Fibromyalgia is a chronic pain syndrome with unsatisfactory response to current treatments. Physical trauma, including traumatic brain Injury (TBI) is among the etiological triggers. Hyperbaric Oxygen therapy (HBOT) is an intervention that combines 100% oxygen with elevated atmospheric pressure. HBOT has been applied as a neuro-modulatory treatment in central nervous system–related conditions. The current study investigated the utility of HBOT for TBI–related fibromyalgia. Fibromyalgia patients with a history of TBI were randomized to either HBOT or pharmacological intervention. HBOT protocol comprised 60 daily sessions, breathing 100% oxygen by mask at 2 absolute atmospheres (ATA) for 90 minutes. Pharmacological treatment included Pregabalin or Duloxetine. The primary outcome was subjective pain intensity on visual analogue scale (VAS); Secondary endpoints included questionnaires assessing fibromyalgia symptoms as well as Tc-99m-ECD SPECT brain imaging. Pain threshold and conditioned pain modulation (CPM) were also assessed. Results demonstrated a significant group-by-time interaction in pain intensity post-HBOT compared to the medication group (p = 0.001), with a large net effect size (d = -0.95) in pain intensity reduction following HBOT compared to medications. Fibromyalgia related symptoms and pain questionnaires demonstrated significant improvements induced by HBOT as well as improvements in quality of life and increase in pain thresholds and CPM. SPECT demonstrated significant group-by-time interactions between HBOT and medication groups in the left frontal and the right temporal cortex. In conclusion, HBOT can improve pain symptoms, quality of life, emotional and social function of patients suffering from FMS triggered by TBI. The beneficial clinical effect is correlated with increased brain activity in frontal and parietal regions, associated with executive function and emotional processing. Fibromyalgia Syndrome (FMS) is a common, chronic condition clinically characterized by widespread pain, dyscognition and associated symptoms . FMS is Current treatment for FMS relies on multidisciplinary interventions, with only a modest role for pharmacological agents , 6. NotaWhile the etiology of FMS remains incompletely understood, the interaction between genetic predisposition and exposure to various types of triggers is considered to underlie many cases. Among these triggers, traumatic brain injury (TBI), resulting from an external mechanical force, such as an impact during a fall, a rapid acceleration or deceleration during a motor vehicle accident or a blast wave, has frequently been described as an inciting factor –9. PatieHyperbaric oxygen therapy (HBOT) is a medical treatment in which 100% oxygen is administered at an environmental pressure greater than one atmosphere absolute (ATA) –20. PrevIn the current study, we have attempted to evaluate the therapeutic effect of HBOT on FMS patients with a clear clinical history of TBI and to compare it to the current standard pharmacological treatment. Our objective was to ascertain the clinical utility of this treatment in this specific subgroup of FMS patients, as well as studying the neuroplasticity effects of the intervention through metabolic brain imaging.Study inclusion criteria included age ≥18 years old, diagnosis of FMS according to the updated 2016 diagnostic criteria , and witA prospective randomized, single blind (outcomes assessors), controlled trial was conducted at the Shamir Medical Center (SMC), Israel. After signing an informed consent, patients were randomized to either HBOT or pharmacological intervention groups in a 1:1 ratio according to a computerized randomization table, supervised by a blinded researcher. Evaluation was performed at baseline for both groups and 1–3 weeks after the last HBOT session or three months of medications protocol. All evaluators were blinded to the patients’ group allocation. Intention to treat analysis was performed on all included patients. The study was approved by Shamir Medical Center’s institutional review board (IRB) (No. 058-17-ASF) and all participants signed an informed consent prior to their inclusion. All research was performed according to the relevant guidelines and regulations. This study was registered with ClinicalTrials.gov, number NCT03325959 on 30/10/2017.HBOT protocol was administrated in a multi-place Starmed-2700 chamber . The protocol comprised 60 daily sessions, five sessions per week, within a three-month period. The HBOT protocol included breathing 100% oxygen by mask at 2ATA for 90 minutes with five-minute air breaks every 20 minutes. Compression/decompression rates were 1.0 meter/minute.Patients in the medication group were assigned to receive pharmacological intervention for three-month period, with one of the two medications currently approved in Israel for FMS, Duloxetine and Pregabalin, as outlined in the local rheumatology guidelines for the diagnosis and treatment of FMS . Drugs wThe primary outcome of the study was subjective pain intensity evaluation using the visual analogue