These findings indicate that there is an unmet need for improved access to adequate and free or affordable pain management among cancer survivors.In the article that accompanies this editorial, Halpern et al3 suggest that improving pain management among cancer survivors could be a solution. Using data from a nationally representative sample of cancer survivors, Halpern et al3 found a relationship between pain, employment, and financial outcomes. Specifically, they identified a dose-response relationship between the level of pain and retiring early, feeling less productive at work, and changing to a part-time or otherwise less demanding job. They also identified a dose-response relationship between pain and cost-related delays in filling of a prescription or seeking medical care, defined as a visit for treatment or to see a specialist. Although these findings are based on a cross-sectional survey, and the exact causal relationships between these outcomes have not been described, we may infer two potential inter-related pathways linking pain, financial hardship, and employment  and cost-sharing exemptions for low-income and/or chronically ill patients. Additionally, we should improve access to nonpharmacologic pain management options, such as physical therapy and acupuncture, which are inconsistently covered by health insurance plans.7As a society, we must do better to ensure that people have access to high-quality medical care, regardless of their ability to pay, without risking financial hardship. The study accompanying this editorial, as well as others previously published, has linked financial hardship to delayed or inadequate care  and to symptom burden.8 When writing a prescription for pain medication, we should check to make sure that patients are financially able to fill it and to take the medication as intended. If that is not the case, it is our job to link patients to resources that can help, such as hospital-based financial assistance programs or grants from nonprofit organizations. Additionally, early referral to palliative care for help with optimization of pain control and management of medication side effects is critical. The American Board of Internal Medicine's Choosing Wisely campaign reminds us to not delay palliative care because a patient is pursuing disease-directed treatment.9 We have data, now more than a decade old, that demonstrated benefits in terms of quality of life, mood, and overall survival among patients with metastatic non–small-cell lung cancer who were randomly assigned to receive early palliative care compared with those who received standard of care.10 Subsequent studies have confirmed a benefit in other tumor types.11 Yet late referrals to palliative care are still common, occurring in up to 45% of patients according to a recent study.12 Finally, we should offer to provide our patients with documentation to facilitate their requests for reasonable accommodations, as mandated by the Americans with Disabilities Act, that will allow them to continue to work if that is what they choose or need to do during cancer treatment.13 Additional details about how we can help our patients at work can be found at Cancer and Careers,14 a nonprofit organization and an excellent, free, online resource that provides information for patients and clinicians about working during and after cancer treatment.As clinicians, in addition to advocating for policy changes that would improve our patients' access to care, we must advocate for our individual patients. To ensure that our patients who experience pain have access to adequate treatment, we should follow the guidelines from the American Society of Clinical Oncology that tells us to screen our patients for pain at every clinical encounter.3 suggest the need for an intervention to better manage pain among cancer survivors who have stopped working to promote their reintegration into the workforce. One relevant intervention could be to develop better treatments for pain, with fewer side effects, such as sedation, which can affect work ability. Another intervention could be to improve access to both pharmacologic and nonpharmacologic pain treatments through vouchers or access to free care. These approaches could be tested in a randomized trial to determine their efficacy in preventing job loss or promoting workforce re-entry.As researchers, we must continue to investigate the drivers of job loss and financial hardship among cancer survivors with the goal of identifying modifiable risk factors that can lead to interventions. For example, the data presented by Halpern et al15 However, issues surrounding pain, work, and finances affect patients treated in both the curative and palliative settings, as we showed in a small study at our institution.16 Work has important psychologic and financial benefits, and for many people, it is linked to health insurance.18 Furthermore, the advent of more effective therapies means that larger numbers of patients with incurable cancer are being treated for longer periods of time. Adequate symptom management is a critical tool to enable those who want, or need, to work to continue to do so.Additional research is also needed specifically to address pain management and work among patients treated in the palliative setting. Although the National Cancer Institute considers a patient with cancer to be a survivor from the time of diagnosis until the end of life, most research on financial hardship and work outcomes focuses on patients treated with curative intent.21 Disparities in level of pain were also identified by Halpern et al3; Hispanic and non-Hispanic Black survivors in their data set more commonly reported moderate or severe pain than non-Hispanic Whites. In response to increasing awareness of health disparities, organizations such as the American Medical Association have developed strategic plans to promote health equity.22 As researchers, we can contribute to these efforts by ensuring that our studies include analyses of how social determinants of health affect study outcomes and what interventions can be developed to attenuate disparities. As clinicians, we must do better to ensure that we provide equitable health care into our clinical practices, which may require ongoing education for ourselves and for all staff who engage with patients. As a society, we must work to create a more equitable health care system in which cancer survivors can access the medical care they need to thrive and continue to be valued members of our social fabric, including our workplaces, from the time of diagnosis until the end of life.Finally, it is critical to be aware that disparities on the basis of race, ethnicity, and English proficiency have been documented in pain control, access to pain medication, financial hardship, and employment outcomes in the United States.


Two randomised controlled trials assessing the effect of vitamin D supplementation in a total of 80 subjects found conflicting results, with pain reduction in one and none in the other. It is likely there exists an association between VDD deficiency and fibromyalgia in a large subset of patients, although establishing primary causation is difficult. There is a need for larger randomised controlled trial designs with more effective comparison with healthy subjects and control for confounding factors. Given VDD is a major problem in the general population, we recommend supplementation be recommended by healthcare professionals to fibromyalgia patients for the purpose of maintaining bone health given their potentially increased susceptibility to developing deficiency and its sequelae.Fibromyalgia is a debilitating chronic condition which poses a therapeutic challenge to the clinician. With a large backlog in patient flow subsequent to the COVID-19 pandemic and rising numbers of patients with post-acute sequelae of COVID-19 (PASC) presenting with fibromyalgia-like clinical features, there is an increasingly pressing need to identify broad cost-effective interventions. Low levels of vitamin D have previously been reported in patients with fibromyalgia, though any causative link has been difficult to establish. A systematic literature review on the association between vitamin D deficiency and fibromyalgia was performed examining retrospective evidence both for and against an association between vitamin D deficiency (VDD) and fibromyalgia and evaluating the therapeutic benefit from supplementation. A group of six studies were selected based on relevance, use of controls, quality of research and citations. Four primary studies assessing the prevalence of VDD in fibromyalgia patients versus controls were evaluated with a total 3,496 subjects. Three included females only and one larger study assessed males. Two ( Fibromyalgia is a chronic condition characterised by diffuse musculoskeletal pain lasting at least 3 months and the presence of multiple tender points on physical examination. It affects 5.4% of the UK population and 13.7A literature review on the association between vitamin D deficiency and fibromyalgia was performed. A database search on Scopus, PubMed and Google Scholar was conducted to look for articles in English with the search terms “vitamin D deficiency”, “fibromyalgia” and “vitamin D supplement”. Six articles were ultimately selected based on relevance, use of controls, quality of research and citations.Defining VDD and fibromyalgia is problematic; there is no consensus on the cut-off values for VDD or insufficiency as defined by serum 25-hydroxyvitamin D levels (25-OHD). Also, the criteria for fibromyalgia diagnosis, as defined by the American College of Rheumatology (ACR), changed in 2010 , and fibromyalgia patients had significantly higher serum 25-OHD in Maafi et al.’s study (p = 0.001). This difference was explained by the possibility that fibromyalgia patients took over-the-counter vitamin D supplements due to their pain. No significant correlation between 25-OHD concentrations and pain intensity or the number of positive tender points was observed, reinforcing the conclusion that VDD is not linked to fibromyalgia. Maafi et al. also recorded no association between 25-OHD levels and self-reported fatigue and anxiety scores derived from the Fibromyalgia Impact Questionnaire (FIQ).Both studies found no association between VDD and fibromyalgia because no statistically significant difference was observed between patients and controls in Pena et al.’s study  and showed a greater prevalence of deficiency. BMD at the lumbar spine was significantly lower in fibromyalgia patients, and at the femoral neck and radius spine, it showed no significant difference. Fibromyalgia patients were more likely to have impaired short-term memory, depression, sleep and mood disturbance.Olama et al. studied vitamin D levels and bone mineral density (BMD) in 50 premenopausal Egyptian fibromyalgia patients (ACR 1990 criteria) and 50 age-matched healthy female controls between May and July 2010.