Bone-targeted agents (BTAs) are widely used in the management of patients with bone metastases from solid tumors. Knowledge of the impact of their routine care use on patient-reported pain and bone pain-related quality of life (QoL) is limited.This real world, cross-sectional study enrolled patients over a 3-month period through oncologists across Switzerland. Patients were ≥ 18 years, had solid tumors and at least one bone metastasis, and received routine care for bone metastases. Physicians provided data on BTA-related practices, risk of bone complications and BTA regimen. Patients completed questionnaires about pain (BPI-SF), general and bone pain-related QoL  and treatment satisfaction (FACIT-TS-G).p = 0.031) and bone pain-related QoL  than those treated with a BTA. All pain and other QoL scales did not differ between groups. Patients perceived at ‘low risk of bone complications’ by their physician not receiving a BTA reported less pain and better QoL than those considered at ‘low risk’ but receiving BTA treatment or those considered at ‘high risk’ regardless of BTA treatment. Overall satisfaction with the treatment was good; almost 50% of patients reporting that they were completely satisfied.Eighteen sites recruited 417 patients. Based on the FACT-BP, 42% of the patients indicated not having bone pain. According to the BPI-SF, 28% reported no, 43% mild, 14% moderate, and 15% severe pain, respectively. Patients not treated with a BTA had better overall QoL (FACT-G: Overall, pain and QoL did not differ according to BTA treatment or physicians’ risk perception. Patient with low risks not receiving BTA treatment reported least pain and highest QoL scores. These results may suggest that treating physicians assess bone complication risk appropriately and treat patients accordingly, but they need to be confirmed by objective determination of longitudinal skeletal complication risk.The online version contains supplementary material available at 10.1186/s12885-021-07903-8. Bone metastases are common in patients with solid tumors and are frequently associated with skeletal complications, known as skeletal-related events (SREs) and symptomatic skeletal events (SSEs) . An incrThe effect of BTAs on QoL has mainly been evaluated by comparing the RANK ligand inhibitor denosumab with bisphosphonates. In a pooled analysis of three double blind randomized clinical trials (RCTs) with patients with solid tumors , clinically meaningful improvements in QoL were similar for both agents . HoweverIn addition to the ongoing collection of robust data on the long-term safety and QoL impact of BTA therapy in randomized clinical trials, data from observational studies on current practices of BTA use in routine care have been published –11. A stA recent multicenter, observational study provided real-world insight into the routine care of BTA prescribing practices of physicians treating patients with bone metastases from solid tumors in Switzerland . PROs weThis cross-sectional observational survey study aimed at obtaining information on the real-world use or non-use of BTAs and their effect on patients’ bone pain, general and bone-pain-related QoL in Switzerland. Participating physicians all over Switzerland documented every patient with bone metastases coming for a regular visit during a given time period of 3 months. This allowed capturing all patients with bone metastases independent from BTA treatment and BTA administration interval. The study was approved by the cantonal ethics committee of Zurich BASEC 2017–01337 for all participating sites.Physicians participating in the study were identified via the Swiss Group for Clinical Cancer Research network supported by the Swiss medical oncology association. They could practice at either public hospitals or private clinics/practices and had to be personally responsible for patient treatment decisions at their center. The physicians who agreed to participate identified patients under their treatment. Patients were eligible if they were aged ≥18 years; had solid tumors and at least one bone metastasis. They had to attend regular visits during the 3 months the physician’s center was participating in the study. All patients provided written informed consent before participating.Physicians had to provide details on their clinical context  and BTA prescribing behaviors  . They alPatients assessed their pain severity with the Brief Pain Inventory – Short Form (BPI-SF) at the time of their visit. The BPI-SF is a well-validated and commonly used self-report measure to assess pain severity and pain interference with daily activities and QoL . In thisIn addition, patients completed a cancer-specific QoL questionnaire, the Functional Assessment of Cancer Therapy – General (FACT-G), and a bone-pain module, the FACT-BP . The FACTo evaluate expectations and satisfaction with treatment, patients further completed the FACIT-TS-G  . PatientAs this is a cross-sectional descriptive study, no formal sample size calculation was performed. All eligible patients were included in the analysis. Categorical variables are reported as frequencies and percentages. Continuous variables include the total scores, subscales and single items of the FACT-G, FACT-BP, FACIT-TS-G and BPI-SF , 20. DifN = 69) of the participating physicians reported working in public hospitals and 20% (N = 17) in private institutions. Almost half (48%) had 10–20 years’ medical expertise, 20% had between 5 and 10 years’ experience, 17% had ≤5 years’ experience, followed by 15% with > 20 years’ medical expertise.Between November 2017 and May 2018, 86 oncologists from 18 sites across Switzerland participated in the study. The 3-month period of participation varied for each center, resulting in a longer than 3 months overall study period. Eighty percent  with available BPI-SF scores were not experiencing pain; 43% (174/400) reported mild pain, 14% (55/400) had moderate and 15% (59/400) had severe pain. According to the FACT-BP single-item (Table Sp < 0.001).While 114 (29%) patients experienced moderate-to-severe pain (BPI-SF ≥ 5), physicians reported moderate to severe pain in 62 (15%) patients  scores, approximately half of the patients  were not receiving analgesics, 33% (133/399) were receiving non-opioid analgesics and 17% (66/399) strong opioids. In the majority of patients, analgesic use corresponded with their pain reports Fig. . Among pp = 0.031) and bone pain-related QoL  compared to patients treated with a BTA (Table Mean BPI-SF pain severity did not significantly differ between patients who received BTA treatment compared to those who did not Table . When loTA Table .Table 2p = 0.025) and better bone pain-related QoL scores (p = 0.012) than those considered at ‘low risk’ but receiving BTA treatment or those considered at ‘high risk’ regardless of BTA treatment  were considered to be at high risk of bone complications by their treating physicians. No association between pain or any of the QoL outcomes and perceived risk of bone complications  were observed (Table The majority of patients (80%) rated the effect of BTA treatment as “good” to “excellent” Table S. More thThis study provides complementary data on patient-reported pain and bone pain-related QoL from a multicenter, observational study about BTA prescribing practices of physicians treating patients with bone metastases from solid tumors . PatientIn comparison, a pooled analysis based on individual patient data from three RTCs showed no or mild pain in 53% of patients with solid tumors and bone metastases before starting treatment with denosumab or zoledronic acid . AverageData from our study indicates that treating physicians achieve an adequate pain management for their patients. The majority of patients in each pain severity group received analgesics corresponding to their pain reports whereas data from another real-world study suggests under-treatment of pain in patients with prostate cancer and bone metastases . PatientThe comparison of patients who were treated to those who were not treated with a BTA showed no differences between these groups for pain severity or for physical, social, emotional and functional wellbeing. Interestingly, patients not treated with a BTA reported clinically relevant better overall and bone pain-related QoL than patients treated with a BTA. In contrast, existing real-world practice data indicated that advanced breast cancer patients who were receiving a BTA presented with significantly lower average pain severity than those not receiving a BTA . MoreoveAccording to the physicians in our study, ‘high risk’ of bone complications and bone pain were the most common drivers of BTA initiation . PhysiciAmong patients who received a BTA almost 50% of patients reported complete satisfaction with treatment, 80% perceived the effect of BTA treatment as “good” to “excellent”. These estimations underpin the appropriate pain management and low incidence of SREs observed in this population most likely due to the relatively high proportion (71%) of physicians reporting a guideline-recommended BTA prescription . A recenn = 135), 76% received radiotherapy. We did not control for the time since diagnosis and can therefore not estimate the effect of radiotherapy on the relationship between BTA treatment, pain and quality of life.The cross-sectional nature of the study requires a cautious interpretation of our findings. The PROs highlight a snapshot of a single time point on the individual patient’s illness trajectory. It is therefore not possible to deduce or anticipate the evolvement of pain or QoL over time, also because we did not control for the time since BTA treatment start. Randomized trials incorporating repeated pain and QoL measurements showed a delay of worsening rather than an improvement in these outcomes when treated with denosumab compared to zoledronic acid . Local eOur sample may have been overrepresented with patients who were at an early stage of BTA treatment, although some measures were taken to minimize potential sources of selection within the patient and physician populations. The 3-month study period was determined and informed by current clinical practice guidelines for BTAs and commonly used chemotherapeutic agents to ensure inclusion of all patients with bone metastases, regardless of BTA treatment. The observational nature of the study ensured that findings reflect patients’ experiences while receiving treatment in real-world practice.In addition to a pain severity measure, we used the FACT-BP, a QoL measure specific to cancer patients with bone metastases. The only other validated tool for this subgroup of patient is EORTC QLQ-BM22 . The choIn conclusion, PROs support the findings based on the physicians’ perspective suggesting high levels of pain control . OverallAdditional file 1: Table S1. Patient characteristics and treatment questionnaire. Table S2: Bone pain (FACT-BP) distribution of answers to single items. Table S3. QoL scores by pain severity. Table S4. Patient vs. physician reported pain scores. Table S5. Use of analgesic medication according to patient-reported BPI worst pain scores (N=399). Table S6. Pain and QoL scores according to BTA treatment and risk status. Table S7 Satisfaction with BTA treatment (FACT-TS-G): Distribution of answers to single questions.