scale (VAS) . PatientThe secondary outcomes include the following measures:Fibromyalgia—related symptoms questionnaires:(1) Widespread pain index (WPI)—a count of the number of painful body regions. The WPI ranges from 0 to 19 . (2) FibQuality of life related questionnaire: (1) The RAND Health Status Survey, Short Form-36 (SF-36) was used to assess quality of life. The questionnaire evaluates physical functioning; bodily pain; role limitations due to physical health problems; role limitations due to personal or emotional health; general mental health; social functioning; energy/fatigue; and general health perception. Each index ranges between 0 and 100, with a high score indicating better health  (2). MedPsychological related questionnaires: (1) The Brief Symptom Inventory−18 (BSI-18) was used to evaluate psychological distress. The questionnaire generates a summary scale and three subscales: depression, anxiety, and somatization, and ranges between 0 and 24 . (2) BecDue to the subjective nature of pain, and the complexity and diversity of FMS symptoms, we defined the following indexes for quantifying this complex constellation of symptoms more precisely: Pain index = mean  and FMS index = mean .2 probe . PPTs were measured three times at the upper trapezius muscle. The baseline pressure applied was 0 kPa, with incremental increases of 30 kPa per second, up to a maximal pressure of 1000 kPa. The participant was instructed to report when the sensation changed from pressure to pain, at which point the probe was removed. The average of the second and third measurements was used in further analyses. For evaluating conditioned pain modulation (CPM), The PPT test was repeated during immersion of the non-dominant hand in 10°C cold water. The CPM is the difference in mean pain intensity between the two tests . Thus, effective pain inhibitory mechanisms are represented by higher (positive) values [Pressure pain threshold (PPT) was assessed using a handheld computerized pressure algometer with a circular 1 cm) values , 36.Brain single photon emission computed tomography (SPECT) was conducted using 925–1,110 MBq (25–30 mCi) of technetium-99m-methyl-cysteinate-dimmer (Tc-99m-ECD) at 40–60min post-injection, using a dual detector gamma camera , equipped with high resolution collimators. Data was acquired in 3-degree steps and reconstructed iteratively with Chang method (μ = 0.12/cm) attenuation correction. Both pretreatment and post-treatment SPECT images were normalized to the median maximal brain activity in the entire brain and were then reoriented into Talairach space using Oasis Neurology—NeuroGam application  to identify Brodmann cortical areas and to compute the mean perfusion in each Brodmann area (BA) .Continuous data are expressed as means ± standard deviations (SD). Two-tailed independent t-tests were performed to compare variables between groups when a normality assumption held according to a Kolmogorov-Smirnov test. Net effect sizes were evaluated using Cohen’s d method, defined as the improvement from baseline after pharmaceutical intervention, subtracted from the improvement after HBOT, divided by the pooled standard deviation of the composite score. Categorical data were expressed in numbers and percentages, compared by chi-square/Fisher’s exact tests. To evaluate HBOT’s effect, a repeated-measure ANOVA mixed-model was used to compare post-treatment and pre-treatment data. The model included time, group and the group-by-time interaction. In questionnaire analysis, a Bonferroni correction was used for multiple comparisons. In SPECT analysis, FDR correction was used for multiple comparisons. A value of p<0.05 was considered significant. Pearson’s correlations were performed between Pain test scores or SPECT activation changes and the change in questionnaire scores before and after treatment. Data analysis was performed using MATLAB R2021b  Statistics and Machine Learning Toolbox.According to Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) recommendations, pain intensity reductions of 30% to 50% or more are considered useful. Therefore, the estimated sample size was calculated based on a reduction of 50% in the HBOT group and a reduction of 20% in the medication group, with a standard deviation of 40% , 39. AssSeventy-six patients were eligible to participate in the study. Twelve patients were excluded before randomization. Thus, 64 were randomized to one of the two arms. Two patients from the HBOT group were excluded, one due to intercurrent illness, and one due to poor compliance and did not complete the post protocol assessments. Two additional patients withdrew their consent during treatment and did not complete evaluations. From the medication group, two patients were excluded due to poor compliance and did not complete the follow up assessments. Accordingly, 29 patients from the HBOT group and 29 patients from the medication group completed the protocol and were included in the analysis. The patient flowchart is presented in There was a significant group-by-time interaction in pain intensity