[McBeth et al. carried out a large cross-sectional study encompassing 3075 men from the European Male Ageing Study (EMAS), of which 263 reported fibromyalgia and 1550 reported “other pain” that did not satisfy the 1990 ACR criteria, and 1262 reported no pain. Pain ascBoth studies concluded that VDD is associated with fibromyalgia. This relationship could be explained by musculoskeletal pain or depression in fibromyalgia reducing physical activity and hence reducing exposure to sunlight. Indeed, one cross-sectional study found VDD to be associated with anxiety and depression in fibromyalgia patients, which woOlama et al. demonstrated that VDD in fibromyalgia is a risk factor for developing osteoporosis as it reduces BMD in the lumbar spine. A nutritional programme rich in calcium and vitamin D is necessary to prevent bone loss and reduce fractures in fibromyalgia patients. Whilst sThere was little difference in VDD prevalence between patients with fibromyalgia and “other pain” in McBeth et al.’s study see Fig. . Althougn = 3075, male). One limitation of the EMAS study was the pain assessment method; pain history and location were ascertained by self-reported postal questionnaires, introducing reporting bias if patients do not reveal accurate information regarding pain severity. This is pertinent in this male study population as males are more likely to withhold pain-related information.[The study population size of the EMAS study was one of the largest yet to investigate the relationship between vitamin D and fibromyalgia  by Warner et al., 50 femalWepner et al.  randomisIn Warner et al.’s study, ergocalciferol was used for 3 months, achieving an increase in average 25-OHD levels from 16.8 to 31.3 ng/ml. In contrast, Wepner et al. used cholecalciferol, and within 3 months observed an increase in average 25-OHD from 19.0 to 50.96 ng/ml, demonstrating a more significant increase with cholecalciferol. This confirms the result of a recent meta-analysis that found cholecalciferol to be more effective in raising serum 25-OHD than ergocalciferol and is tWarner et al. concluded that correction of VDD did not alleviate musculoskeletal pain, whereas Wepner et al. found it to be a safe and cheap treatment for pain in fibromyalgia. However, Wepner et al. indicated no benefit of vitamin D supplementation on mental health symptoms or health-related quality of life. The results did indicate a significantly better outcome regarding morning fatigue, and this was reinforced by the fact that the pattern of reduction of morning fatigue corresponded to that of pain intensity as measured by VAS. This selective response indicates that fibromyalgia is an extensive syndrome in which VDD may only be a contributing factor.Wepner et al. found seemingly contradicting outcomes. Although the treatment group experienced a significant reduction in pain intensity compared to the control group, there was no correlation between doses of Vitamin D3 and the change in pain severity within the treatment group itself, even though different subjects received different doses depending on their baseline vitamin D status. The selectivity of this response invites further research into the effect of vitamin D on fibromyalgia-specific pain rather than general chronic widespread pain.Both trials randomised patients in a double-blinded manner, reducing the possibility of observer bias (the tendency for researchers to see a reduced pain score in the treatment group) and performance bias , which would reduce the validity of their conclusions. However, the method of allocation of patients to either the treatment or control group in Warner et al.’s study was not revealed, which may skew the outcomes if dissimilar groups were generated. However, baseline characteristics of each group demonstrated no significant difference between the treatment and placebo group with respect to age, ethnicity, serum 25-OHD, pain duration and intensity. Wepner et al. adjusted for BMI also, whereas Warner et al. notably did not assess subject body weight. Obesity has been consistently associated with lower concentrations of 25-OHD and obese/overweight individuals may require greater supplementation levels to achieve adequate serum vitamin D levels, potentially contributing to the reduced efficacy of supplementation observed in their study..n = 30 and 50 respectively), the former invited patients from the general population and local fibromyalgia support groups, not just secondary care settings where patients may have multiple comorbidities which confound the data, and therefore is more indicative of the general fibromyalgia population.Both RCT’s had a small sample size, limiting external validity. Although Wepner et al. used a smaller sample than Warner et al. , which allowed for a more accurate indication of the long-term effect of vitamin D supplementation. Wepner et al. also followed up patients after 24 weeks of no supplementation, allowing them to assess whether any effects observed after 24 weeks were treatment-specific. This was not undertaken by Warner et al. The latter restricted treatment to 3 months, based on the resolution of bone pain in biopsy-proven osteomalacia within 1–3 months, not the There is conflicting evidence regarding the association between vitamin D and fibromyalgia (see Table Evidence regarding the effect of supplementation on quality of life in fibromyalgia patients was also inconclusive, with both RCT’s reaching different results. Sample sizes were small, necessitating a larger RCT involving different ethnicities and latitudes that can be more representative of the global fibromyalgia population and account for the seasonal, cultural and dietary habits that have a major impact on vitamin D status. A “stratified” designed randomised controlled trial is suggested for future research, whereby fibromyalgia patients are stratified into vitamin D replete and deficient at baseline for the purpose of analysis to determine whether the effect of the intervention differs in the two groups whilst still being conducted in a blinded manner.In conclusion, evidence linking the prevalence of VDD and the effect of vitamin D supplementation in fibromyalgia patients is inconclusive, with evidence and mechanisms to support a case for and against. Nonetheless, VDD is a major problem in the general population and supplementation should be recommended by GP’s to fibromyalgia patients for the purpose of maintaining bone health given their increased susceptibility to developing deficiency.


Up to 25% of people who have had carpal tunnel release surgery (CTR) fail to report improvement; however, evidence for prognostic indicators in this surgical cohort is limited. To identify candidate prognostic factors, this study investigated the association of quantitative sensory testing (QST) derived sensory phenotype and attendant impairment with patient-reported surgical outcome.With ethical approval and informed consent, this prospective observational longitudinal study recruited patients from two London hospitals. Multimodal phenotyping measures including quantitative sensory testing (QST), pain parameters, insomnia, pain-related worry, mood and function, were evaluated prior to; and at 3- and 6-months post-surgery. Pain in median nerve distribution with electrophysiologically confirmed conduction delay and DN4 score ≥ 4 was defined as neuropathic. Primary outcome was patient-rated change at 6 months, dichotomised as poor outcome; “worse” or “no change” and good outcome; “slightly better”, “much better” or “completely cured”.p < 0.001), as did functional ability (p < 0.001). Symptom severity diminished (p < 0.001), as did pain-related worry (p < 0.001), anxiety (p = 0.02) and insomnia (p < 0.001). Patient-rated surgical outcome was good in 92% of the cohort, poor in 8%. Baseline sensory phenotype category was not associated with surgical outcome however pain-related worry, anxiety and functional interference were significantly associated with outcome (p ≤ 0.05).Seventy-six patients participated. Prior to surgery, substantial heterogeneity in established categories of somatosensory function was observed with 21% of participants categorised as having a healthy sensory phenotype; 29% with thermal hyperalgesia; 32% mechanical hyperalgesia and 18% sensory loss. Seventy six percent of participants were classified as having neuropathic pain, 33% with high levels of pain related worry and 64% with clinical insomnia. Observed differences in pain, sleep impairment, psychological factors and function, between sensory phenotypic groups, was