Nearly 500,000 older Americans die a cancer-related death each year . Following a diagnosis of a serious illness like cancer, maintaining a sense of dignity is central to a patient’s wellbeing. Dignity Therapy (DT) was recently introduced as an intervention to enhance dignity for terminally ill patients . This therapy provides patients opportunities to foster a sense of dignity though making meaning of their lives . To date, whether meaning-making actually occurs as a central mechanism of effective DT has not been tested. The current study investigates (i) how often and in what forms meaning-making occurs during DT, and (ii) how patients’ baseline feelings of dignity relate to meaning-making during DT. Participants were 25 male and female cancer outpatients . They completed the Patient Dignity Inventory  and then participated in Dignity Therapy with a trained provider. Sessions were audio recorded, transcribed, and reliably content-analyzed for meaning-making using an established coding scheme . Content-analysis revealed that all patients made meaning of past life events at least once (range: 1-12 occurrences). Multiple forms of meaning-making emerged, with Finding Benefit and Personal Growth most common. Patients reporting more dignity-related distress prior to DT showed greater meaning-making during the DT session . This study provides foundational evidence that meaning-making is a key mechanism of Dignity Therapy, helping older adults with cancer enhance dignity at end-of-life.


We examined how extra-hepatic comorbidity burden impacts mortality in patients with cirrhosis referred for liver transplantation (LT).Adults with cirrhosis evaluated for their first LT in 2012 were followed through their clinical course with last follow up in 2019. Extra-hepatic comorbidity burden was measured using the Charlson Comorbidity Index (CCI). The endpoints were 90-day transplant free survival , and overall mortality .p = 0.002)) but not MELD-Na ≤17. At last follow-up, 69 patients were alive, 100 underwent LT and 171 died without LT. CCI was associated with increased overall mortality in the competing risk analysis .The study included 340 patients, mean age 56 ± 11, 63% male and MELD-Na 17.2 ± 6.6. The CCI was 0 (no comorbidities) in 44%, 1–2 in 44% and > 2 (highest decile) in 12%, with no differences based on gender but higher CCI in patients with fatty and cryptogenic liver disease. Thirty-three (10%) of 332 patients not receiving LT within 90 days died. Beyond MELD-Na, the CCI was independently associated with 90-day mortality (hazard ratio (HR), 1.32  1.02–1.72). Ninety-day mortality was specifically increased with higher CCI category and MELD ≥18 (12% (CCI = 0), 22% (CCI = 1–2) and 33% (CCI > 2), (Extra-hepatic comorbidity burden significantly impacts short-term mortality in patients with cirrhosis and high MELD-Na. This has implications in determining urgency of LT and mortality models in cirrhosis and LT waitlisting, especially with an ageing population with increasing prevalence of fatty liver disease. Cirrhosis is a serious consequence of chronic liver diseases, and represents a substantial burden of morbidity, mortality and health-care expenditure. It carries a poor prognosis in the setting of decompensation or development of hepatocellular carcinoma, with liver transplantation (LT) being the only definitive and lifesaving therapy. In this context, extra-hepatic comorbidities may carry multiple hazards to patients with cirrhosis in need of LT. They carry direct risk of mortality related to the impact of comorbidity , 2, as wshort-term and overall mortality in patients with advanced cirrhosis referred for LT has not been well-studied or quantified. The assessment of overall comorbidity burden, rather than individual comorbid conditions considered by transplant centers, may provide an aggregate measure of risk posed by the burden of extra-hepatic conditions.The Charlson Comorbidity Index (CCI) is a well described and validated instrument determined by the presence, and in some cases severity, of 16 comorbid conditions, including liver disease . The CCIIn this study we measured the extra-hepatic medical comorbidity burden in a cohort of consecutive patients referred for LT using CCI (excluding the contributions of liver disease and HCC). The aims of the study were to determine the impact of extra-hepatic comorbidity burden on 90-day mortality and overall mortality in the study cohort.This study was approved by the Indiana University institutional review board, and was performed and reported per standardized reporting guidelines for qualitative research . All patPatients with prior LT, absence of cirrhosis, or referred for multi-organ transplant were excluded. Demographic and clinical data were collected, including age, gender, body mass index (BMI), race, and etiology of liver disease. The severity of liver disease was measured using the MELD sodium equation (MELD-Na) . PatientExtra-hepatic comorbidity burden was measured using the CCI . For example, a patient with no extra-hepatic comorbidities but with cirrhosis and HCC would have a CCI of 0. The CCI was chosen as an easily calculated and widely recognized comorbidity score that is validated in multiple populations including patients with chronic and acute liver disease , 9, 12.The CCI was analyzed primarily as a continuous variable in all risk-models. In addition, to examine the impact of low and high comorbidity burden we described outcomes within CCI categories using the following two thresholds; (i) patients with CCI = 0, a physiological reference group with the lowest extra-hepatic comorbidity burden, and (ii) the highest decile of CCI (> 2 in this cohort) to reflect the impact of the highest comorbidity burden. Patients with CCI = 1–2 represented an intermediate comorbidity burden group.90-day (short-term) mortality without LT from the time of initial evaluation, which was examined in patients not undergoing LT within 90-days. The secondary outcome was overall mortality (longer-term) with LT as a competing risk, which was examined in all patients.The cohort was followed through the LT evaluation process with long-term follow up. The primary outcomes were As a means of sensitivity testing for the association of comorbidity burden with mortality, we repeated all analyses while measuring comorbidities with an alternate score to CCI. The extra-hepatic comorbidity burden was measured and analyzed using the Cirrhosis Comorbidity score (CIRCOM), which has been validated in patients with cirrhosis . Both CCFinally, we examined the impact of extrahepatic comorbidity burden on LT eligibility after excluding patients with obvious prohibitive conditions and those deemed too early for or declining evaluation for LT.p-value< 0.05, and were performed using SPSS 26  or Stata SE 16 .The analyses for factors associated with the study endpoints were performed using univariable and multivariable Cox proportional hazards regression for 90-day mortality, and univariable and multivariable competing risk regression for overall mortality, with LT as competing risk. The analyses were adjusted for age, gender, BMI, race, etiology of liver disease, MELD-Na and HCC. All analyses were two-sided with significance set at a p = 0.06)). Mean CCI and patient age differed significantly according to etiology of cirrhosis (fatty liver (1.3 ± 1.1 and 61 ± 8), cryptogenic (0.9 ± 1.4 and 62 ± 8), viral (1.1 ± 1.3 and 57 ± 8), alcohol with viral (1.1 ± 1.4 and 54 ± 7), alcohol (0.6 ± 0.8 and 53 ± 10) and autoimmune (0.5 ± 1.1 and 51 ± 15) disease (p = 0.003 and < 0.001), respectively). While CCI did not correlate with patient age per se ), mean age increased with higher CCI category  (p = 0.025).Among the 387 patients evaluated for LT 47 were excluded, including 30 patients who were referred for multi-organ transplant, 7 with prior LT and 10 without underlying cirrhosis. The remaining 340 patients met the inclusion criteria. Baseline demographic and clinic characteristics are summarized in Table Among the 340 patients evaluated 33 died within 90 days without LT, while 8 underwent LT within 90-days and were excluded from this specific analysis. Causes of death included multiorgan failure (7), infection (4), gastrointestinal bleed (4), cardiac (3), stroke (1) and undetermined (14). The CCI was independently associated with increased 90-day mortality on multivariable Cox regression analysis Table , as was p = 0.03)). Whereas in patients with MELD-Na ≤ 17, 90-day mortality was 1% with CCI = 0, 1% with CCI = 1–2 and 4% with CCI > 2, (p = 0.5)). Patients with MELD-Na ≥ 18 also had increasing 90-day mortality with higher categories of CIRCOM , (p = 0.002)).On closer examination, the impact of CCI on 90-day mortality was largely related to increasing risk in patients with MELD-Na above the median value of 17. In patients with MELD-Na ≥ 18, 90-day mortality was 12% with CCI = 0, 22% with CCI = 1–2 and 33% with CCI > 2, . During this time 186 patient died with a median time to death of 303 days . The median follow-up in 54 patients alive at last contact without LT was 6 years , and in 100 patients who underwent LT was 5.7 years . Post-LT patient and graft survival rates were both 90% at 1 year and 81% at 5 years. Patients who died without LT had higher comorbidity burden than those who survived or underwent LT . Extra-hepatic comorbidity burden as measured by CIRCOM was also associated with overall mortality . The CCI was associated with overall mortality irrespective of baseline MELD-Na (adjusted sub-HR 1.3 (95%CI 1.1–1.6) with MELD-Na ≤ 17, and adjusted sub-HR 1.2 (95%CI 1.1–1.4) with MELD-Na ≥ 18).The CCI was associated with increased overall mortality on multivariable competing risk regression analysis Table . The risFig. . Extra-hWe examined the association of individual components of the CCI and CIRCOM with 90-day and overall mortality using univariable models due to small numbers of patients with each condition Table . Only reAfter the initial visit, 40 patients