effect between the intervention group and the sham-controlled group Fig. , Table 1This randomized controlled trial is being conducted at three nursing homes in Yinchuan, China. These institutions are urban and public in the region, with approximately 2000 permanent residents.All 206 patients who met the inclusion and exclusion criteria are being recruited from the three nursing homes. Recruitment is expected to take place from December 2020 to December 2021. The recruits with informed consent before entering research will be randomly allocated to an intervention or a sham-controlled group in a 1:1 ratio. Furthermore, it is feasible to have enough patients to meet the target sample size in three nursing homes. The inclusion criteria include the following: (1) aged 60 or above with speaking Chinese, (2) dementia was diagnosed by the Diagnostic and Statistical Manual of Mental Disorders (DMS-V) criteria [Trials. Prior to the protocol, researchers will describe the method and duration of the intervention and the potential risk involved to the participants in detail [The intervention group will be planned to receive auricular-plaster therapy, with one piece of Semen Vaccariae®  attaching to the center of a piece of medical adhesive tape (6 mm × 6 mm). This study initially selected four active acupoints including shenmen (TF4), subcortex (AT4), adrenal (TG2P), and two auricular points corresponding to pain sites based on the Nogier auricular point diagram for managing pain . A resean detail . In the n detail .Sequence numbers of the patients with dementia will be generated by a computer-produced random list, which is performed by a statistical expert from Ningxia Medical University. But she is independent of the trial. The randomization schedule in a sealed envelope will be kept in a dedicated research office. There are many strategies to ensure the concealment of data distribution and minimize selection bias as well as create a double-blind environment. It will be blind to the randomized lists for participants  except the investigator responsible for conducting the intervention . The proEach patient’s demographic data  will be recorded by a self-designed questionnaire. Other information including physiological parameters , sore spot, pain score, adverse effects, the use of analgesics in the intervention, satisfaction of caregivers, and acceptance of patients, will be more rigorously documented. The MoCA is made to identify the severity of dementia among the patient. And locality of the pain will be shown clearly according to the Brief Pain Inventory Chinese version (BPI-C) . The FPSThe level of pain relief at T1 and T2 will be considered as the primary outcome. It is accurately recorded by a researcher in charge of recording on the basis of the FPS-R.outcome measures will consist of physiological parameters, any adverse reactions observed, satisfaction from caregivers, acceptance of patients, and additional use of analgesics during the intervention. The duration of the intervention will also be included in the secondary outcomes.Secondary α = 0.05, two-tail) and a 90% power (β = 0.10), the sample size of the study scheme was calculated by the statistical expert, which was 86 patients in each group. According to our study design and considering the particularity of this research subject (they are less likely to complete the entire experiment), we assume a 20% drop-out rate. The total sample size of 206 cases (per group was 103 cases) is required to reduce the underpower of the study.After obtaining the ethical approval of our study protocol, a preliminary experiment with a sample size of 30 was conducted in Nursing Home, Yinchuan, in January 2020. The results of the pilot study indicated that the FPS-R score of the control group and the intervention group was 5.97 ± 1.81 and 4.79 ± 1.96, respectively. We have consulted a statistician from the School of Medical Statistics and Epidemiology at Ningxia Medical University, who finished the randomization list of the recruits. With a type 1 error rate of 0.05  database, which is password protected . A separP value < 0.05 will be considered to be statistical significance. Therefore, subjects’ personal information, such as nationality, education, and medication history, will be used to consider whether to perform statistical analysis in subgroups.On the basis of the intention-to-treat (ITT) principle, SPSS version 22.0  will be recommended to run the data statistical analysis on both the real APP group and the sham APP group. Information on all patients in the random list should be included in the final analysis. If data is missing, the missing data imputation should be used to analyze the validity of the statistical analysis. The statistical description of categorical variables (the population demographic data) will be mainly presented by the relative number . The continuous variables  will be compared by analysis of variance (ANOVA) or the Kruskal-Wallis test (or chi-squared tests) for the two groups. Other categorical variables  will be described by the nonparametric test (Wilcoxon’s rank sum test). A two-sided Every patient is endowed with his or her basic and undeniable right of eliminating pain. Meanwhile, within the scope of our expertise, medical professionals have an obligation to consider giving patients reasonable pain management , but manWhat we know is that our study protocol is the first randomized controlled trial to identify the analgesic effectiveness of APP for acute pain in patients with dementia in nursing homes, China. It has the potential to develop preliminary evidence-based guidance for relieving pain in patients with dementia in nursing homes if the analgesic efficacy of APP appears beneficial and safe. We hope that the results generated by the trial will be published in peer-reviewed journals.One of the biggest limitations of this study is that it only evaluates the one-time efficacy of the intervention. But this trial really only evaluates the analgesic effect of APP therapy for dementia patients with acute pain in nursing homes. We also plan to move forward with the study after certifying the analgesic effect of APP therapy.