evaluated using VAS score post-HBOT compared to the medication group, with a large net effect size  , Table 2Questionnaire analysis is summarized in Fibromyalgia related symptoms and pain questionnaires demonstrated significant improvements induced by HBOT. In both FIQ and GPS score, the HBOT group improved with a significant group-by-time interaction, and a large net effect size of  and .Regarding quality of life, the HBOT group improved in most health domains of the SF-36 questionnaire. Most significant domains were energy, social function, and pain with group-by-time significant interactions of . In the MOS, the HBOT group improved in sleep problems index, with a significant group-by-time interaction .Improvements in psychological symptoms were also demonstrated after HBOT. In the BSI, the HBOT group improved in the total and the somatization scores, with a significant group-by-time interaction  and . Post-HBOT improvement was also found in the BDI score, with a significant group-by-time interaction and a large effect size . Correlations between all questionnaire domains is illustrated in Changes in PPT and CPM-PPT are illustrated in st version of the protocol those were not included in the SPECT analysis. Increased post-treatment activation in Brodmann areas (BAs) is detailed in Seventeen participants in the treatment group and 25 participants in the medication group completed all brain SPECT evaluations. Sixteen participants underwent PET-CT imaging per the 1Pharmacological treatment related side effects are provided in Eighteen (48.6%) participants in the HBOT group experienced side effects. Thirteen participants experienced mild middle ear barotrauma and one patient had sinus frontal pain. All resolved completely after taking a few days off treatment. Due to inability to equalized ear pressure, one patient underwent tympanic ventilation tubes insertion to continue protocol sessions, per his request to continue. One patient experienced temporary blurred vision during treatment session 25, which spontaneously resolved. Two patients reported tinnitus during HBOT, that spontaneously resolved within a few days. One patient reported an allergic reaction. All events were treated conservatively, and all participants completed their protocol.The current study presents a prospective, active—control clinical trial, evaluating the effect of HBOT on FMS patients following Traumatic Brain Injury (TBI). We found that HBOT induced significant improvements in all FMS pain measures, quality of life, emotional and social function. The clinical changes were correlated with increased brain activity in the frontal and parietal regions, which extends previous findings and provides additional information regarding the etiology and treatment of FMS.Chronic widespread pain is the central defining feature of FMS and thus pain intensity was chosen as the primary endpoint of the current study. The significant improvement in VAS—pain intensity documented in patients treated with HBOT compared to the standard of pharmacological care, implies a meaningful and significant effect on the core symptom of FMS. Although VAS is a subjective marker which has several limitations, it is considered the standard endpoint in pain—related disorders in general and in FMS studies in particular. While the effect on pain was evident in the primary endpoint, it was also evident in pain-related secondary outcomes, including the FMS diagnostic criteria, SF-36 pain domain and the GPS. Notably, the WPI significantly improved in the HBOT group compared to baseline, while no improvement was notice in the control group, however this improvement did not reach statistical significance on ANOVA analysis . Since Wper se and have the ability to bring about a significant improvement in function in general. This finding is of great importance in the context of treating a highly prevalent syndrome such as FMS, which frequently affects young individuals at early stages of their carriers, and which may carry a devastating functional effect on this large population of patients.Highly significant improvement was observed following HBOT in outcome measures related to function, including the FIQ, which is the standard tool used for measuring the functional impact of FMS, as well as on the "Social function" component of the SF-36. The physical functioning and physical limitations components of the SF-36 were also significantly improved. Levels of energy and emotional wellbeing were found to be significantly increased as well. Moreover, a significant improvement was found in the Symptom severity scale (SSS), a tool which aggregates the non-pain related functional symptoms of FMS such as fatigue, dyscognition, abdominal pain and others. Taken together, these findings indicate that the beneficial effects of HBOT in the population of post–TBI FMS patients extend well beyond pain–reduction In the current study, we chose both pressure pain threshold (PPT) as well as Conditioned pain modulation (CPM) in order to evaluate the psychophysical effects of HBOT. While PPT has frequently