not significant. At 3- and 6-months post-surgery there was significant improvement in all phenotyping measures with a moderate to large effect size. Thermal and mechanical measures of somatosensation improved (In patients undergoing carpal tunnel surgery, pain-related worry, anxiety and pain functional interference are candidate prognostic outcome factors and require further elucidation. Carpal tunnel syndrome (CTS), compression of the median nerve at the wrist, is the most prevalent of the entrapment neuropathies . PrevaleClearly, it would be advantageous if clinicians, prior to surgery, could anticipate treatment response for a given patient. This might underpin a personalised medicine approach, guiding patient stratification, modification in care pathways or enabling the use of ‘prehabilitation’ approaches to surgery preparedness . HoweverWhile pain is prevalent in CTS  and is nIt is acknowledged that neuropathic pain, caused by a lesion or disease of the somatosensory nervous system , 35 poseSensory phenotype has previously been described in patients with carpal tunnel syndrome, demonstrating heterogeneity in small and large median nerve fibre somatosensory dysfunction , 41, howWe aimed to investigate the association of sensory phenotype and concomitant pain parameters, psychological factors, sleep restriction and functional impairment with outcome at 6 months post carpal tunnel surgery in order to identify candidate prognostic factors for future investigation. Secondarily, we aimed to explore heterogeneity in sensory phenotype and associated comorbidity in the domains of pain, mood, sleep and function in order to establish whether symptom clusters are identifiable within the population of patients with carpal tunnel syndrome. The hypothesis being, in patients with carpal tunnel syndrome, there is a constellation of neuropathic pain associated clinical features which predispose this phenotypic group to symptoms which do not improve or worsen following surgery.Ethical approval was granted by the Camberwell St Giles National Research Ethics Committee (14/LO/1436) on 29 August 2014 for a prospective, longitudinal observational study. Two patient-collaborators , previewed the study measures and procedures and edited study documents for clarity and acceptability. Sequential adult patients listed for open carpal tunnel decompression surgery at two London National Health Service (NHS) hospitals were recruited by poster and in person at their hospital clinic appointment and by post. A comparable surgical technique was used at the two recruitment sites; open decompression with a median nerve block under tourniquet control. Incisions were closed with non-absorbable sutures. Participants were not paid for study participation however travel was reimbursed.Exclusion criteria were significant cognitive dysfunction, patient-defined lack of English language adequate for completing study questionnaires and participating in psychophysical testing, a history of potentially confounding conditions , steroid injection of the study limb within the previous 4 weeks or previous carpal tunnel surgical release in the study hand, anatomic abnormalities of the wrist or hand, median nerve injury or compression secondary to traumatic injury and pregnancy.Participants were stratified by sensory phenotype using the German Research Network on Neuropathic Pain (DFNS) quantitative sensory testing (QST) protocol  and algoThe measure used to categorize surgical outcome as good or poor (binary outcome) was a patient-reported global rating of change (PGRC) at 6 months post-surgery. The PGRC is a 5-point ordinal scale whereby 1 = worse; 2 = unchanged; 3 = slightly better; 4 = much better and 5 = completed cured , 49, 50 Median nerve somatosensory function, pain parameters, psychological state and quality of life measures were evaluated prior to and at 3- and 6-months post-surgery. Baseline measures were completed within 6 weeks prior to surgery; 3- and 6-months post- surgery assessments were completed within ±21 days. Where participants failed to attend a 3- or 6-month assessment, outcome questionnaires were posted. At baseline, demographic data and medical history was recorded. Clinical history taking utilised the Sangha Comorbidity Questionnaire, a patient-reported tool validated for quantifying comorbid conditions and their impact on function, thereby enabling the comparison of general health between participants . Comorbiand where pain was present in the median nerve distribution as reported on a participant completed pain map  / standard deviation of controls)  . At baseQST results, priority to surgery, clearly illustrate this marked heterogeneity in somatosensory function. Loss of small fibre function  was observed in up to 25% of patients Fig. ; whereasp < .001) (Table ). Of the 32 participants who continued to report pain at 6 months post-surgery, in 24 (38%) this was mild, 8 (13%) moderate and 3(5%) severe ) decreased at 3 months (median 3.5 [IQR 2]) (p = .02) and 6 months (median 4 [IQR 2]) (p = .04) while positive outlook scores increased from baseline (median 11 [IQR 5]) to 3 months (median 12 [IQR 5]) and 6 months (median 11 [IQR 5]) (p ≤ .02).The DAPOS scales for depression, anxiety and positive outlook were analysed separately, there is no “total” DAPOS score. No change in depression scores were observed post-surgery for the sample   indicated 49(64%) participants had insomnia ranging from subthreshold to severe, with insomnia persisting in 31(46%) participants at 3 months post-surgery. Change in ISI scores across the 3 assessments was statistically significant; baseline [(median (IQR) 10.0 (11.25)]; 3-months post-surgery 5.5 (11.5), 6 months post-surgery 7 (11.5)] Pain interference and functional impairment was disparate at baseline, with a large proportion of participants reporting moderate to severe dysfunction and interference. Fig. a; 8b. FoPre-surgical health status, mood and functional deficit have been identified as potential prognostic factors for the outcome of carpal tunnel surgery. Therefore, we included these measures in an exploration of attendant burden related to QST derived sensory phenotype Table . At baseAt 6 months post-surgery, 5 (8%) of participants reported a poor surgical outcome (worse or unchanged), 59 (92%) a good outcome  (Table p = .51). Neither were the participant’s age, BMI, Comorbidity Score, duration of symptoms, nerve conduction study measured disease severity or pain parameters associated with surgical outcome (p > .05). However, the association of baseline psychological factors and functional interference with surgical outcome was statistically significant. The Pain Catastrophizing Scale score ; anxiety subscale of the DAPOS  and BPI Interference scale  were inversely correlated with patient reported surgical outcome; greater pain-related worry, greater anxiety and higher levels of functional interference were associated with a poorer surgical outcome.Observed differences in pain, sleep impairment, psychological factors and function, between sensory phenotypic groups, was not significant. However, because sample size was predicated on one prognostic factor (difference in QST for a CTS cohort and controls), the study may have been under powered to detect between phenotypic group differences. The association of QST derived sensory phenotype, participant demographics and baseline multimodal phenotyping measures including pain parameters, psychological factors, sleep and functional impairment measures with patient global rating of change at 6 months post-surgery were investigated to identify potential factor candidates related to surgical outcome  was chosen a priori to determine surgical success. If a more stringent cut-point of grade of 4 (much better) was taken, then a good outcome would have been reported by 80% of participants and is more in keeping with the literature . Our finIn patients with peripheral neuropathic pain, the frequency of DFNS QST derived sensory phenotypes, thought to reflect different neurobiological mechanisms, differ between aetiologies . In the In this sample, prior to decompression surgery, loss of thermal detection  and/or mechanical detection (large fibre) was more prevalent than gain to thermal or mechanical stimuli. Post-surgery, significant improvement is observed in large fibre function , however at 6 months sensory function remains impaired compared to healthy controls, demonstrating recovering but persistent dysfunction. In contrast, a greater degree of small fibre function recovery is observed post-surgery. Cold detection threshold and thermal sensory limen improve significantly but remain reduced at 6 months, whereas warm detection threshold and cold pain threshold normalise at 3 months. These findings are consistent with the work of Baskozos et al.  who demoFindings for pain and symptom severity measures demonstrate that for patients with CTS, pain intensity, frequency and quality are heterogeneous experiences. At baseline 91% of participants reported pain of some severity (mean [standard deviation] pain severity score 4.17 [2.73]) however, of interest, pain parameters at baseline were not associated with patient rated surgical outcome. A significant improvement (reduction) for all pain parameters  was observed at 3 and 6 months post-surgery, consistent with findings in other carpal tunnel surgery cohorts , 76, howIn CTS, the mechanisms driving pain are not clearly elucidated and may change over the course of the disease. Theories based on the pathophysiology of nerve compression implicate ischemia secondary to raised intraneurial pressure, fibrosis and subsequent traction on a nerve that has been rendered immobile or possibly localised inflammatory processes beneath the transverse