were deemed too early for LT and 38 patients chose not to pursue LT, and did not complete testing. Half of these patients were female, with mean MELD < 15, mean CCI < 1, and < 10% had HCC .One hundred and seventy-seven patients completed the evaluation process and were discussed formally in the transplant selection committee. They were predominantly male 69%), with mean baseline MELD 17 ± 5.8, mean CCI 0.98 ± 1.26, and 31% had HCC . These differences would have impacted comorbidity burden measurement in 19.4 and 27.1% of patients, respectively. Both scores still performed well as measures of extra-hepatic comorbidity burden with very similar adjusted hazard and sub-hazard ratios. It is not within the scope nor the intent of this study to suggest modifications of comorbidity scoring systems, but we acknowledge the interesting differences between these scores that could impact 1 in 4 to 5 patients with advanced cirrhosis.The CCI was developed as a continuous scale or variable and the categorical descriptive analysis warrants discussion. A CCI = 0 reflects a physiologically important reference group with no or very low comorbidity burden. A CCI > 2 highlighted the risks associated with the highest decile of extra-hepatic comorbidity burden, e.g. in patients with higher MELD-Na. Notably, other studies have demonstrated increased mortality in patients with cardiac disease and in patients without cirrhosis presenting with acute liver injury, using the same threshold , 15, 16.A higher comorbidity burden was observed in patients with fatty and cryptogenic liver disease. The latter is commonly attributed to undiagnosed fatty liver disease, which is known to be associated with extra-hepatic comorbidities and increasingly driving the need for LT in the United Sates , 18. WhiIn practice, LT candidate selection is impacted by individual clinically relevant comorbidities and psychosocial considerations rather than a comorbidity burden score such as CCI. There is a dearth of data in this area, but Arya et al. have demonstrated that less than half of patients evaluated for LT were deemed ineligible, mainly for being too early, medical conditions or addiction problems . We obseThe strengths of this study include the comprehensive characterization of comorbid conditions and the long-term follow up of patients with cirrhosis consecutively evaluated for LT. The assessment of extra-hepatic comorbidity burden using two validated systems (CCI and CIRCOM) and convergence of the observed associations also support the clinical premise of the study. The limitations of the study include the retrospective design, limited racial diversity, the absence of comprehensive information on socioeconomic status, and in some cases limited follow-up intervals in patients not undergoing LT. Finally, the use of CCI and CIRCOM in this study was demonstrative of the impact of comorbidity burden on mortality and was not a judgement of superiority of a specific score over other available instruments.In summary, this study demonstrates and quantifies the risk associated with extra-hepatic comorbidity burden with increased short and long-term mortality in patients with advanced cirrhosis. These data are timely, given an ageing population and increasing burden of fatty liver disease and comorbid conditions on transplant and other healthcare resources. Assessment of comorbidity burden may identify a subset of patients with the highest mortality risk and increased LT urgency. If validated, standardized measurement of extra-hepatic comorbidity burden may also be an important modifier of mortality risk models and mortality-related healthcare metrics in cirrhosis. Further studies are needed to confirm these findings, and to determine the ideal comorbidity scoring system and thresholds in patients with advanced cirrhosis.Additional file 1: Supplemental Table 1. The extra-hepatic conditions and their relative weights comprising the Charlson Comorbidity Index (excluding liver disease and hepatocellular carcinoma) and the cirrhosis comorbidity score (CIRCOM). Supplemental Table 2. Baseline demographic and clinical characteristics of the patients evaluated for liver transplantation (LT) for complications of cirrhosis among patients who; (i) were deemed too early for LT (ii) did not want to pursue LT (iii) did not complete LT evaluation (iv) died before competing LT evaluation, or (v) completed LT evaluation with selection committee review. Data are shown as mean ± standard deviation or percentage. Supplemental Table 3. The barriers to liver transplant (LT) eligibility in 28 patients not completing LT evaluation and 57 patients completing evaluation but not approved for LT after selection committee review. Data shown as numbers (and percentages for the main categories of barriers). Supplemental Table 4. The univariable Cox regression analyses of association of individual components of the Charlson Comorbidity Index (excluding liver disease and liver cancer) and CIRCOM, with the study endpoints of liver transplant eligibility and post liver transplant survival.


Despite its widespread use in common clinical practice, the biochemical effects of O2O3 are still far from being understood, although its chemical properties seem to play a pivotal role in exerting its positive effects on different pathological conditions. Indeed, the effectiveness of O2O3 therapy might be partly due to the moderate oxidative stress produced by O3 interactions with biological components. O2O3 therapy is widely used as an adjuvant therapeutic option in several pathological conditions characterized by chronic inflammatory processes and immune over-activation, and most musculoskeletal disorders share these pathophysiological processes. The present comprehensive review depicts the state-of-the-art on the mechanisms of action, safety and effectiveness of O2O3 therapy in the complex scenario of the management of musculoskeletal disorders. Taken together, our findings suggest that O2O3 therapy seems to reduce pain and improve functioning in patients affected by low back pain and knee osteoarthritis, as reported by several studies in the literature. However, to date, further studies are warranted to clearly investigate the therapeutic effects of this promising therapy on other musculoskeletal disorders in the field of rehabilitation.In recent years, the interest in oxygen–ozone (O Moreove0 °C) [3 . In rece tissues ,11,12,13isorders ,19,20,212O3 therapy application in this field has considerably increased in recent years [Musculoskeletal disorders include several pathological conditions characterized by a consistent prevalence and burden in terms of sanitary costs and residual disability, mainly related to musculoskeletal pain ,23. In tnt years .2O3 therapy as an effective therapeutic option in the management of several musculoskeletal disorders [2O3 therapy in the complex management of the most common musculoskeletal disorders in the PRM field.However, to date, although many studies have suggested Oisorders ,30,31, c2O3 mixture. However, despite its various and heterogenous medical applications, the biochemical effects of the O2O3 mixture are far from being understood in detail, even though its chemical properties seem to play a pivotal role in exerting its positive effects in different pathological conditions [In the last four decades, several hypotheses have been proposed to clarify the mechanisms underpinning the antioxidant, antalgic, anti-inflammatory and immunomodulatory actions of medical Onditions ,33,34,353 is considered one of the most powerful oxidizing molecules in nature, although, at high concentrations, it rapidly decays into ordinary oxygen [3 rapidly reacts with water and polyunsaturated fatty acids (PUFA), creating, respectively, hydrogen peroxide (H2O2) and a mixture of lipid ozonation products (LOP), mainly composed by 4-HNE (from omega-6 PUFA) and 4-HHE .Oy oxygen ,37. As ry oxygen ,37,38,392O2 is considered the fundamental reactive oxygen species (ROS), and acts as an ozone messenger [−) [Hessenger . Howevernger [−) . Given tnger [−) ,40. HoweIn human tissues, the moderate oxidative stress caused by ROS is nullified by endogenous radical scavengers, such as superoxide dismutase, glutathione peroxidase, catalase, and NADPH quinone-oxidoreductase ,41,42. IPrevious studies on human cytosol showed that Nrf2 is usually bound with Kelch-like ECH-associated protein 1 (Keap-1), creating an inactive complex in the intracellular space ,44. It h3 could induce the upregulation of Nrf2, conditioning human cells to transcript different AREs. This could result in a better response to pathological radical stress, common in most chronic inflammatory diseases [Thus, through repeated mild oxidative stresses, Odiseases ,42. Intrdiseases  showed tdiseases ,48,49,503 might also have a role in the regulation of prostaglandin synthesis, the release of bradykinin, and in increasing secretions of macrophages and leukocytes [Furthermore, studies on hepatic and heart ischemia-reperfusion suggested that the inflammatory response might be directly downregulated by the suppression of crucial inflammatory mediators and cytokines like IL-6, IL-8 and TNF-a ,52,53. Sukocytes ,55.2O3 therapy in different pathological conditions related to musculoskeletal pain [2O3 therapy might play a key role not only in the management of inflammation but also in nociceptive perception and modulation [2O3 administration, and these antioxidant molecules could induce pain relief by stimulating antinociceptive pathways [Several studies have assessed the effects of Otal pain ,33,34,35dulation ,33,34,35pathways ,58,59,602O3 therapy in hypoxic tissues may be related to an increased production of nitric oxide, adenosine and prostaglandins, with a resulting positive role in the vasodilatation process. Lastly, another study by Bocci et al. [2O3 in human blood, related to the shift to the right in the oxyhaemoglobin dissociation curve due to the increase in 2,3-diphosphoglycerate production and