been used in order to diagnose FMS, as well as in order to measure response to treatment , 41, thiIn the current study, functional neuroimaging was performed using brain—SPECT testing with ECD as a marker for brain activity. This method has been used extensively in previous research for evaluating brain activity and perfusion patterns in FMS and changes in response to treatment , 47, 48.SPECT imaging has been used extensively in previous research for evaluating brain activity and perfusion patterns in FMS, and treatment response , 47–49,.Several limitations are worthy of mention regarding the current study. First, we do not have data regarding the long-term effects of HBOT treatment in our patient population. FMS is considered a chronic disorder, and while the effects of HBOT appear to be robust, further information will be necessary regarding the long-term effects of treatment. Second, the HBOT protocol used in this study included 60 daily sessions of HBOT. This protocol was found to have a significant neuroplasticity effect in previous studies; however, it might be possible that different protocols can be used for different patients in order to optimize the outcome per patient and further studies are needed to address this possibility. Third, the comparison group was treated with FMS medications, rather than a sham controlled intervention. Lastly, as the neuroscience of FMS continues to unravel, significant insight is being gained through implementation of additional functional neuroimaging, including fMRI , 51, MagHBOT can improve pain, quality of life, and function in TBI triggered fibromyalgia, while increasing brain activity in frontal and parietal regions.S1 Checklist(DOCX)Click here for additional data file.S1 Table(DOCX)Click here for additional data file.S1 AppendixLegends for S1: SN- serial number, VAS- Visual analog scale for pain, PPT- Pressure pain threshold, CPM- conditioned pain modulation, WPI—Widespread pain index, SSS—symptoms severity scale, FIQ—Fibromyalgia Impact Questionnaire, BSI—Brief Symptom Inventory, BECK- Beck Depression Inventory, MOS—Medical Outcome Sleep Scale, GPS—Global pain scale.(XLSX)Click here for additional data file.S1 File(DOCX)Click here for additional data file.S2 File(PDF)Click here for additional data file.


Increasing the access to and improving the impact of pain treatments is of utmost importance, especially among youths with chronic pain. The engagement of patients as research partners (in contrast to research participants) provides valuable expertise to collaboratively improve treatment delivery.This study looked at a multidisciplinary exposure treatment for youths with chronic pain through the lens of patients and caregivers with the aim to explore and validate treatment change processes, prioritize and develop ideas for improvement, and identify particularly helpful treatment elements.Qualitative exit interviews were conducted with patients and caregivers at their discharge from 2 clinical trials . Six independent co-design meetings were held with patients and caregivers as research partners to establish a consensus within and between groups. The results were validated in a wrap-up meeting.Patients and caregivers described that exposure treatment helped them better process pain-related emotions, feel empowered, and improve their relationship with each other. The research partners developed and agreed upon 12 ideas for improvement. Major recommendations include that pain exposure treatment should be disseminated more not only among patients and caregivers but also among primary care providers and the general public to facilitate an early referral for treatment. Exposure treatment should allow flexibility in terms of duration, frequency, and delivery mode. The research partners prioritized 13 helpful treatment elements. Most of the research partners agreed that future exposure treatments should continue to empower patients to choose meaningful exposure activities, break long-term goals into smaller steps, and discuss realistic expectations at discharge.The results of this study have the potential to contribute to the refinement of pain treatments more broadly. At their core, they suggest that pain treatments should be disseminated more, flexible, and transparent. Chronic pain is among the largest contributors to disability in children , and subRooted in the fear-avoidance model , a gradeIn the planning of the next GET Living iteration, we faced several questions that are also asked in the broader literature: How can pain exposure treatments be improved to produce long-lasting effects? How can we ensure that patients receive and participate in pain exposure treatments on a larger scale? Although the COVID-19 pandemic forced us to take unusual pathways, is the remote delivery format something we want to continue? Therefore, we decided to take an intermediate step to engage with people with lived experiences before deciding which action should be taken next.Co-design is a “meaningful end-user engagement in research design that includes instances of engagement