carpal ligament , 27. It Determining whether pain that is symptomatic of carpal tunnel syndrome is neuropathic in nature is important as this may have implications for treatment. Equally, it is important to understand the nature of persistent post-surgical pain in this group of patients for the same reason. Estimates of neuropathic pain in patients with carpal tunnel syndrome have ranged from 48 to 80% based on the tools used for diagnosis and sample characteristics , 77, 79.For many patients with CTS, pain control prior to surgery is not adequate. Furthermore, for a proportion of patients who undergo carpal tunnel decompression surgery, pain is not resolved. This unmet need has spurred a growing interest in the efficacy of vitamins and nutraceuticals for the reduction of pain and symptom severity in this patient population. Of particular interest, alpha-lipoic acid (ALA) is reported to exert an antioxidative, anti-inflammatory effect on peripheral nerves, thereby reducing sensory symptoms associated with peripheral neuropathy . In patiPain catastrophizing, or exaggerated, persistent thoughts related to painful experiences  has emerp < .001) with a parallel reduction or improvement in pain severity scores (<.001) from baseline to 6 months post-surgery, suggesting that when pain is effectively treated, catastrophic thought or pain-related worry diminishes.At baseline 33% of study participants were categorized as being high in pain-related worry based on their Pain Catastrophizing Scale (PCS) score. There was a significant decrease in scores up to 6 months, at which time 13% continued to report a high degree of pain-related worry. There is debate as to the nature of pain catastrophising as a construct, whether pain catastrophising is representative of a stable state or a situational trait , 87. OurIn this sample, greater pain-related worry, prior to surgery, was found to be associated with poorer surgical outcome. This finding is supported by a recent prospective, observational study in 417 patients undergoing carpal tunnel decompression surgery; Mosegaard et al.  reportedFor three quarters of a century, preoperative anxiety has been recognized as a potentially modifiable risk factor for post-surgical complications , 90. It Surprisingly, in this sample of patients, Insomnia Severity Index (ISI) scores were not associated with patient-rated outcome. At baseline, ISI scores for 64% of participants suggested insomnia ranging from subthreshold to severe in intensity while at 6 months the frequency of insomnia was decreased to 46% of participants. In CTS, sleep interruption is a hallmark of the condition and is reported as a primary driver for patients to seek surgery. It is clear from the literature that the bidirectional relationship of sleep disturbance and pain is complex. A recent systematic review and meta-analysis in clinical populations reported that impaired sleep quality and quantity are associated with an increased risk of developing a chronic pain condition, small elevations in inflammatory markers and worse patient reported function . There ip = .053). However, a significant association was identified between baseline pain functional interference scores and patient reported global rating of change at 6 months post-surgery. The FSS comprises eight hand function specific items, including writing, fastening buttons and opening jars. In contrast, the pain interference scale of the Brief Pain Inventory (BPI) explores the degree to which pain interferes with seven areas of function, including general activity, mood, walking, work, interpersonal relationships, sleep and enjoyment of life [Reportedly, greater functional impairment prior to surgery, as evaluated with the Functional Status Scale (FSS) of the Boston Carpal Tunnel, is associated with poorer long-term outcome following carpal tunnel surgery . In the  of life . The twoAt 6 months post- surgery 65% of CTS participants continued to report some degree of surgical scar pain and 47% reported scar interference. This finding is in keeping with the literature, scar pain and interference are reported to persist in some patients at up to 2 years post-surgery –99. DespStudy sample size was determined to enable the detection of a difference in somatosensory function (via quantitative sensory testing) between patients undergoing carpal tunnel surgery and healthy controls. Therefore, the study may have been underpowered to detect between-group differences in other phenotyping measures.It was anticipated that up to 25% of participants enrolled in this study would report a poor surgical outcome, enabling the use of multivariate analysis of variance or regression analysis to robustly identify candidate prognostic factors. However, as only a small proportion of patients reported a poor outcome this was precluded; correlation was used to identify the association of phenotyping measures and surgical outcome.At both study sites, surgery was performed by multiple surgeons. While the operating surgeon was not included as an outcome variable, patient-reported surgical outcome was consistent with that reported in the literature.All patients scheduled for carpal tunnel surgery were invited to participate, however it is impossible to control for participant-selection bias. In clinical studies of this nature, the clinician-patient interaction cannot be ruled out and may influence or bias the patients’ perception or judgment of outcome. To reduce the likelihood of assessor bias the investigator (DLK) was blinded to patient reported results of surgical outcome until patients completed the trial. The completed measures were placed in pre-labeled, coded envelopes by the study participants and secured in the written case report form. As the baseline and post-surgical measures were completed by one investigator in this study, one cannot rule out the risk of investigator bias.Study findings may not be generalizable to other care pathways, for example in settings where there is minimal waiting time from patient presentation to surgery.This study explored the association of QST derived sensory phenotype and associated comorbid burden with the outcome of carpal tunnel surgery with the aim of identifying candidate prognostic outcome factors for future investigation. Our findings demonstrate that patients with CTS present with significant heterogeneity in somatosensory function; while post-surgical recovery is observed, dysfunction persists in both small and large fibre function at 6 months. Differences between sensory phenotypic groups in pain parameters, pain catastrophising, mood, insomnia and functional impairment were observed, suggesting greater burden in patients with a mechanical hyperalgesia or sensory loss phenotype, however these differences did not reach statistical significance in this sample size. Similarly, phenotypic group differences in surgical outcome were observed but did not reach statistical significance. In patients with CTS, pain-related worry is prevalent but improves significantly post-surgery with a concomitant reduction in pain. Sleep impairment, assumed secondary to symptom severity, persists in a large proportion of patients post-surgery, despite symptom reduction. Greater pain-related worrying, anxiety and pain interference prior to surgery, are associated with poorer surgical outcome. These candidate prognostic outcome factors require further investigation in prognostic factor modelling studies.There is a growing body of evidence that pain-related worry and anxiety are associated with the outcome of carpal tunnel surgery. At present, pre-surgical clinical assessment does not routinely include the evaluation of known psychological risk factors. Where high levels of anxiety are identified, cognitive behavioural therapy (CBT) has been shown to be effective  and warrPrior to carpal tunnel surgery, patients should be informed as to the possibility of prolonged or persistent scar discomfort and interference. Scar outcomes have important implications particularly so for those returning to manual work.Consistent with previous reports , patient


Injury to the infrapatellar branch of the saphenous nerve (IBSN) is a relatively common complication after knee surgery, which can interfere with patient satisfaction and functional outcome. In some cases, injury to the IBSN can lead to formation of a painful neuroma. The purpose of this study was to report the results of surgical treatment in a series of patients with IBSN painful neuroma.We retrospectively identified 37 patients who underwent resection of IBSN painful neuroma at our institution, after failure of non-operative treatment for a minimum of 6 months. Injury to the IBSN resulted from prior orthopedic surgery, vascular surgery, tumor resection, trauma, or infection. Leg pain and health-related quality of life were measured using the numeric rating scale (NRS) and EuroQol 5 dimensions (EQ-5D) questionnaire, respectively. Clinically meaningful improvement in leg pain was defined as reduction in NRS by at least 3 points. Predictors of favorable and unfavorable surgical outcome were investigated using multivariable logistic regression analysis.p < 0.01) and the average EQ-5D functional score improved from 10.48 ± 2.33 to 7.84 ± 2.19 (p < 0.01). Overall patient reported satisfaction with the surgical outcome was good to excellent for 18 patients (72.0%). Older age, multiple prior orthopedic knee surgeries, and failed prior attempts to resect an IBSN neuroma were associated with non-favorable surgical outcome.Patient-reported leg pain, health-related quality of life, and overall satisfaction with the surgical outcome were obtained at 94 ± 52.9 months after neuroma surgery. Postoperative patient-reported outcomes were available for 25 patients (68% of the cohort), of whom 20 patients (80.0%) reported improvement in leg pain, 17 patients (68.0%) reported clinically meaningful improvement in leg pain, and 17 patients (68%) reported improvement in health-related quality of life. The average NRS pain score improved from 9.43 ± 1.34 to 5.12 ± 3.33 (We conclude that surgical intervention is efficacious for appropriately selected patients suffering from IBSN painful neuroma. The infrapatellar branch of the saphenous nerve (IBSN) is a small nerve that originates at the medial aspect of the knee and provides sensation to the area of the tibial tuberosity without a motor component , 2. The Surgical approaches to the anteromedial knee may be complicated by iatrogenic injury to the IBSN, which has been reported after total knee arthroplasty (TKA), arthroscopic knee surgery, anterior cruciate ligament reconstruction, and surgical meniscectomy –10. PatiInjury to the IBSN may also result in neuroma formation due to Wallerian degeneration and subsequent axonal growth , 12. DueThe purpose of this study was to report on postoperative outcomes from surgical neurolysis and neuroma resection in a contemporary cohort of patients with chronic knee pain due to neuroma of the IBSN and to identify prognostic factors to guide patient selection for IBSN neuroma surgery. We hypothesized that multiple prior knee surgeries, prior surgery for resection of IBSN neuroma, and higher self-reported preoperative depression or anxiety may be associated with unfavorable postoperative pain and functional outcomes.A retrospective review of patients who underwent resection of painful IBSN neuroma at our institution from 2001 to 2015 was performed. We included patients with painful IBSN neuroma secondary to prior surgery, trauma, or infection who had failed a trial of non-operative treatment for a minimum of 6 months.Physical examination findings supportive of IBSN-related pain included isolated anteromedial knee pain in the distribution of the IBSN, tenderness elicited on palpation of the medial femoral condyle (Tinel sign), and associated paresthesia in the distribution of the ISBN . SelectiPreoperative leg pain and health-related quality of life were reported via a standardized questionnaire, which patients completed at a clinic visit. Postsurgical outcomes were obtained by phone interviews conducted by one of the authors (D.B.S). Patient-reported outcomes included leg pain, health-related quality of life, patient satisfaction, and sustained need for analgesic medications, physiotherapy, and/or other pain management therapies as determined by a qualified pain specialist Table . Leg paiAn incision was made at the medial aspect of the distal thigh approximately 3 cm above the knee and carried 3 cm over the medial surface of the knee. The deep fascia to vastus medialis was opened and the muscles were retracted. Under a surgical microscope, the saphenous nerve and its infrapatellar branch were identified, and neurolysis of the infrapatellar nerve was performed. Proximal transection of the IBSN close to its origin from the saphenous nerve was performed. Marcaine 0.5% was injected into the proximal nerve stump epineurally. The proximal nerve stump was implanted firmly into an adjacent skeletal muscle and the implantation was secured with sutures. All surgeries were performed by the senior author (S.R).t test parametric analysis and categorical variables were compared by Fisher’s exact test. Multivariable analysis was performed using multiple logistic regressions to identify independent predictors of postsurgical outcome. Data was analyzed using IBM SPSS Statistics for Windows, version 24.0 . Statistical significance was defined as p < 0.05.In univariable analysis, preoperative and postoperative NRS and EQ-5D scores were compared by paired Approval for this research was obtained from the Institutional Research Ethics Board. All patients provided informed consent prior to enrollment in the study.From 2001 to 2015, surgical neurolysis and IBSN neuroma resection were performed for 37 patients, including 17 females and 20 males, at our institution of whom 25 patients (67.6%) were available to answer a self-reported pain outcomes questionnaire at 94 ± 52.9 months post-surgery and 21 patients (57%) were available to answer the EQ-5D questionnaire. Average patient age was 38.9 ± 12.5 years.Injury to the IBSN was associated with prior orthopedic surgery in 20 patients 54.1%), vascular surgery with saphenous vein harvesting or femoral-popliteal arterial graft in 3 patients (8.1%), tumor resection in 6 patients (16.2%), blunt trauma in 5 patients (13.5%), penetrating trauma in 2 patients (5.4%), and Erysipelas infection in 1 patient (2.7%) . In addition, ultrasound imaging of the knee was obtained for 15 patients and IBSN neuroma was identified in 7 patients (46.7%). All patients underwent ambulatory surgery and were discharged from the hospital on the same day. Only 1 patient required wound revision and antibiotic treatment for postoperative wound infection. No other intraoperative or postoperative complications were reported.p < 0.01) and the average EQ-5D functional score improved from 10.47 ± 2.19 to 7.84 ± 2.33 (p < 0.01)  reported improvement in leg pain, 17 patients (68.0%) reported clinically meaningful improvement in leg pain, and 17 patients (68.0%) reported improvement in health-related quality of life (Table p < 0.01), female gender (p < 0.01), multiple prior knee surgeries (p < 0.01), prior resection of IBSN neuroma (p < 0.01), lower preoperative leg pain (p < 0.01), lower self-reported preoperative depression or anxiety (p < 0.01), lower preoperative mobility (p < 0.01), and higher preoperative difficulty with usual activities (p < 0.01) and self-care (p < 0.01) , female gender (p < 0.01), multiple prior knee surgeries (p < 0.001), lower self-reported preoperative depression or anxiety (p < 0.01), and higher preoperative difficulty with usual activities (p < 0.01)  Fig.  whereas 01) Fig. .Fig. 2MIn this study, we identified younger age, male gender, absence of multiple prior knee surgeries, no prior resection of IBSN neuroma, higher preoperative leg pain, and higher preoperative quality of life in the physical functioning and emotional domains as favorable prognostic factors for postoperative improvement.Neurolysis for IBSN entrapment was first described by House and coworkers who reported excellent postoperative outcomes in 4 patients suffering from medial knee pain without prior surgery . In 1996In this study, we verified the efficacy of surgical neurolysis and neuroma resection in reducing neuromatous knee pain in a contemporary cohort of patients with IBSN neuroma secondary to various orthopedic knee surgeries, vascular surgery, tumor resection, trauma, or infection. Whereas painful neuroma of the IBSN was almost exclusively related to prior TKA or knee trauma in previous decades , our insPatients with persistent knee pain from neuroma of the IBSN are often severely debilitated. Mean preoperative leg pain severity in our cohort was 9.32  and mean preoperative leg pain severity reported by Nahabedian and coworkers was 8.5  . As suchIn a prior case series, surgical intervention was only offered to patients with reduction in knee pain by at least 5 points after selective nerve block with 1% lidocaine and insufficient pain relief by selective nerve block was identified as a predictor of poor surgical outcome . SurgicaPreoperative sensory NCV studies demonstrated nerve conduction abnormality in 24 of 27 patients (88.9%) but may not be routinely available as an experienced neurophysiologist is required to perform such specific nerve conduction studies. In comparison, IBSN pathology was identified on preoperative ultrasound imaging of the knee in only 7 of 15 patients (46.7%). Future research should attempt to clarify the clinical utility of selective nerve block and sensory NCV studies in guiding patient selection for surgery.Although mean postoperative leg pain severity remained relatively high (5.12 ± 3.33) and 5 patients (20.0%) subsequently underwent repeat surgical neurolysis and neuroma resection, 12 patients (48.0%) were very satisfied and 6 patients (24.0%) were moderately satisfied with the overall surgical outcome. Similar findings were published by Nahabedian and coworkers, who reported overall patient satisfaction in 21 of 25 patients (84.0%) despite relatively high mean postoperative leg pain severity . Our finThis is a retrospective single institution study, which is also limited by small sample size, as IBSN neuroma is relatively uncommon and probably under-recognized and under-diagnosed. We also acknowledge potential selection bias due to loss to follow-up. However, our findings are similar to reported results from prior studies, which lend credit to overall accuracy and reliability. We await results from other contemporary cohorts to verify our current findings.Neuroma of the IBSN should be suspected in patients who develop neuropathic medial knee pain following orthopedic surgery or trauma. IBSN neuroma as a cause of debilitating chronic knee pain is likely under-recognized, particularly in community hospitals and other institutions without a dedicated peripheral nerve surgery unit. In recent years, greater emphasis has been placed on translational medicine in an effort to connect specialists to solve complex medical and surgical problems . As utilIn properly diagnosed and selected patients, surgical neurolysis and resection of painful IBSN neuroma provide clinically meaningful pain improvement in a majority of patients as well as improvement in health-related quality of life. Future research should verify risk factors for poor postsurgical outcome and optimize selection criteria for surgical intervention.