lipid peroxidation.Hypoxia and vascularization impairment are a common pathological feature in muscle wasting and musculoskeletal disorders; thus, as suggested by Clavo et al. , the poti et al.  reported2O3 might exert its positive effects in several tissues due to the moderate oxidative stress produced by O3 interactions with biological components. However, it should be noted that “the thin red line” between O3′s beneficial effects and toxicity could be related to the strength of the oxidative stress.Taken together, all these findings suggested that O2O3 and to deeply understand the complex regulation of different human pathways responsible for the therapeutic effects of this innovative and promising intervention.However, up to now, further studies are warranted to better characterize the biochemical and biomolecular modifications induced by O2O3 therapy is widely used as an adjuvant therapeutic option in several pathological conditions characterized by chronic inflammatory processes and immune overactivation and most musculoskeletal disorders share these two pathophysiological processes [2O3 in the management of common vertebral column degenerative diseases. Several studies performed in low back pain (LBP) patients showed good perspectives for the conservative treatments of disc herniation or protrusion and in case of failed back surgery syndrome [2O3 could be used with an indirect and minimally invasive approach, targeting the paravertebral muscles corresponding to the metamer of the herniated disc [Orocesses . In thissyndrome ,63,64,65ted disc ,63.2O3 therapy is the knee joint. A recent systematic review performed by Sconza et al. [2O3 intra-articular administration in patients affected by knee osteoarthritis (KOA). Similarly, disorders at the tendon level are another potential target for O2O3 therapy that have recently gained interest in the scientific literature. A recent randomized controlled trial (RCT) assessed the efficacy of O2O3 therapy in patients with shoulder impingement, showing that it might be considered an intriguing alternative treatment in case of contraindication to corticosteroids [2O3 injective treatment in patients affected by lateral chronic epicondylitis not respondent to conventional treatment. Furthermore, promising results have been reported even in rheumatic diseases, where O2O3 rectal insufflations or autohemotherapy showed a high safety profile and encouraging positive results in fibromyalgia [2O3 therapy are depicted in Another site worthy of interest for Oa et al.  reportedsteroids . Moreovesteroids  reportedomyalgia . The mos2O3 is not devoid of potential side effects. O2O3 therapy contraindications are mainly related to the antioxidant characteristics of this mixture [3. Other contraindications could include pregnancy , uncontrolled hyperthyroidism, severe cardiovascular diseases and heart failure.Like any other therapeutic intervention, O mixture ,9,10. In2O3 concentrations should be set to a specific range to ensure safety; however, patients might present a sensation of heaviness at the injection site that spontaneously decreases in a few minutes. On the contrary, other adverse effects might be related to an incorrect administration technique, including vagal crisis, pain, hematoma in the injection site, local infections, and even death [2O3 injection, allowing the physician to precisely target the area of interest and to monitor the gas spreading in the tissues, in order to reduce the occurrence of adverse events [2O3 therapy efficacy in musculoskeletal pain management is lacking. This might be due to recurrent bias, low quality studies and the heterogeneity in treatment protocols and administration methods. Therefore, in the following sections of this review, we will summarize the current evidence on the therapeutic effects of O2O3 in the most common musculoskeletal disorders in the PRM field.Oen death ,68. In te events . To date2O3 therapy has been proposed for several years as an effective treatment in patients affected by LBP due to intervertebral disc herniation [2O3 might exert its action in reducing LBP with a coupled mechanical and anti-inflammatory effect. The oxidizing action might break glycosaminoglycan chains in the nucleus pulposus, reducing their ability to retain water, thus decreasing the size of the herniated position and helping to reduce hernial conflict [2O3 might have also an effect on the inflammatory cascade by altering the breakdown of arachidonic acid into inflammatory prostaglandins [Orniation ,71,72. Arniation  highlighconflict ,42. O2O3glandins ,55. Lastglandins .2O3 technique used to treat patients affected by LBP is the intramuscular–paravertebral injection. However, even intradiscal and intraforaminal O2O3 therapy have been recently proposed and investigated for the complex management of LBP in the rehabilitation setting.At present, the most widely used O2O3 into the paravertebral muscles at the level of the metameres of the herniated disc . The threshold level varies between 15 and 30 μg/mL, depending on the individual’s antioxidant capacity, which is directly related to older age, obesity, and alteration of the physiological sagittal spine curvatures [This procedure commonly consists of a paravertebral intramuscular injection of 20 mL of Orvatures ,63.2O3 therapy [Furthermore, an adequate differential diagnosis is mandatory to exclude other musculoskeletal conditions with a similar symptomatology . It should also be taken into consideration that pain might spontaneously regress in up to 90% of patients with acute-onset herniated disc, Indeed, a natural, positive progression of the herniated disc and the spontaneous reduction in herniated volume over time might be confounding factors. Starting from these considerations, a follow-up evaluation with an adequate assessment of outcome measures ) should be performed at three months after the end of O therapy .2O3. A significant difference was observed between the two groups in the percentage of cases who had become pain-free. The authors concluded that in case of non-responsivity to conservative approaches, intramuscular lumbar paravertebral O2O3 injections seem to be a safe and effective way to relieve pain and reduce disability and the intake of analgesic drugs in LBP patients.A multicenter randomized, double-blind, simulated therapy-controlled trial performed by Paoloni et al. in 2009  on 60 pa2O3 therapy in back pain rehabilitation, comparing three groups of patients suffering from chronic back pain associated with disc herniations. Patients underwent three different treatments: intramuscular–paravertebral O2O3 injections, global postural re-education, or a combination of O2O3 injective therapy and rehabilitation. At the end of the treatment protocol, pain severity  was lower in patients who performed O2O3 therapy than in those who undergone global postural re-education only.Similarly, in 2014, Apuzzo et al.  assessed2O3 on trauma-induced lumbar disc herniation. They enrolled 80 patients and divided them into a control group and a low O2O3 (20 μg/mL), medium O2O3 (40 μg/mL) and high O2O3 (60 μg/mL) group. The authors used a CT scan and an enzyme-linked immunosorbent (ELISA) assay to detect serum IL-6 levels, SOD activity, IgM and IgG levels upon admission and at 6 and 12 months after follow-up. All patients showed a CT disc volume reduction at 6- and 12-month follow-up. Moreover, the study demonstrated that O2O3 concentration of 40 μg/mL provided the optimal anti-inflammatory treatment efficacy, while low concentrations of O2O3 (20 μg/mL and 40 μg/mL) reduced the serum IL-6, IgG, and IgM concentrations, showing relevant anti-inflammatory effects. On the contrary, high concentrations of O2O3 (60 μg/mL) increased the serum IL-6, IgG, IgM expression, exacerbating pain and proinflammatory effects in these patients.In 2018, Niu et al.  investig2O3 therapy  in 122 patients with LBP. The authors reported a statistically significant improvement in Visual Analogue Scale and Oswestry Disability Index (ODI) scores at first month follow-up, concluding that paravertebral O2O3 is a reliable and effective treatment in the complex management of LBP related to lumbar disc herniations. Similarly, Biazzo et al. [2O3 therapy in 109 patients affected by LBP, showing that 79% of patients had a significant pain and back disability reduction, corroborating the hypothesis that intramuscular O2O3 injections can be considered a safe, reliable and effective therapeutic intervention in LBP management.A recent paper by Özcan et al.  assessedo et al.  investig2O3 therapy in a 68-year-old woman with an acute episode of severe LBP, not respondent to opioids. The patient presented with several disc herniations  and a concomitant sacral insufficiency fracture and was treated with intramuscular–paravertebral injections of O2O3 for 4 weeks (once per week), using a O3 concentration of 20 μg/mL . We found a consistent reduction in pain  and an improvement in HRQoL  at 1 week after the first injection , confirmed at the one-month follow-up visit .Accordingly, our study group  has rece2O3 in a 73-year-old woman affected by acute LBP due to a facet joint syndrome. The patient was treated with O2O3 (1 injection at 20 μg/mL per week for 3 weeks) under ultrasound guidance, and after a break of 1 week, she also performed exercises for water rehabilitation (twice a week for 4 weeks) with intriguing results.Furthermore, another recent case report performed by Bellomo et al.  evaluate2O3 in patients affected by LBP. More in detail, in 2011, Magalhaes et al. [2O3 in LBP due to disc herniations. Despite the lack of precise LBP diagnosis and the frequent use in some studies of mixed therapeutic agents, the authors concluded that O2O3 therapy seemed to yield positive results and low morbidity rates when applied percutaneously for the treatment of chronic LBP.To date, three systematic reviews ,76,77 has et al.  systemat2O3 therapy in LBP patients with lumbar disc herniations. As previously described, most