that occur at all stages of the research process and range in intensity from relatively passive to highly active and involved” . PatientIn this study, we partnered with patients and caregivers who had previously received GET Living treatment . From anThis project comprises two parts: (1) semistructured exit interviews and (2) co-design meetings. Qualitative exit interviews were conducted with patients and caregivers during a discharge session after they received the GET Living intervention as research participants. Subsequent co-design meetings were held with the patients and caregivers as research partners to refine the intervention in a formative research process.This project involves 2 separate examinations of GET Living: one was a single-arm trial  and the other was an RCT . The Boston trial NCT01974791) used a sequential replicated and randomized single-case experimental design (SCED) with multiple measures evaluate the effect of GET on youths with chronic pain for the first time 4791 used. The forIn the Boston trial, patients were recruited from the Pain Treatment Service at Boston Children’s Hospital between December 2013 and February 2017 (data collection was completed in January 2018). In the Stanford trial, patients were recruited from the Pediatric Pain Management Clinic at Stanford Children’s Health from January 2019 to May 2021 (data collection was completed in January 2022). Treatment providers referred patients to GET Living during clinic visits. A study flyer and additional brochures were also available in the patient waiting room for patients to self-refer to the study. Patients were deemed eligible to participate in GET Living if they were aged 8 to 17 years, had a diagnosis of chronic pain, had moderate to high pain-related fear, and had moderate to high functional disability .Interview data were analyzed to identify themes related to treatment change processes. In addition, interviews were conducted to create a pool of ideas for intervention improvement and helpful treatment elements, which were later ranked and discussed in the co-design meetings.Only the patients and caregivers who completed all treatment sessions were included in the qualitative analysis to ensure that the data were reflective of the entire treatment experience. The interview that was conducted with a patient and their caregiver who withdrew their participation was excluded. Both the patient and caregiver felt that the treatment’s focus on pain and anxiety was not a good fit. In the Boston trial, 26 interviews of patients and caregivers were analyzed. In the Stanford trial, 26 interviews of patients and caregivers who were randomized to the exposure intervention were analyzed. The patients and caregivers were interviewed separately. More details on the interviewed cohorts are presented in The semistructured exit interviews were conducted by research assistants during the discharge visit following the completion of GET Living. All research assistants were trained by the principal investigator LES. In the Boston trial, most interviews were conducted in person. In the Stanford trial, most interviews were conducted via phone or video calls. The patient and caregiver interview schedules both comprised 8 questions . The quetruthful” or objective meaning of the data but is rather conceptualized as an analytical resource for data interpretation  said, “Your daughter’s gonna be okay. Her pain is real, but she’s gonna be ok.” That was really important for me to hear that. Finally, someone put it all together and made me feel like, okay she’s not gonna break.GS33, caregiverSome even expressed a newly found admiration toward their children:So, I guess I admire kids and people who get through the pain somehow, and it’s without a break and they still manage. I guess my admiration for [child] and for people who’ve experienced that has increased.B33, caregiverAnd then, you know, I knew that [child] had it in him that he could push himself. I just think he needed help kinda pushing himself past that initial pain.S9, caregiverTaken together, the overwhelming experience of living with chronic pain was felt by the entire family. The caregivers mostly expressed feeling anxious or sad for their child; however, they were able to shift their perception by reinterpreting this struggle as a strength. Instead of feeling sad or anxious, they expressed an admiration for their children for handling painful situations.The second theme described how the patients and caregivers felt empowered during treatment. Whereas the patients experienced becoming more confident, the caregivers gave their children more space to handle difficult situations by themselves. Both felt that they learned concrete strategies for navigating difficult situations.The patients’ experiences changed their perceptions of themselves. Many patients felt empowered and more confident. Some patients learned that they were capable of doing things despite their pain:The only thing stopping me was myself...Well of course it was my back pain and all that. But I kind of held on to my