Research suggests that attendance by physical therapists at continuing education (CE) targeting the management of low back pain (LBP) and neck pain does not result in positive impacts on clinical outcomes. The aim of this study was to determine if therapists attending a self-paced 3-hour online Pain Neuroscience Education (PNE) program was associated with any observed changes to patient outcomes and also clinical practice.Participants were 25 different physical therapists who treated 3,705 patients with low back pain (LBP) or neck pain before and after they had completed an online PNE CE course. Change in outcomes measures of pain and disability at discharge were compared for the patients treated before and after the therapist training. Clinical practice patterns of the therapists, including total treatment visits, duration of care, total units billed, average units billed per visit, percentage of ‘active’ billing units and percentage of ‘active and manual’ billing units, were also compared for the patient care episodes before and after the therapist training.There was no significant difference for change in pain scores at discharge for patients treated after therapist CE training compared to those treated before regardless of the condition (LBP or neck pain). However, patients with LBP who were treated after therapist CE training did report greater improvement in their disability scores. Also after CE training, for each episode of care, therapists tended to use less total visits, billed fewer units per visit, and billed a greater percentage of more ‘active’ and ‘active and manual’ billing units.Attending an online 3-hour CE course on PNE resulted in improved disability scores for patients with LBP, but not for those with neck pain. Changes in clinical behavior by the therapists included using less visits, billing fewer total units, and shifting to more active and manual therapy interventions. Further prospective studies with control groups should investigate the effect of therapist CE on patient outcomes and clinical practice. The ultimate aim of clinical research is to better the lives of the end-user, the patient . With neOnce a new intervention or approach is developed and validated, clinical researchers have to find a way to disseminate their work to front-line clinicians, with the intent to impact the patient. To do so, post-professional continuing education (CE) is often used . In mostIn musculoskeletal care, an educational approach known as pain neuroscience education (PNE) has emerged as a means to teach people more about the underlying biology and physiology of their pain experience –20. The The aims of this study were two-fold. First, to determine if therapists attending a self-paced 3-hour online PNE program was associated with any observed changes to their clinical practice. To achieve this, we compared their clinical outcomes for patients with LBP and neck pain prior to the PNE with their clinical outcomes for patients with LBP and neck pain after completing the PNE program. Our second aim was to determine if those therapists exhibited more efficient treatment, employed more active treatment approaches, and displayed more cost-effective billing/care patterns after completing the 3-hour online PNE program.This study was a retrospective cohort study using de-identified episodic patient data provided by a large national outpatient PT provider (BLINDED). All data (patient and therapist) was fully anonymized prior to access and therefore, the Institutional Review Board obtained from (BLINDED) University and ethics committee from (BLINDED) PT waived the requirement for informed consent. Only patient episodes for whom the primary treating physical therapist completed a 3-hour online PNE course were examined. Patient reported outcomes and other data derived from these patient episodes were compared prior to- and post- the 3-hour online PNE continuing education course.A convenience sample yielded 3,705 completed patient cases of LBP and neck pain  who wereTherapists working for the national PT group had been given access to online, self-directed CE content, including PNE. The content of PNE is well-documented and consistent with other studies –32. A 3-For Aim 1, the following 4 outcomes were analyzed for each of the completed patient cases before and after the PNE training program: 1) change in pain at rest; 2) change in pain with activity; 3) change in disability; and, 4) residual disability.Change in pain at rest and with activity were analyzed using the numeric pain rating scale (NPRS). The NPRS is an 11-point numeric scale anchored with ‘0’ representing one pain extreme (no pain) and ‘10’ respecting the other pain extreme (worst pain imaginable) . Change Disability was ascertained using the Neck Disability Index (NDI)  for caseChange in disability was calculated by subtracting the percentage disability at discharge from the percentage disability at initial evaluation for each patient case. For this study, a change of ≥ 12% was chosen as meeting the MCID for the ODI , and a cResidual disability was based off recent research which defined it as actual patient reported outcome change (minus) risk adjusted predicted patient reported outcome change . A positFor Aim 2, the following 6 outcomes were analyzed for each of the completed patient cases before and after the PNE training program: 1) number of total treatment visits; 2) total duration of care in days; 3) number of total units billed for the entire case; 4) average number of units billed per visit; 5) percentage of “active” billing units relative to total units billed and 6) percentage of “active and manual” billing units relative to total billing units. “Active” billing units were considered therapeutic exercise (CPT code 97110), therapeutic activity (CPT code 97530), neuromuscular reeducation (CPT code 97112), and gait training (CPT code 97116). “Active and Manual” billing units were considered any active billing units as above plus manual therapy (CPT code 97140).Data were analyzed using SPSS version 28.0  at α = 0.05. Cases with missing data were removed from the analysis. For Aim 1, a 2 (time: before and after PNE) X 2 (region: back and neck) ANCOVA was conducted for each of the four outcomes: pain at rest, pain with activity, disability, and residual disability. The following physical therapist characteristics were included