of the reviewed studies were of poor quality; however, they all reported a consistent pain reduction after O2O3 therapy and few adverse events (mostly minor).Costa et al.  in 2018 2O3 in the treatment of LBP. The authors concluded that the use of intramuscular–paravertebral O2O3 in LBP patients could be suggested as an effective and safe intervention, especially when compared to surgery.Lastly, in 2020, Barbosa et al.  performe2O3 therapy seems to be safe, reliable and effective to reduce pain in patients affected by LBP not responding to anti-inflammatory/analgesic drugs. Intramuscular–paravertebral O2O3 might be considered a promising technique that could be integrated as part of the multidisciplinary rehabilitation management of these patients. However, to date, medical guidelines about O2O3 use in LBP are still warranted to improve the knowledge on the specific indications and therapeutic modalities of this promising intervention.In conclusion, intramuscular–paravertebral O2O3, aimed at reducing intradiscal pressure through glycosaminoglycan lysis, proteoglycan reduction and disc dehydration [In the past, several studies have investigated the role of intradiscal and intraforaminal ozone applications in pathological spinal disc conditions. However, the need for a fluoroscopy or tomographic guide has limited the spread of this technique in the common clinical rehabilitative setting . This thydration .2O3 injection in patients with LBP or sciatica due to a herniated disk. The authors did not record any neurological or infective complications, while they observed a significant success rate in 80% of patients at short-term follow-up (six months). In more detail, the data obtained suggested a lower response rate in patients affected by a calcified herniated disk, spinal canal stenosis, a recurrent herniated disk or a small descending herniated disk of the lateral recess.In 2004, in an observational study on 2200 participants, Muto et al.  assessedOn the other hand, the conservative management of LBP has been deeply studied by Bonetti and colleagues . They pe2O3 versus the steroid injections only. After six months of follow-up, the authors reported a significantly higher success rate in the combined treatment group compared to the steroid alone group (74% vs. 47%: p < 0.05).Similarly, a RCT performed by Gallucci et al.  compared2O3 chemonucleolysis procedures. The authors concluded that intradiscal intraforaminal O2O3 therapy can be considered a safe and cost-effective technique with positive results in LBP and sciatica patients.In 2008, Muto et al.  conductep < 0.05) after intradiscal and intraforaminal injection of ozone concentrations of 25–30 µg/mL in patients with low back pain and radicular pain. Thus, the authors suggested that O2O3 mixture could be considered as a first-choice treatment before surgery in patients with herniated disc nonresponsive to other conservative therapies.In 2013, Zhang et al.  showed a2O3 injection with steroids injection. Interestingly, six months after the treatment, the authors reported a successful outcome in 80% of patients treated with both intradiscal ozone therapy and intraforaminal corticosteroid injection, while 31.5% of the control group treated with intraforaminal corticosteroid injection only.Similarly, a prospective randomized double-blind trial by Perri et al.  performe2O3 in 60 patients with radicular leg pain and LBP, comparing different doses of the mixture. In particular, the treatment proposed was composed of 10 mL with concentration of 40 µg/mL O3 compared to 30 µg/mL O3. Although the authors did not underline significant differences between groups, the data showed a significant improvement in both the pain and functional outcomes after a single intradiscal injection of O2O3 in all the study groups. Thus, the authors concluded that intradiscal injection might be considered a very valuable maneuver to improve pain and disc herniation.In 2018, Elawamy et al.  assessed2O3 mixture containing 40 μg/mL O3, with or without intraforaminal injection of 8 mg of dexamethasone and 1 mL of 0.05% bupivacaine. The authors found a significant improvement in terms of pain, disability, and HRQoL in both groups after the mini-invasive procedure, without significant differences between the groups.In 2020, a double-blinded RCT performed by Ercalik and Kilic  assessed2O3 volume and concentration. Therefore, further research should focus on assessing the best approach to improve the treatment effectiveness.In conclusion, the available literature reported a high safety profile of intradiscal and intraforaminal oxygen–ozone administration. Although the need for a fluoroscopy or tomography guide could limit the feasibility of this treatment in the common rehabilitation setting, positive effects were reported when compared to other therapies such as steroid intraforaminal injection. Lastly, the beneficial effects of the treatment could be related to the size and localization of the herniated disk, patients’ characteristics, and OKOA is frequent condition, characterized by joint pain and periarticular muscle weakness, with subsequent loss of function, increased disability, lower performance in the activities of daily living and a relevant reduction of HRQoL ,89. Thus2O3 therapy [Among nonpharmacological approaches, intra-articular injectable forms of hyaluronic acid (HA) are frequently used in the PRM clinical practice to improve the viscoelastic properties of the synovial fluid in patients affected by KOA and are considered a safe and well-tolerated intervention ,93,94. H therapy ,103,104.2O3, HA, and a combined therapy of both in patients with KOA. They reported significant (p < 0.05) pain reduction (VAS) and disability  after all three approaches  at the end of treatment cycle and at the two-month follow-up evaluation. Moreover, the combination of O2O3 and HA treatment led to a significantly better outcome, especially after two months.In more detail, in 2016, Giombini et al.  firstly 2O3 therapy versus HA intra-articular injection in patients affected of KOA. The authors randomly allocated the study participants into two groups: an O2O3 group and a HA group, both treated with a protocol consisting of three weekly injections. The total Western Ontario and McMaster Universities Arthritis Index (WOMAC) score decreased from 40.8 ± 9.8 to 20.4 ± 4.9 (p < 0.01) in the O2O3 group and from 38.5 ± 7.9 to 17.1 ± 4.2 (p < 0.01) in the HA group. The authors concluded that knee pain, stiffness, and function significantly improved in both groups, without any difference between the two interventions at six-month follow-up.In 2018, another RCT , compare2O3 therapy (22 patients) and a cycle of hyaluronic acid (20 patients). Patients in both groups showed a significant reduction of VAS (p < 0.013) compared to baseline during both cycles. At follow-up evaluations, VAS was significantly lower in the HA group (p < 0.013). Thus, we concluded that intra-articular O2O3 might be comparable to HA in reducing pain in KOA patients, albeit that VAS was significantly lower in the HA group at both follow-up visits.Lastly, our group  recently2O3 therapy has been compared with other therapeutical approaches, including corticosteroids, oral celecoxib and glucosamine [2O3 therapy for the treatment of KOA. The study included 62 patients suffering from knee pain in the last six months, who were divided into two groups: the first group was treated with 40 mg of triamcinolone and the second group with 10 cc of O2O3 injected in the knee joint with the support of ultrasound guidance. The authors concluded that both steroid and O2O3 injections might be effective in the management of KOA patients, and, although steroid injection showed an earlier improvement in knee pain, the effects of O2O3 seem to last longer.In addition to HA, Ocosamine ,104. A R2O3 therapy to anti-inflammatory drugs and nutraceuticals for the treatment of KOA. The study enrolled 76 patients and randomly assigned them into two groups: a control group undergoing oral celecoxib and glucosamine and another performing intra-articular O2O3 therapy. Their findings showed a greater pain reduction in the O2O3 group compared to the control group three weeks after the end of the treatment.In the same way, Feng et al.  compared2O3 therapy in KOA patients. Lopes de Jesus et al. randomly divided 98 KOA patients into two groups: 63 patients in the O2O3 group (eight injections once a week) and 35 patients in the placebo group. After eight weeks of treatment, O2O3 was more effective than the placebo in terms of pain reduction , ambulation , and HRQoL . Moreover, only three patients (one in the O2O3 group and two in the placebo group) experienced minor adverse events (puncture accidents), suggesting a favourable safety profile of intra-articular O2O3.To date, there has only been one randomized, double blinded, placebo-controlled study  that inv2O3 therapy for KOA patients has been investigated in six systematic reviews and meta-analyses [2O3 therapy with HA injections in KOA patients.To date, the effectiveness of intra-articular Oanalyses ,105,106.analyses ,102 aime2O3 therapy at one month after treatment. Similarly, Javadi Hedayatabad et al. [2O3.Li et al.  performed et al.  confirme2O3 efficacy in KOA patients. Raeissadat et al. in 2018 [2O3 group and 47% in the control group. The authors concluded that the efficacy of intra-articular O2O3 therapy in pain reduction was significantly superior to the placebo and not statistically different from the other treatments , suggesting a putative role of O2O3 in the nonsurgical short term (3–6 months) management of mild–moderate KOA.On the contrary, four recent systematic reviews and meta-analyses ,105,106  in 2018  included2O3 therapy had a significant short-term effectiveness in reducing knee pain  lasting on average between three and six months, and these results were also confirmed by another recent meta-analysis performed by Noori-Zadeh et al. [Similarly, in 2019, Arias-Vàzquez et al.  