back pain a little too much, for a little bit too long.S33, patientI learned that because I’ve been in a lot of pain and I put things off, that I am actually capable of doing a lot more.B25, patientI also learned that I can do anything even with my neck pain.S24, patientOther patients expressed a more generalized sense of being capable:I am stronger than I thought I was.B31, patientI got more confident and stronger doing all the activities.B22, patientI learned that I was more determined and stronger than I thought.S17, patientTaken together, the patients changed their self-perception and appeared to be more confident in their ability to handle difficult situations in the face of pain and other challenges.The caregivers came to understand how to balance control and letting go. Some caregivers expressed that they could better see the benefits of giving their children more opportunities to handle their pain by themselves:As parents, we do want to help out and control as much as we can, and to some extent I do still believe that we should be looking out for each other, you know, trying to prevent them from having pain, if it’s possible. But if it’s, in this kind of situation with the chronic pain thing, you learn to relinquish the control more and give them more options to handle it themselves.S3, caregiverI learned that [child] can be a lot more independent than I sometimes give him credit for. So sometimes I have to ease off in helping him. So, I think I learned that it is okay to let him tumble through something because then he will feel like he really did it himself.S60, caregiverOther caregivers reported that they became more aware of the negative effects of being overly controlling:Well obviously, that we were holding her back from trying new things and not presenting things that would challenge or take her outside of her comfort zone. And we didn’t realize what we were doing.B19, caregiverI learned that I can be pretty intense and anxious which contributes to my child’s troubles or doesn’t help her cope. I learned to be more relaxed. Was too rigid before, let go of that now.B5, caregiverGenerally, the caregivers were able to hold back on responding with their initial reaction to better respond to the specific needs of their children:For me it was really about my own responses to her and how to control my responses and be more understanding of where she was at. I was so caught up in my own being tired and stuff that I was going through. I really had the opportunity to stop and take a look and understand how much she was impacted and how I could really help her.B19, caregiverTaken together, the caregivers were better able to control their initial reactions. After reflecting on the consequences of their own behavior, many caregivers said that they needed to relinquish some control to empower their children to manage challenging situations independently.The patients and caregivers broadened their knowledge of concrete strategies to better cope and live with chronic pain:But also offering additional strategies for feeling like we don’t have to be helpless in the face of the pain when it’s severe. I think that was super helpful to both of us.S22, caregiverI liked the emphasis on creating a sense of confidence and broadening the toolkit for dealing with pain and the headaches. Kind of finding ways to carry forward. To make life worth living, kind of, you know, preserve some quality of life.S22, caregiverWith strategies of knowing how to cope with pain, okay, I am gonna be able to approach those challenges of life more so because I have that tool under my belt that says, oh you are hurting today, you are not having a good day, how are you gonna get going and in the end come out the other side successful.B23, caregiverThe patients learned to break down activities in pursuit of long-term goals:I learned that taking a [small] step at a time can help me improve so much more than trying to take a big step.B36, patientI learned to just make accommodations instead of stopping the activity altogether.B30, patientI think her learning how to set goals that are achievable and measurable. And for her to be able to make them so that they are realistic. So, it was really her individualized goals. She made them up and she decided with the team where her values were.B19, caregiverThe caregivers felt that they had solid action plans to encourage activities:To give me a bit more vocabulary or instructions how to talk about things, like...