At 3-month follow-up (T2), both scores decreased slightly, remaining however superior to the pre-treatment values. Only VAS was still significant (p = 0.0184). Conclusions: Despite the small size of the case series, this pilot study is unique in supporting Fascial Manipulation in the nonoperative treatment of MS. Further studies are needed with a large cohort of gender balanced patients to confirm the encouraging results obtained.Background and Objective: Morton’s syndrome (MS) is a common cause of neuropathic chronic forefoot pain, characterised by the development of a swelling of the common digital plantar nerve, whose aetiology is not fully known. There is currently no gold standard of treatment; nonoperative management commonly involves manual therapies, orthoses therapy and infiltrative techniques, while surgery is indicated after failure of conservative measures. The present preliminary study prospectively evaluates patients affected by MS treated by Fascial Manipulation technique (FM), a noninvasive manual therapy, focused on the release of the deep fascia, reducing its stiffness. Materials and Methods: Patients with clinical and sonographic diagnosis of MS with at least a 4-month history of neuropathic symptoms underwent a cycle of three weekly FM sessions. Clinical follow-up, including VAS and AOFAS scores, was performed 21 days (T1) and 3 months (T2) after treatment. Results: Nine patients, among 28 recruited initially, completed the manual therapy sessions and relative follow-up points. This noninvasive pain treatment led to significant improvement of VAS ( Morton’s syndrome (MS) is a common cause of neuropathic chronic forefoot pain with an estimated prevalence of 88 women in every 100,000 and 50 men in every 100,000 . It is cIn the literature, a myriad of possible therapeutic approaches for MS management is described; however, the current clinical management of MS is far from identifying a “gold standard” of treatment .First-line management is nonoperative . The mosTherefore, manual therapy seems appropriate in cases of pain and potential tissue stiffness, particularly when alternative options have not provided convincingly good outcomes ,28. In pGiven these considerations and the experience in treating chronic pain due to several musculoskeletal conditions by FM ,37,38,40Our study hypothesis was that the fascial release provided by FM could reduce the stiffness of the intermetatarsal space and decrease CDPN compression with consequent improvement of the neurological symptoms. Finally, to the best of our knowledge, our experience is unique because no previous clinical trials have used FM for the conservative treatment of MS.In this single-centre pilot study, patients with a mean age of 62 ± 21 years , clinical history and confirmation of MS by dynamic ultrasound diagnosis were prospectively and consecutively enrolled before evaluating their outcomes.Their demographics, including age, sex and clinical data were recorded from January 2018 to June 2019 at our level-1 healthcare trauma centre, a multi-disciplinary and multi-specialty regional university hospital. All patients participating in the study received a thorough explanation of the risks and benefits of inclusion and gave their oral and written informed consent to publish the data. This study was approved by the Institutional Ethics Committee .For this analysis, patients with diagnosis of MS after dynamic ultrasound assessment had to match the following inclusion criteria: at least a 4-month history of chronic pain and neuropathic symptoms, pain on palpation of either the second or third intermetatarsal space, a positive Mulder’s click test and a positive digital nerve stretch test. These tests and dynamic ultrasound diagnosis  were conExclusion criteria were as follows: concomitant presence of the most common forefoot deformities ; previous infiltrative treatment or alcoholisation, previous surgical interventions to the involved foot, multiple neuromas, diabetes mellitus, neuropathies, uncooperative patients and psychiatric diseases.Fascial Manipulation is a manual therapy focused on the deep muscular fascia, involving deep digital pressure exerted over specific points defined by the biomechanical model of the method. This biomechanical model, developed by Luigi Stecco, describes the fascia not just as an idle membrane but more like a three-dimensional continuum, characterised by definite relationships with the underlying muscles. This dynamic structure assumes a coordinating role for motor units, merged in the more complete “myofascial unit”. Many adjacent and unidirectional myofascial units develop a “myofascial sequence” ,42. HencFascial dysfunctions have been implied in various clinical conditions, such as abnormal proprioception, alterations of mechanical coordination, balance and pain ,44,45.For these reasons, it is important to recognize that different modalities of approach have to be taken into consideration for planning treatment.The analytical approach of FM produces a personalised treatment for each patient: a combination of specific movements and palpatory tests allows the therapist to identify the sequences involved in the connective tissue dysfunction. The treatment is applied to a specific area of the involved myofascial sequence, known as the centre of coordination (CC) , where tThe adopted protocol involved a survey phase first, followed by a three-step treatment, which the patients underwent from January to July 2019 at our institution. The survey consisted of a short interview regarding recent and past medical history to identify any possible pathogenic factors. Particular attention was paid to previous injuries with a problematical recovery, overuse conditions, chronic and neuropathic pain and internal dysfunctions.Clinical examination included palpation of the involved webspace and Mulder’s test; these parameters, other than for diagnostic confirmation, were obtained to evaluate the inflammatory state of the area. All preliminary data were obtained by the authors (I.F. and G.A.), not directly involved in the treatment.After this phase, three weekly sessions of FM treatment were provided. All treatments were performed by a registered practitioner physiotherapist, certified for the Stecco method (S.G.) with more than 10 years of experience in the technique of FM, unaware of the study protocol, not involved in the investigations and compilation of questionnaires nor in data analysis. Especially in the first phase, the treatment was done far away from the site of pain, following the anatomical continuity of the fascial structures and the current characteristics of the patients, as the treatment of an oedematous and painful foot would have been useless and extremely uncomfortable for the patient. Consequently, in cases of marked local inflammation, the first treatment involved myofascial sequences proximal to the inflamed area. After a week, before the second physiotherapy session, the operator made a quick re-evaluation of both the foot and treated myofascial points to adapt the treatment according to patient feedback. The third session followed the same practice.To test the effectiveness of the FM method on symptomatic patients, no form of foot-care education was provided to them during the treatment period and their follow-up; neither were specific changes in their daily life or physical activity level suggested. However, because of the persistent pain on their forefoot, they were used to wearing comfortable shoes, generally sporty.From January to October 2019, the clinical analyses were carried out by two independent investigators who were not directly involved in the patients’ treatment. The visual analogue pain scale (VAS) and the American Orthopaedic Foot and Ankle Society (AOFAS) questionnaire  were admp < 0.05 was considered the threshold for statistical significance.Statistical analysis was performed by an independent statistician. The mean value and standard deviation (SD) of the measurements were considered the representative estimators of the scores. Normal distributions were tested using the Kolmogorov–Smirnov test. Differences in the VAS scale and in the AOFAS questionnaire at different time points were statistically analysed by the Kruskal–Wallis test followed by Dunn’s multiple comparisons test. All of the analyses were performed using GraphPad PRISM 3.03 , and During a 15-month period, 28 Caucasian patients (28 feet) with diagnosis of chronic pain due to MS confirmed by dynamic ultrasound met the inclusion and exclusion criteria of this study. However, we could not evaluate 19 patients as 11 refused to participate in FM sessions, while 8 completed only one of the three steps scheduled in the study treatment protocol.Hence, 9 patients, 1 male and 8 females, with a mean age of 62 ± 21 years  were enrolled in the study. An average symptom duration of 23 months (range 4–60) was recorded. The neuroma was located in the left foot in seven patients and in the right foot in two cases. The second intermetatarsal space was involved in one case, while in the remaining cases the third space was affected. No cases of bilateral neuroma were recorded. In 6 patients, the diameter of the lesion exceeded 5 mm upon ultrasound examination with an average dimension of 5.9 ± 2 mm.The foot was the region with the greatest number of treated points (53 out of 143). However, the majority of points were located outside the foot, both in the lower limb , in the pelvis (16 points) and in the lumbar region (9 points). The distribution of the treated points is reported in p = 0.0034). Three months after treatment (T2), the average value was 3.714, remaining significantly lower than the pre-treatment value (p = 0.0184). No significant difference was found between the T0 values and the results at T3. Data are shown in An average pre-treatment VAS (T0) of 6.429 was observed in the treated patients. After treatment (T1), the VAS decreased to a mean value of 3.143, showing a statistically significant difference with the previous (p = 0.0240). After 3 months (T3), the average score decreased to 69 points, remaining higher than pre-treatment (p = 0.2957), although showing no significant difference compared to pre-treatment. Results are shown in Before treatment (T0), an average AOFAS score of 58.29 was found. At the first evaluation after treatment (T1), the score reached a mean value of 73.43, with significant improvement  and for the improvement of foot function, as shown by the significant increase of the AOFAS score (p = 0.0240). As the fascial tissue is the exclusive target of the applied treatment, it can be considered the only variable affected by this technique. The efficacy of the treatment further supports the previous hypothesis of a fascial involvement in CDPN compression and in MS development, thus giving a rationale to the use of this manual therapy aimed at relieving fascial tension and associated neuropathic symptoms [Although further research will be required to prove the initial hypothesis of the study definitively, our preliminary findings suggest that FM was effective for chronic pain control in the short term (T1) with significant VAS reduction after treatment  showed that the results tend to decrease with time, particularly regarding foot function, the FM technique could be considered an important aid to treat