confirmeh et al. .2O3 treatment efficacy in KOA patients. A total of 11 studies involving 858 patients were included; however, none of the studies included reached a “good quality” standard. Thus, the authors concluded that no clear indications emerged from the comparison of O2O3 with other established treatments for KOA, but this technique was proven to be safe and effective in reducing pain in the short–middle term in these patients.Lastly, in 2020, Sconza et al.  performe2O3 therapy might be considered as a safe and effective treatment in the short–middle term (up to six months) in patients affected by KOA; however, further high-quality studies are warranted to improve the scientific knowledge regarding this promising conservative intervention.Taken together, all these findings suggested that intra-articular O2O3 therapy that is commonly used in the PRM clinical practice. However, only a few papers have investigated the effects of O2O3 therapy on other musculoskeletal disorders leading to disability .Several other musculoskeletal diseases might take advantage of the OCervical pain is commonly due to cervical spondylolysis or osteoarthritis, a chronic degenerative condition inducing changes in the bones, intervertebral discs and/or joints connected to the neck. Cervical osteoarthritis might induce progressive functioning impairment and disability and conservative approaches, including rehabilitative exercise, are the most recommended therapeutic interventions .2O3 therapy is widely used in the PRM common clinical practice in patients with cervical pain, albeit that there is still little evidence supporting its efficacy. In 2018, Raeissadat et al. [2O3 injection in 72 patients affected by chronic nonspecific cervical pain lasting more than three months despite conservative treatments and with active trigger points in the upper trapezius muscles. In this single-blinded study, they compared O2O3 therapy with other two interventions commonly used in clinical practice: 2 cc of lidocaine 2% injection in the trapezius trigger points and dry needling, respectively. All three of these interventions were significantly effective in terms of reducing VAS reduction and increasing pain pressure threshold after a four-week follow-up. However, O2O3 and lidocaine treatment showed superior, although not statistically different, results compared to dry needling group.Among the pool of conservative interventions, Ot et al.  firstly 2O3 injections around the cervical dorsal root ganglions in patients affected by cervical pain due to zoster. The authors treated 30 subjects with zoster-associated pain with ultrasound-guided percutaneous O2O3 injection around the cervical dorsal root ganglion at the injured nerve level (C2-C8). Patient improvements in pain and neurologic function were evaluated during a follow-up period from one to three months, showing that percutaneous O2O3 injection around the dorsal root ganglion might be an effective intervention for treatment-resistant cases of zoster-associated pain at the cervical level.Furthermore, a retrospective study conducted by Lin and colleagues  assessed2O3 in 168 patients affected by cervicobrachial pain. The study participants received 12 cervical intramuscular injections of an O2O3 mixture (5 mL) with an O3 concentration of 16 μg/mL once a week, showing a significant pain reduction (p < 0.001) at one, two, three, four and five years of follow-up.Lastly, a recent study performed by Martinelli et al.  in 2020 2O3 injections might be considered as a promising conservative approach in patients affected by cervical pain, although the data about safety are lacking. It is mandatory that further prospective studies will better investigate the role of O2O3 in reducing pain and pain-related disability in patients suffering from cervical pain, with a special focus on the safety profile of this approach.In conclusion, despite the few papers in the literature addressing this issue, intramuscular–paravertebral O2O3 therapy is a promising conservative approach used in common clinical practice as an alternative to local corticosteroid treatment. However, to date, clear indications about the use of O2O3 therapy in patients affected by tendinopathies are lacking.Acute and chronic pathological modifications at tendon level are a pool of musculoskeletal disorders that might involve physicians from different fields, including orthopedics, sports medicine specialists, and PRM specialists . The con2O3 therapy on pain reduction. Corticosteroid injection was administered once a week for three times, while O2O3 injection was administered eight times (every three days). Both treatments significantly reduced pain without differences between groups. Moreover, O2O3 showed better results in terms of pain reduction than corticosteroids at three, at six and at nine months after the injections, suggesting that O2O3 could be considered an effective therapeutic option in the treatment of chronic lateral epicondylitis.Ulusoy et al. , in 20192O3 therapy in these patients [Furthermore, another musculoskeletal condition of rehabilitative interest is fibromyalgia, due to the high burden in terms of disability that affects a high percentage of these patients . Fibromypatients ,112,113.2O3 therapy administered by rectal insufflation as a complementary intervention in the complex multidisciplinary fibromyalgia management. Thirty-six patients affected by fibromyalgia received 24 sessions of O2O3 therapy  during a 12-week period with a significant reduction in fibromyalgia physical symptoms assessed with the Fibromyalgia Impact Questionnaire (FIQ).Hidalgo-Tallòn J. et al.  in 2012,2O3 autohemotransfusion therapy for the management of fibromyalgia symptoms. The authors included 65 patients with a diagnosis of fibromyalgia according to the definition of the American College of Rheumatology [2O3 autohemotransfusion and 10, with O2O3 rectal insufflations, twice a week for one month and then twice a month as maintenance therapy. There was a significant improvement in terms of pain and fatigue in 45 patients and no adverse events occurred during the whole study, suggesting that O2O3 therapy could be considered as a safe complementary/integrative treatment in patients affected by fibromyalgia.More recently, Tirelli et al.  evaluatematology ; 55 of t2O3 autohemotransfusion  and assessed FIQ, serotonin serum levels, and peripheral mononuclear cell concentrations. Autohemotherapy with O2O3 showed an important decline in tender points and FIQ score, as well as a decrease in oxidative stress levels, in patients with fibromyalgia.Similarly, Moreno-Fernàndez et al.  evaluate2O3 therapy in different administration modalities  could have a role in the complex multidisciplinary management of fibromyalgia patients as a complementary intervention. However, further investigations including wider samples should be carried out in the future to better address this issue.In conclusion, O2O3 therapy in the complex management of musculoskeletal disorders in the field of rehabilitation. As previously described, musculoskeletal disorders include several pathological conditions characterized by a consistent prevalence and burden in terms of sanitary costs and residual disability.In conclusion, this comprehensive review described the state-of-the-art about the mechanisms of action, safety and effectiveness of O2O3 therapy might be considered as a promising conservative and mini-invasive intervention with an active role, both alone or in combination with other treatments, in order to reduce pain and improve functioning in patients affected by musculoskeletal disorders. At present, O2O3 therapy’s efficacy and safety has been mainly investigated in LBP and KOA, as reported by several studies. However, up to now, the evidence about the impact of O2O3 therapy in other musculoskeletal diseases is still lacking. Thus, further high-quality studies are warranted to deeply understand its therapeutic effects and safety profile in musculoskeletal disorders of PRM interest.In this scenario, O


Fibromyalgia (FM) is a generalized, widespread chronic pain disorder affecting 2.7% of the general population. In recent years, different studies have observed a strong association between FM and psychological trauma. Therefore, a trauma-focused psychotherapy, such as eye movement desensitization and reprocessing (EMDR), combined with a non-invasive brain stimulation technique, such as multifocal transcranial current stimulation (MtCS), could be an innovative adjunctive treatment option. This double-blind randomized controlled trial (RCT) analyzes if EMDR therapy is effective in the reduction of pain symptoms in FM patients and if its potential is boosted with the addition of MtCS.Forty-five patients with FM and a history of traumatic events will be randomly allocated to Waiting List, EMDR + active-MtCS, or EMDR + sham-MtCS. Therapists and patients will be kept blind to MtCS conditions, and raters will be kept blind to both EMDR and MtCS. All patients will be evaluated at baseline, post-treatment, and follow-up at 6 months after post-treatment. Evaluations will assess the following variables: sociodemographic data, pain, psychological trauma, sleep disturbance, anxiety and affective symptoms, and wellbeing.This study will provide evidence of whether EMDR therapy is effective in reducing pain symptoms in FM patients, and whether the effect of EMDR can be enhanced by MtCS.NCT04084795. Registered on 2 August 2019.ClinicalTrials.gov The online version contains supplementary material available at 10.1186/s13063-021-05042-w. Fibromyalgia (FM) is a chronic pain (CP) disorder characterized by generalized and widespread pain, sleep disturbance, fatigue, cognitive dysfunction, and affective symptoms. The average prevalence of FM worldwide is 2.7%, affecting mainly female patients . AlthougEye movement desensitization and reprocessing (EMDR) is a relatively new integrative psychotherapeutic approach developed by Francine Shapiro in the 1980s. It has