“remember you wanted to do this because of the goals you set for yourself.”S60, caregiverAnd maybe just validate that we get it and when she does something that we recognize that. It does really help because when you are in the middle of it, you don’t really think about how we are going to react and it changes how she feels.B19, caregiverIt empowered us as parents to say, we know your pain is real, we know it might cause a little bit of back pain, and you can take breaks. It gave us strategies for what we can say and what we can do to help encourage her still do her everyday activities.S33, caregiverTaken together, the patients and caregivers learned concrete strategies to navigate through difficult situations. These strategies helped reduce feelings of helplessness in both the patients and caregivers.The third theme described how GET Living helped improve the relationship between patients and their caregivers. Being able to better understand the complexity of chronic pain, the caregivers were more able to validate their child’s experiences and felt closer to them. The patients also indicated that they felt more supported by their caregivers.The caregivers better understood their child’s pain experience in their day-to-day difficulties:I knew that she was hurting every day and that lots of things were difficult for her, but I think that I understand in more detail that even simple tasks, how and why they are difficult for her.S57, caregiver[Clinicians] taught me a lot regarding just [child]’s pain and how it can really, I don’t know, change her behavior. In that if [child] is grumpy or tired. I never associated the pain with her emotions before, neither did my husband. So, it was really eye opening for us to understand the correlation.S24, caregiverThe caregivers also understood the driving mechanisms of pain chronicity in more detail:I was also kind of surprised in the session when he was doing the soccer practice because he kind of attributed the time when all his leg pain started with soccer, even though soccer did not, you know, cause it.S60, caregiverIt took away my anxiety that it will hurt, but it won’t harm her. The program made her try something. And some of the things she did, I knew that she would hurt herself. Not harm herself, but hurt herself.B19, caregiverThe caregivers also reported being better able to validate the experiences of their child:It never dawned on me before about how [child] could be feeling about this because no one can see it. And we just gave her a hard time about school and that she is not feeling it. And sometimes with that they have to keep validating it and hold on to it. And maybe just validate that we get it and when she does something that we recognize that. It does really help because when you are in the middle of it, you don’t really think about how we are going to react and it changes how she feels.B19, caregiverMy mom and dad...actually knew how I feel now and what I was going through.B20, patientTaken together, the caregivers became more aware of the difficulties of their children. They better understood the impact of chronic pain on pain-related disability and distress. The caregivers also became aware of the driving mechanisms of chronic pain, including emotional responses and misattributions. This allowed them to validate their child’s experience more.The patients and caregivers reported that GET Living fostered improved family connections. The patients became more aware that they were not alone because they had their caregivers and families to support them:And that my family can help me do whatever, that I don’t just have to rely on myself to help these things. I have a support system.S33, patientI learned that my family are very enthusiastic and willing to do those things with me.S22, patientAnd my family, I think, learned if I am in pain how they can help me deal with it.S15, patientThe caregivers also felt a closer connection with their children:We kind of had a better connection than we did before. Not that we had a bad connection, it’s just the drives to the sessions.S9, caregiverI felt like some of the sessions led to more discussions with [child] and I afterwards, like I felt that there were certain things, like as a mother daughter, that it was positive.S46, caregiverTaken together, the relationships between the patients and their families improved. While the patients felt supported, the parents felt a closer connection with their children.A total of 12 ideas for improvement were prioritized in multiple groups  and are presented in Interestingly, these improvement ideas were not specific to exposure treatments and could be applied to any form of behavioral or physical pain treatment. For example, the research partners agreed that pain exposure treatment should be disseminated more. There was absolute consensus  that pain exposure treatment should use patient testimonials to (1) provide patients with narratives of how other patients are dealing with similar difficulties, (2) inform future patients about what treatment will be like, (3) provide a role model, and (4) promote positive expectations. Most research partners also agreed that more efforts should be made to create awareness among the general public and primary care providers to facilitate an early referral for treatment .A total of 13 treatment elements were considered helpful in promoting change in multiple groups , break long-term goals into smaller steps , and help patients become aware of their own values and motivators .Overall, the co-design meetings were evaluated as good, with mean values being consistently at the upper end of the agreement scale  and 6. TThis study looked at