neuropathic pain, especially as part of a more comprehensive plan, representing a valid alternative to the heterogenous group of conservative methods  already described in the literature ,11,23,25Hence, in agreement with other authors , we beliThese effects of FM of pain treatment are strengthened also by the fact that the deep fasciae are very well innervated , and conAnother favourable aspect of FM is related to the localisation of the treated points. A common issue of other manual therapies already discussed in the literature is that treatment is mostly focused on the foot. Sault et al., for instance, described the case of a patient with MS treated by multiple grade IV mobilisations of hindfoot and midfoot joints, with improvement of neuropathic symptoms . CashleyIt is important to note that other authors also considered a treatment strategy based on the release of the CDPN. Recently, Elghazy et al.  proposedThe diagnosis of MS is usually clinical, based on the patient’s history and forefoot examination. In this study however, diagnosis was confirmed by dynamic ultrasound because it is simple, unexpensive and reliable in the presence of an experienced radiologist despite its high dependence on the operator . MoreoveThis pilot study has several limitations. The number of evaluated patients was limited to 9 at final follow-up because of the patients who chose not to participate, and this may have influenced the outcomes. This is partly due to the difficulty of recruiting chronic pain patients with isolated clinical and ultrasound diagnosis, including positive Mulder’s click test, of MS not being associated with the most common forefoot deformities  despite the diffusion of this canalicular syndrome. Further, some of our initially selected patients refused to undergo FM treatment because of misleading beliefs about the possible pain of manual therapy. Symptomatic patients without sonographic examination were excluded to minimise the risk of enrolling false positive patients. Nevertheless, the number of patients in our study is similar to or higher than that in some recent reports for manual therapy of Morton’s neuroma.Further, two other aspects of our study protocol could have affected the potential number of participants recruited: constant presence of the chronic pain of at least 4 months instead of 3, as generally defined, and a positive Mulder’s click test. However, the authors believe the sample would not have increased appreciably. First, a cut-off of 4 months of chronic pain was established because patients generally turn to the orthopaedic consultant after several months of pain, initially being not well localised in the forefoot and perceived more as burning or discomfort rather than a true pain. Often, the symptoms are not continuous, as the patient benefits from the summer period in wearing wide shoes; while the pain becomes stronger again during autumn when patients start wearing stiffer footwear. Second, the presence of the Mulder test in our clinical practice is fundamental in the clinical differential diagnosis to distinguish neuroma, bursitis or metatarsalgia. Thus, the symptoms and clinical signs had to be very specific for Morton neuroma to allow the potential participants to be included in this pilot study.Moreover, patients treated by orthoses with forefoot modification before the enrolment were not excluded by the original study protocol. However, none of the 9 out of 28 patients evaluated used orthoses previously.Although no foot-care education was provided to the participants during the treatment period and their follow-up, to test the effectiveness of the treatment, they were used to wearing comfortable footwear. However, this aspect may have only marginally influenced our results, as patients used to wear these even before their enrolment.Another limitation of the present report is the lack of specific scores dedicated to myofascial pain and of a clear diagnostic test to confirm and quantify the involvement of fasciae in MS, which partially impair results assessment. AOFAS is a technical score mainly employed for evaluating clinical outcomes after foot surgery, which also considers structural alterations of the forefoot, such as severe toe deformities, forefoot alignment and joint stiffness or instability . As thesDespite the small number of patients recruited, this preliminary study supports the effective application of Fascial Manipulation in the nonoperative treatment of MS, showing significant reduction of chronic pain and improvement of neuropathic symptoms at least in the short term. As no high-quality evidence currently exists to indicate which intervention should be the gold standard for non-invasive treatments, this innovative physical therapy protocol could be considered an alternative to conservative methods already proposed before proceeding with operative intervention. However, further studies are needed to evaluate the medium- and long-term effects of the protocol, which will have to be extended to more FM sessions, and to improve the generalisability of our encouraging findings on a larger group of patients affected by MS. Its future major advantages could be not only potentially resolving pain with equal efficacy as CDPN excision, but also doing so without incurring the additional potential risks of stump neuroma formation or permanent numbness.


The global burden of osteoarthritis (OA) is steadily increasing due to demographic and lifestyle changes. The nervous system can undergo peripheral and central neuroplastic changes (sensitization) in patients with OA impacting the options to manage the pain adequately. As a result of sensitization, patients with OA show lower pressure pain thresholds (PPTs), facilitated temporal summation of pain (TSP), and impaired conditioned pain modulation (CPM). As traditional analgesics  are not recommended for long-term use in OA, more fundamental knowledge related to other possible management regimes are needed. Duloxetine is a serotonin-noradrenalin reuptake inhibitor, and analgesic effects are documented in patients with OA although the underlying fundamental mechanisms remain unclear. The descending pain inhibitory control system is believed to be dependent on serotonin and noradrenalin. We hypothesized that the analgesic effect of duloxetine could act through these pathways and consequently indirectly reduce pain and sensitization. The aim of this mechanistic study is to investigate if PPTs, TSP, CPM, and clinical pain parameters are modulated by duloxetine.This proof of concept study is a randomized, placebo-controlled, double-blinded, crossover trial, which compares PPTs, TSP, and CPM before and after 18 weeks of duloxetine and placebo in forty patients with knee OA. The intervention periods include a titration period (2 weeks), treatment period (60 mg daily for 14 weeks), and a discontinuation period (2 weeks). Intervention periods are separated by 2 weeks.Duloxetine is recommended for the treatment of chronic pain, but the underlying mechanisms of the analgesic effects are currently unknown. This study will investigate if duloxetine can modify central pain mechanisms and thereby provide insights into the underlying mechanisms of the analgesic effect.ClinicalTrials.govNCT04224584. Registered on January 6, 2020. EudraCT 2019-003437-42. Registered on October 22, 2019. The North Denmark Region Committee on Health Research Ethics N-20190055. Registered on October 31, 2019. Osteoarthritis (OA) is highly prevalent in the elderly population, and the prevalence of OA increases with increasing age and obesity, and thereby the prevalence is expected to rise . DuloxetRecent reviews have concluded that a neuropathic pain-like component is present in subpopulations of patients with OA , 33, 38.Limited evidence is currently available on how to treat sensitization in OA patients, but emerging indications suggest that duloxetine might be such a treatment .It is expected that patients with OA pain may benefit from the duloxetine therapy as a central modulator of pain processing .This proof-of-concept randomized placebo-controlled double-blinded crossover trial aimed to investigate the effect of 18 weeks of duloxetine on mechanistic pain profiles when comparing to placebo in patients with severe OA. The primary objective was to assess the treatment effect on mechanistic pain profiles  when comparing duloxetine to placebo.This proof of concept study is a randomized, placebo-controlled, double-blinded, crossover trial, which compares PPTs, TSP, and CPM before and after 18 weeks of duloxetine and placebo. Forty patients will be randomized to one of two equally sized sequences: (1) duloxetine followed by placebo or (2) placebo followed by duloxetine  and questionnaires. In addition, patients are continuously asked to rate adverse events using a daily diary and the diary is assessed at each visit. Please find a complete outline of the intervention periods and assessments in Fig. Patients are recruited through Synexus, Aalborg, Denmark (a contracting research organization). Women and men, 40–75 years of ages, with OA of the knee, who are eligible to be included in the study, agree to participate and fill in an informed consent, will be included. Patients fulfilling the inclusion criteria will be invited to a screening visit (visit 1) where a physical and psychological examination  will be conducted by a medical doctor. The screening includes x-ray of the knee, screening of medical records, and screening of the eligibility criteria and will be handled by Synexus, Aalborg, Denmark.Patients will be asked to discontinue the use of all analgesic pain medication (including NSAIDs) during the entire trial and any need of rescue medication (paracetamol) must be noted in the diary.Patients who are eligible according to the inclusion and exclusion criteria will be invited to visit 2 where they will be included in the study and randomized.Following visits 1, the entire trial including all patient communication and randomization will be handled by MechSense, Department of Gastroenterology and Hepatology, Aalborg University Hospital, Denmark.The allocation sequence will be generated by the Hospital Pharmacy at Aarhus University Hospital, Aarhus, Denmark, and all study personal  and patients are blinded to the allocation sequences.Patients diagnosed with unilateral or bilateral OA of the knee according to the American College of Rheumatology (ACR) criteria based on clinical and radiographic evidence  will be Enrolment is restricted to people aged 40 years or older because knee pain in younger patients is mainly due to trauma rather than to naturally occurring OA. Patients are screened for suicidal risk using the Columbia-Suicide Severity Rating Scale  and patiSince the purpose of the study is to evaluate the mode of action of duloxetine in treating the pain of osteoarthritis of the knee, patients with other conditions that might produce pain in or alter the perception of the osteoarthritic pain in the index knee are excluded to avoid confounding the assessment of the primary outcome measure.Patients will be informed that they are free to discontinue from the study at any time and for any reason. The investigator may remove a patient from the study in case of any clinical adverse event, laboratory abnormality, or current illness, which in the opinion of the