as covariates in the analysis: years of experience, gender, training  certification and/or residency). The following patient characteristics were included as covariates in the analysis: gender, body mass index, median income determined by zip code, payor status , age, number of total visits, number of total comorbidities. Because collinearity was found among training groups (certification and residency), those separate categories were combined into one variable. Gender concordance of the therapist and patient was not statistically correlated with any outcome and was, subsequently, omitted from the ANCOVA. Likewise, initial mental and physical component scores were not correlated with any outcome, so both were removed. Collinearity was observed between duration of care and total number of PT visits, so only total number of visits was retained.For Aim 2, a 2 (time: before and after PNE) X 2 (region: back and neck) ANCOVA was conducted for each of the 6 outcomes: number of total treatment visits, total duration of care in days, number of total units billed for the whole case, average number of units billed per visit, percentage of “active” billing units relative to total units, and percentage of “active and manual” billing units relative to total billing units. The covariates entered in the Aim 2 analyses were the same as Aim 1.at rest and F = 2.169, p = .140 with activity (at rest (p = .250) or with activity (p = .800).With covariates added, there was no interaction between time and region, F = .003, p = .958 activity . LikewisWith covariates added, there was a statistically significant interaction between time and region, F = 9.672, p = .002 . Post hoResults for residual disability paralleled disability. There was a statistically significant interaction between time and region, F = 8.718, p = .003 . Post hoWith covariates added, there was no interaction between time and region, F = 1.297, p = .255 . There wWith covariates added, there was no interaction between time and region, F = .203, p = .652 . LikewisWith covariates added, there was no interaction between time and region, F = 1.310, p = .252 . There wWith covariates added, there was no interaction between time and region, F = .162, p = .687 . LikewisWith covariates added, there was no interaction between time and region, F = 2.169, p = .140 . HoweverWith covariates added, there was no interaction between time and region, F = .014, p = .905 . Howeverat rest was 1.9 points and the total mean change in pain with activity was 2.9, indicating that patients reported decreased pain regardless of region (LBP and neck pain). While there was a statistically significant change in disability scores and residual disability for patients with LBP pre- and post-CE, the mean change scores did not meet our 12% threshold to be considered clinically meaningful. The PNE course utilized in this retrospective study was online, self-directed, and only 3 hours in duration. It may not have been of sufficient rigor and duration to make any difference in outcomes, however; these findings are similar to several studies that examined the effect of clinicians attending CE on patient reported outcomes for LBP and neck pain. Brennan et al. [Results from this study show that there was no significant change in pain scores for patients with LBP or neck pain when they were treated by physical therapists after they had attended an online, self-directed CE course on PNE. The total mean change in pain n et al.  comparedn et al. . In a mon et al. . They fon et al. .This study did find that fewer number of visits were used by therapists after PNE than before PNE, regardless of body region treated. However, the mean difference was 0.6 visits and there was no difference in the total duration of care in days. Perhaps associated with this, was the finding that the total number of units billed for each case was less after PNE regardless of body region treated. The mean difference was 4.5 units, and this was also the average number of billing codes per visit, which did not show any change. As the cost of the average billing unit charged by the national outpatient PT provider was $30, this represents a cost savings of $135 per patient. There were 1,277 patients seen by the therapists after PNE training, which would indicate a total of $172,395 saved.Finally, the data showed that while therapists billed a greater percentage of active billing units for cases of LBP regardless of time (56.2% vs 45.1%), they also billed a greater percentage of active billing units after the PNE training regardless of body region treated (55.6% vs 48.7%). A shift from passive interventions (billing codes) to more active treatments suggests a greater focus on patients’ health locus of control and self-efficacy which have been shown to moderate rehabilitation outcomes in people with LBP ,51. ThisThe study contains various limitations. First, there was no control group to compare the PNE group to, which limits the causal inference of this study. Secondly, this study was limited to the use of a 3-hour self-paced online PNE CE course, and there was no opportunity to explore of the optimal dosage of PNE CE. Future studies should explore non-PNE interventions and possibly varying durations and delivery messages for optimal PNE CE training. Finally, the data made available to us for this sample of therapists and treatments was from one large PT group which may well reflect the organization’s philosophy, in part, to treating LBP and neck pain and care should be taken to extrapolate these to all PTs treating LBP and neck pain. Future studies should explore therapists that are representative of various clinical settings, organizations, regions, and backgrounds.While attending an online 3-hour CE course on PNE was not associated with improved patient reported pain and disability outcomes for cases of neck pain, it was associated with improved disability outcomes for cases of LBP. For both LBP and neck pain, it did appear to result in some changes in the clinical behavior of the therapists. Therapists used less PT visits, billed fewer total units, and shifted their billing to more active and manual therapy interventions following their training. We recommend prospective studies with control groups to further explore the effect of CE on patient outcomes and clinical practice.S1 File(SAV)Click here for additional data file.