been recognized by the World Health Organization as a first-line therapeutic tool for PTSD –14 and cGiven the complex etiology of FM, combining psychotherapy with other treatment options might increase the effectiveness of the treatment and maximize therapeutic success. Due to the key role that CNS sensitivity plays in FM, pioneering non-invasive brain stimulation (NIBS) techniques, such as transcranial direct current stimulation (tDCS), are increasingly being investigated, as these can modify neural activities related to pain. This neurophysiological technique represents a promising intervention option, given its capacity to modulate cerebral excitability in a safe, not invasive, and painless manner . The priThere is increasing evidence which shows that, in addition to psychotherapeutic and pharmacologic interventions, tDCS is useful in treating FM and CP in terms of inducing pain relief and improving quality of life –46. InteTaking into account the information presented above, we hypothesize that the combination of a trauma-focused therapy, such as EMDR, combined with tDCS targeted in the left dorsolateral prefrontal cortex (lDLPFC), could be a useful therapeutic option  for the Although in two studies it was found that the application of tDCS on the lDLPFC was generally less effective in reducing pain in FM patients compared to the application of stimulation on the primary motor cortex , 41, othRegarding the mechanisms underlying the effects of DLPFC/tDCS, while no studies have specifically explored them, it is plausible that the cognitive and affective effects of DLPFC stimulation could be induced through the connections with the limbic system (fronto-limbic network) , whilst Recently, multifocal transcranial current stimulation (MtCS) devices have been used to achieve more focal stimulation of specific cortical targets, because they use smaller electrodes compared to tDCS devices. Different methods have been designed to optimize the configuration of MtCS montage for stimulation of brain networks, represented by spatially extended cortical targets . In thisThe main objective of the study is to analyze whether EMDR therapy is effective in the reduction of pain symptoms in FM patients, and if its potential is boosted with the addition of MtCS. As secondary objectives, the study will analyze whether EMDR therapy is effective in reducing psychological trauma symptoms and comorbid symptoms of anxiety and depression, and in improving sleep quality and patient wellbeing, and if these effects are boosted by the addition of MtCS.Within a double-blind randomized controlled design, patients will be randomized to (1) Waitlist Condition, (2) EMDR + active-MtCS (20 sessions), or (3) EMDR + sham-MtCS (20 sessions). All subjects will continue to receive their treatment as usual (TAU), regardless of the group to which they have been assigned during the study. If a participant does not attend 3 sessions consecutively, she will be withdrawn from the study. Psychotherapists and patients will be kept blind for MtCS treatment conditions until the end of the trial, and raters will be kept blind to both EMDR and MtCS conditions. It is not possible for patients to be blind to the EMDR condition due to its use of bilateral stimulation. The experimental condition assigned to the participants will only be revealed if the patient abandons the study. Otherwise, the blind condition will be maintained until the end of the study. All patients will be clinically evaluated at baseline, at post-treatment, and at 6 months from post-treatment as follow-up.Figure This multicenter collaborative project will involve the participation of the Centre Fòrum Research Unit of Parc de Salut Mar as the entity responsible for coordinating the study and carrying out the evaluations, the Rheumatology Department of Parc de Salut Mar for patient diagnosis and referral to the study, the Institut d’investigacions Biomèdiques August Pi i Sunyer (IDIBAPS) for randomization and data base management, and the Cognitive NeuroLab of Open University of Catalonia (UOC) for MtCS. External accredited EMDR psychotherapists, who have extensive experience and have received specific training for this study, will carry out the therapy, with supervision from the Centre Fòrum Research Unit . The study has been approved by the Ethics Committee of the IMIM, Parc de Salut Mar (2019/8772/I). All participants will sign the informed consent prior to enrollment in the baseline visit. Since this study involves a low-risk intervention, a Data Monitoring Committee will not be considered. Any deviation from the initial protocol will be communicated to the Ethics Committee through an official statement as well as to the Clinical Trials register.The patient sample will consist of 45 females who have been diagnosed by the Rheumatology Department of Parc de Salut Mar, Barcelona, Spain, through a clinical interview aligned with the 2016 American College of Rheumatology criteria for FM. Patients with this diagnosis will be referred from the Rheumatology Department, Anxiety Disorders Unit, Adult Mental Health Centers, and other departments of Parc de Salut Mar. When a participant meets the study criteria, she will be informed about the study and asked whether she would like to participate. Once she accepts, the raters will contact her to schedule the baseline visit and then she will be randomized to one of the groups. Inclusion criteria will be as follows: (1) aged between 18 and 70 years, (2) mean pain score of at least 4 on the visual analog scale for pain (VAS pain ≥ 4) in the 2 weeks preceding the clinical trial, (3) presence of one or more traumatic events causing current trauma-related symptoms , (4) current clinical symptoms of depression and/or anxiety , (5) stable medication regimen over the previous 2 weeks, and (6) met internationally established tDCS safety criteria . Exclusip = 2/3. For each subsequent patient, the following biased coin algorithm will be applied: if a group includes at least two more patients than it would have to have to maintain the ratio 2 EMDR / 1 control, the patient will be randomly assigned to the other group with p = 0.6. Otherwise, there will be a simulation of the new patient as it was allocated to EMDR and calculate the between-group standardized difference in pain intensity variable, then simulate that the new patient is allocated to non-EMDR and recalculate the difference, and finally randomly allocate the patient to the group associated to the smallest difference with p = 0.6. This strategy decreases prognostic imbalances between groups because it decreases differences in potential co-founders, yet still includes randomization.The main analysis will be the comparison between patients assigned to EMDR vs those not assigned to EMDR. The secondary analysis, only amongst patients assigned to EMDR, will be the comparison between patients assigned to active-MtCS vs patients assigned to sham-MtCS. Therefore, the individuals will not randomly be assigned to one of the three arms. Instead, the patients meeting the inclusion criteria will be randomized twice: first to EMDR vs non-EMDR, and then those in the EMDR group to active-MtCS or sham-MtCS. For the sake of brevity, only the randomization to EMDR vs non-EMDR is described here, because the randomization to active-MtCS vs. sham-MtCS is identical. The variables used for the randomization will be age, educational level, and pain intensity score. The first two patients will be randomly allocated to EMDR with Once the randomization group has been obtained, the principal investigator (PI) of the study will inform the participants accordingly. If the participants have been assigned to the EMDR group, the coordinator will also contact the therapist responsible of the treatment.Patient history: The therapist collects information about the patient’s biography in relation to the following aspects: history of FM, psychological trauma history, pain as a trauma, and pain triggers. These memories will be therapeutic targets in the following sessions. Treatment aims will be agreed between the patient and therapist.Preparation: The patient will receive an explanation of the EMDR approach and how the therapy functions. The therapist will get to know the patient’s personal resources and check the patient’s preferences with regard to bilateral stimulation. If eye movements are not well tolerated, tapping or auditory tones will be used. Positive resources for emotional regulation and self-care will be installed.Assessment: The therapist will help the patient focus on a traumatic event selected from the first phase. The patient will select the image that represents the most traumatic part of the event and the positive and negative cognitions associated with the memory, as well as the validity given to these cognitions using the Validity of the Cognition Scale . Emotions, sensations in the body, and the level of distress generated by the memory will also be registered by using the Subjective Units of Disturbance scale .Memory desensitization: The patient will focus on the traumatic image and will associate it with the negative cognition, emotions, and bodily sensations reported in the previous phase. At the same time, the therapist will apply bilateral stimulation and the patient will observe any changes. After every set, the patient will inform the therapist about every change that has occurred. The role of the therapist will be to guide and accompany the patient during the processing until the SUD reaches 0.Installing the positive cognition: The patient now focuses on the original memory and is asked to associate it with the positive cognition identified in the third phase. Bilateral stimulation will also be used to install the cognition.Body scan: When the fifth phase is done, the patient will be asked to keep the memory and positive cognition in mind, and to scan their body for any sensations. If there is any negative sensation, bilateral stimulation will be applied until the sensation