investigator indicates that continued participation in the study is not in the best interest of the patient. Patients may be discontinued due to a change in compliance with inclusion/exclusion criteria that is clinically relevant and affects patient safety, occurrence of adverse events, or ingestion of non-permitted concomitant medication that might affect the patient safety or study assessments/objectives.In case of premature discontinuation of study participation, efforts will be made to conduct all end-of-study assessments. All patients who prematurely discontinue will be followed for ongoing and newly occurring adverse events.Study interventions are duloxetine treatment and placebo treatment. Patients are block-randomized (four patients at a time) to either sequence 1  or sequence 2 . All patients will be administered an equal number of capsules containing duloxetine or placebo. Patients are thoroughly instructed on the most common adverse events and on how to report these.Treatment periods include 2-week titration periods (week 1 (7 days): 20 mg/daily, week 2 (7 days): 40 mg/daily), a 14-week full treatment period (week 3–16 (70 days): 60 mg/daily) followed by a 2-week discontinuation period (week 17 (7 days): 40 mg/daily, week 18 (7 days): 20 mg/daily). The treatment periods are separated by at least two weeks.The patients are instructed to take one capsule of study drug orally with approximately 200 mL of water at room temperature after breakfast in the morning of each dosing day.The study drug is encapsulated in a gelatin capsule  with identical size, color, and weight to ensure blinding.The study drug is produced and labeled by the Hospital Pharmacy at Aarhus University Hospital. The blinding and randomization procedures are conducted by the Hospital Pharmacy at Aarhus University Hospital, Aarhus, Denmark. Patients, study personnel, and study management will be blinded until the end of the trial. Unblinding will take place if the patient’s safety is at risk to ensure allocation concealment.The principal investigator is responsible for monitoring the safety of the patients who have entered this study and for alerting Sponsor of any serious adverse event. Adverse events will be monitored from the time when the patient has signed the informed consent form and until two weeks after the last drug administration (end of study).If the participant should become ill or suffer injury as a direct result of the study drug or experimental procedure, he/she must inform the clinical investigator who will arrange for the proper treatment and help with further developments. This also applies if the participant will complain about the treatment.The patients are covered by Aalborg University Hospital Patient Insurance.The primary outcome parameters are the effects of duloxetine on experimental pain stimulations .2) will be placed perpendicularly to the skin and pressure will be applied until the patient defines the pressure as pain and presses a button. Spreading sensitization will be assessed by PPTs from tibialis anterior of the most painful knee and from the extensor brachii radialis muscle on the ipsilateral side. PPTs will be measured twice on each site and the mean of the two measurements will be used in the statistical analysis.Quantitative sensory testing of joint pain will be determined by assessing PPTs from three knee joint locations at the most painful side (the index knee). A hand-held pressure algometer (Somedic) will be used for measuring PPTs. The probe  including a 13-cm wide tourniquet cuff  and an electronic VAS  for recording of the pain intensity. The cuff will be placed at the level of the head of the gastrocnemius muscle of the lower leg at the index knee. The electronic continuous VAS (sliding resistor) is 10 cm long and sampled at 10 Hz; 0 cm indicates “no pain” and 10 cm indicates “maximum pain.” Cuff algometry is a reliable assessment for PPTs, TSP, and CPM , 30 and The pressure of the cuff is increased by 1 kPa/s and the patient will be instructed to rate the pain intensity continuously on the electronic VAS until the tolerance level is reached. The patient will be instructed to press a stop button at this point. The pressure pain detection threshold (cPDT) is defined as the pressure at which the VAS score exceeds 1 cm. The pain tolerance threshold (cPTT) is defined when the patient presses the stop button. The measurements will be conducted once on both the ipsilateral and contralateral lower leg to the most OA-affected knee.Ten short-lasting stimuli (1 s each) at the level of the cPTT will be given at the lower leg with a 1 s break between stimuli. The participants are instructed to continuously rate the pain intensity of the sequential stimuli using the electronic VAS and not return to zero during the breaks. For each cuff stimulus, a VAS score will be extracted.The CPM magnitude is assessed as the absolute changes in cPDT with and without a cuff conditioning stimulus. A conditioning stimulus will be applied to the contralateral lower leg and the cPDT will be assessed on the ipsilateral lower leg as described above. The conditioning stimulus is applied as a constant stimulus with an intensity of 70% of the pain tolerance level on the contralateral leg.Secondary outcomes are assessed to evaluate the effect of duloxetine and placebo on clinical pain intensities and quality, function of the knee, quality of sleep, pain catastrophizing, anxiety, and depression, as described below.Patients will rate the pain severity for worst pain during the day and pain severity at night on a 10 cm VAS scale. Pain severity will be recorded on a daily basis by the patients in the patient diary.This measure begins with an introduction stating that people experience pain sensations differently and explaining how pain unpleasantness differs from pain intensity. After the introduction, the patients are asked to rate the severity of each of the 20 pain domains using 0 to 10 numerical rating scales in which 0 = ”no pain” or “no (sensation/item)” and 10 = “the most (descriptor) pain sensation imaginable.” As mentioned above, the pain domains assessed include two global domains (pain intensity and unpleasantness), two spatial domains (deep and surface), and 16 quality domains .The Pittsburgh Sleep Quality Index is a self-rating questionnaire resulting in a global score between 0 and 21. The questionnaire consists of seven sub-scores  .The Brief Pain Inventory , 55 , which applies a subscale for anxiety and a subscale for depression. The Hospital Anxiety and Depression Scale ranges from 0 to 21: 0 to 7 indicate no symptoms of anxiety/depression, 8 to 10 indicate possible symptoms of anxiety/depression, and 11 to 21 indicate severe symptoms of anxiety/depression .Wang et al. 2019 [Repeated Mixed Models (RMMs) will be used to compare duloxetine to placebo in changes from baseline to treatment for PPTs, cPDT, cPTT, TSP, and CPM. Different variance-covariance structures will be explored using secondary outcomes. Regression analysis using primary and secondary outcomes will be explored to predict the analgesic effect of duloxetine.The secondary efficacy analyses involving duloxetine comparison with placebo will use the secondary outcomes listed above.The secondary efficacy measures will be analyzed using an RMM approach and potentially covariates will be included. If the RMM analysis shows a significant effect for a variable, contrasts will be constructed for that variable to provide a post hoc pairwise comparison for each time point. Furthermore, on an exploratory basis, pairwise comparisons may be carried out between duloxetine and placebo at each time point.Analyses focused on responders and non-responders will be conducted for all study parameters with the responder being defined as a minimum reduction in pain from baseline to follow-up after duloxetine intervention of 30% or 50%.In addition, predictive models using pretreatment parameters will be used to predict the response rate of the duloxetine intervention.Duloxetine has multiple side effects. Therefore, the patients included in the current study are limited by an extensive exclusion criteria list to ensure that included patients tolerate the study drug. The patients are instructed to inform the study personal of any adverse events. Despite the side effects, duloxetine has been documented to provide analgesic effect to patients who are “centrally sensitized” , and theFurther, the patients will experience pain during the experimental pain sessions, to which they would normally not be exposed. However, patients will be instructed to push a stop button when the pain becomes intolerable and the test will stop immediately. The patients might experience redness or soreness in the hours following the experimental pain tests, but no long-term effects have been reported by using the methods proposed in this protocol –46, 51.A radiological assessment of the knee (an x-ray) is required to determine the eligibility of OA in the patients. This exposes the patients to radiation, which would normally not occur. The radiation mSv dose for x-ray of the knee will be less than 0.1 mSv, which corresponds to a few days of background radiation and causes a negligible cancer risk. Blood samples will be collected in the study, which may cause bruising of the skin and involve a minimal risk of infection. Trained personnel will conduct the procedures and optimal equipment will be used to limit the risk of x-ray radiation and infections during blood samples to an acceptable level.The patients enrolled will be asked not to use their current analgesics  and to use the study drug only. Paracetamol might not be able to render complete pain relief to the patients enrolled and therefore the patients are likely to feel pain .AMD, LAN, and KKP participated in the conception of the study design and procured funding. LAN and KKP act as sponsors for the trial, AMD acts as principal investigator and ensures the safety of the study participants and KKP is coordinating the ongoing trial. The steering committee reviews the progress of the trial and agrees on necessary changes to the protocol.Any modifications to the protocol which may impact on the conduct of the study, potential benefit of the patient or may affect patient safety, including changes of study objectives, study design, patient population, sample sizes, study procedures, or significant administrative aspects will require a formal amendment to the protocol. Such amendment will be agreed upon by trial steering committee and approved by the Ethics Committee and the Danish Medicines Agency prior to implementation.All data collected are entered in RedCap  and will be transferred to SPSS  for statistical analysis.https://gcp-enhed.dk/), and the monitor has been appointed by the sponsor. The Danish Medicines Agency and The North Denmark Region Committee on Health Research Ethics may conduct audits which are independent of the sponsor.The trial is monitored by the GCP-unit, Denmark  on 6 January 2020 and EudraCT (number: 2019-003437-42) on 22 October 2019.The trial is ongoing and is currently recruiting patients. The first patient was enrolled on January 24, 2020, and the last visit of the last patient is expected to take place end of November 2022. This document is based on protocol version 6 of 3 June 2020. The trail was registered with