disappears. If there are only positive sensations, these will be installed through sets of bilateral stimulation.Closure: When the session finishes, the therapist will explain that in the following days new material (such as new associations or memories) can arise, in which case the patient should register it for the following session.Reevaluation: In the next session, the therapist will assess the state of the distress caused by the memory processed during the last session. If the memory has been correctly processed and no longer causes distress, the therapist will then proceed to treat other memories following the same protocol.EMDR therapy will consist of a maximum of 20 individual 60-min sessions of psychotherapy, principally using the EMDR protocol for FM . The proCheck that the patient’s pain is at a tolerable level by asking the patient to make a subjective assessment of their pain, evaluating their attitude to it, and ensuring that their pain is sufficiently controlled.The medical diagnosis and the patient’s attitude toward it, including degree of acceptance, are reviewed.The targets for EMDR reprocessing, and the treatment objectives , are identified and put in order of priority and used to draw up a treatment plan. As pain is in many cases related, either directly or indirectly, to a traumatic or stressful event, these are treated first using the standard EMDR protocol explained above.Next, each pain point is treated separately with the goal of helping the patient to relax and to notice changes in pain sensations. Bilateral stimulation is applied while the patient focuses on either current pain or a memory of pain. After each set, the patient explains their pain experience, and whether changes have occurred in the severity of the pain, its type, or where it is felt. The sets of bilateral stimulation are continued until the patient notices a positive change.Finally, the patient is assisted in developing psychological pain management resources, achieved by the cognitive integration of the positive changes in pain sensations. First, the positive change is linked to an image, and this is reinforced through sets of bilateral stimulation. The patient then chooses a word to associate with the positive change, and this is reinforced through further sets of bilateral stimulation. The patient can then bring to mind the positive image and associated word and self-apply bilateral stimulation when they feel pain in the future, thus giving the patient pain management resources.When a patient appears to suffer intense pain during the regular EMDR session, and the pain is threatening the patient’s processing, the CP protocol  will be It is important to mention that this psychological intervention does not usually cause any risk to the health of the participants. However, due to remembering and reprocessing past traumatic experiences, it is possible that emotional discomfort will be felt during the evaluation and the therapeutic sessions. This discomfort usually disappears before the end of a session or, in exceptional cases, can also continue in the following day. If the discomfort continues, a new session with the patient should be immediately scheduled to assist her.Should adverse effects other than those related to emotional discomfort from the therapeutic sessions occur, these shall be reported to the PI of the project. Additionally, if it is likely considered that EMDR was the cause, they will also be reported to the Ethics Committee department and relevant regulatory bodies, as required, indicating expectedness, seriousness, severity, and causality. However, as no problems that are detrimental to the participant are anticipated, no interim analyses or formal stopping rules have been planned.Throughout the duration of the study, no participant may receive trauma-focused therapy sessions in parallel.Multifocal transcranial Current Stimulation (MtCS) montage  will be used with the anode over the lDLPFC. This montage, guided by StarStim® computational modeling data see Fig. , was plaIn the case of patients who have been prescribed medication with effects on the nervous system, such as antidepressants, anxiolytic drugs, anticonvulsants or atypical antipsychotics, an individualized follow-up of the clinical outcomes will be carried out to ensure that there is no interaction with the brain stimulation . AlthougDuring the time of the study, no participant may receive MtCS sessions in parallel.The patients allocated to this condition will follow their usual treatment without receiving any other additional therapy. Treatment as usual consists of regular visits with the rheumatologist, psychiatrist, and general practitioners, who are responsible for prescribing and monitoring the pharmacological treatment, principally in form of analgesics such as non-steroidal anti-inflammatory drugs, opioids, paracetamol, and/or gabapentin, but also antidepressant drugs and anxiolytics/hypnotics. Health psychoeducation by the nursing service and therapeutic physical exercise are also included in the waitlist condition. The patients from the waitlist condition group will be offered 10 sessions of EMDR therapy when their participation in the research project has finished. This has been decided for ethical reasons, but also with the aim that participants in the waitlist condition complete the study and thus the dropout rate in this arm can be reduced.Demographic and clinical variables will be collected through a clinical interview using the medical history of the patients and a specific Case Report Form (CRF) designed for the study which will include age, educational level, personal and family history, drug use, current pharmacological treatment and previous psychological treatment. We will also use the MINI International Neuropsychiatric Interview , SpanishVisual Analog Scale for pain (VAS pain) : The VASPain Disability Index (PDI) , SpanishFibromyalgia Impact Questionnaire (FIQ) , SpanishPain intensity will be assessed using the following scales:Global Evaluation of Post-traumatic Stress (EGEP-5) . The EGEThe Impact of Events Scale-Revised (IES-R) , SpanishThe Holmes-Rahe Life Stress Inventory , SpanishThe Childhood Trauma Questionnaire (CTQ) , SpanishDissociative Experiences Scales (DES) , SpanishSomatoform Dissociation Questionnaire 20 (SDQ-20) , SpanishPsychological trauma and trauma-related symptoms will be evaluated using the following scales:Hospital Anxiety and Depression Scale (HADS) , SpanishAnxiety and depression will be assessed using the following scale:Athens Insomnia Scale (AIS) , SpanishQuality of sleep will be assessed using the following scale:Satisfaction With Life Scale (SWLS) , SpanishWellbeing will be assessed using the following scale:t1), post-treatment (t2), and follow-up evaluation at 6 months from post-treatment (t3)  between two groups with a significance level of 0.05 and statistical power of 80% is 13 and 26. Assuming 15% dropouts, we will aim to randomize 45 patients, i.e., 15 + 30, so that after removing ~ 15% dropouts we would have approximately 13 + 26.The main tests of the study will consist of assessing whether patients assigned to EMDR show different levels in the pain intensity variable using a standard formula for two-tailed t-tests to compare pain levels at post-treatment and follow-up between groups . In order to avoid regression toward the mean and confusion effects, baseline levels of pain will be added as covariates, as well as age, depression and anxiety severity and number of years of education. Due to the sample size, no further analysis is expected. The statistical software used for the analysis will be R. For the principal statistical analysis, an intention to treat (ITT) analysis will be used, and multiple imputation for losses at follow-up. The dataset analyses during the current study will be available from the corresponding author on reasonable request.The distribution of the sociodemographic and clinical variables between groups at baseline will be summarized by descriptive statistics. We will use This scientific paper presents the first protocol of a double-blind RCT to investigate whether EMDR is effective in the treatment of FM and its comorbid symptoms, and if its potential is boosted with the addition of MtCS. Patients with FM can be a great clinical challenge for healthcare professionals, due to their high comorbidities and unexplained symptoms , 88. TheThis protocol is innovative in combining the EMDR approach for treating psychological trauma and reducing pain levels with MtCS. This approach should also help treat comorbidity, which, according to the results of recently published works, may also improve FM symptoms , 92–94. Although there are several studies showing high comorbidity between FM and PTSD , very feSome limitations of our trial have been taken into account. Firstly, the lack of control regarding drug treatment is a potential source of bias. To partly overcome this limitation, the current medication regimen should not be changed, as far as possible, once patients have been included in the study. Secondly, this study only includes females. Further studies would be needed to see if the findings of this study can be replicated in the much lower proportion of male FM patients. Thirdly, this is an exploratory and pragmatic trial with a relatively small size, meaning findings will later need to be replicated in a larger sample. Finally, another possible limitation could be the scalability of the MtCS treatment.This is the first protocol version of the study. Recruitment began on 25 September 2019 and the plan was to finish this trial in December 2021. The COVID-19 pandemic, however, meant that the trial had to be suspended due to the impossibility of applying the intervention remotely. Once the current health situation permits it, our aim is to restart the trial from the beginning, to avoid bias in the results.Additional file 1. SPIRIT 2013 Checklist: Recommended items to address in a clinical trial protocol and related documents.