a multidisciplinary exposure treatment for youths with chronic pain through the lens of patients and caregivers. First, qualitative analysis of exit interviews conducted with patients and caregivers after they received the GET Living intervention explored the treatment change processes. Second, co-design meetings with patients and caregivers as research partners aimed to refine the GET Living intervention. The implications of both aspects are discussed in the subsequent sections.The qualitative analysis revealed a wide range of treatment change processes, indicating that what happens within patients during treatment is complex and difficult to describe from a single theoretical lens . The patThe research partners prioritized 13 core treatment elements that were helpful in promoting change. This feedback can directly inform clinicians which specific behaviors and techniques are perceived as impactful. This is informative for clinicians in general but especially in settings with time constraints. For example, a majority of the research partners agreed that future exposure treatments should continue to assist patients in finding and pursuing meaningful goals. This recommendation agreed with pain scientists, who advise combining exposure treatment with clarification interventions to identify personal goals and goal conflicts . Such teThe research partners also agreed upon 12 ideas for improvement. At their core, these ideas suggest that pain treatments should be disseminated more, flexible, and transparent. The research partners advised that there should be a platform for exchange between people with lived experiences and that the complexity of the individual pain experience should be acknowledged. To our surprise, most ideas were not specific to the content and refinement of exposure treatment; instead, they could inform the implementation of behavioral or physical pain treatments more broadly.The research partners conveyed that increasing the access to and dissemination of pain psychology treatment is of upmost importance, a message also building momentum among pain scientists . At the The research partners considered the remote delivery format with optional in-person check-ins  as promising beyond the pandemic, which aligns with initiatives underway in the pain treatment field, as the pandemic has accelerated the dissemination of remotely delivered pain management services . ContinuWe provided an in-depth analysis of a specialized multidisciplinary exposure treatment for youths with chronic pain. Although we provided an overview of the change processes experienced by patients and caregivers, we could establish whether they contributed to the overall improvement  using the methods we adopted. The patients and caregivers did not report having experienced treatment side effects, although it should be noted that we included only treatment completers in the thematic analysis. We also did not explicitly ask about treatment side effects. Our findings may not be generalizable to other behavioral pain treatments or pain populations, although it is likely that the fundamental processes identified are cross-cutting. Multiple co-design meetings allowed us to establish consensus within and between groups. This can be taken as an estimate of the representativeness of the expressed opinions. However, the included research partners were not representative, even of the US population, in terms of underrepresented groups, with most research partners being White and female. The study was conducted within the US health care system, and the results may not be generalizable to other health care systems and countries. In Germany, for example, the distances between patients’ homes and outpatient pediatric care centers are smaller, and the acceptance of internet-delivered treatments is rather low . We did The GET Living team is poised to iterate and implement the advice learned from the patients and caregivers as research partners. Planned modifications span 3 key domains: publicity and education, treatment delivery, and supporting families after treatment completion. We intend to develop video testimonials that weave in the ingredients the patients and caregivers defined as essential, namely the opportunity to process pain-related emotions, feeling empowered, and improving their relationship with one another. In addition to patient and parent testimonials, we would like to roll out an advertising campaign that targets both patient families and providers regarding the role of psychology in pain treatment and in some instances, more specifically, the GET Living treatment approach. These 2 publicity and education initiatives will better elucidate treatment aims, address misconceptions, and cultivate positive expectations regarding treatment. In the realm of treatment delivery, we have demonstrated in our latest clinical trial the capability to deliver GET Living remotely , and a cThis study has revealed several powerful implications that should be considered in future treatments and studies. The exit interviews with the patients and caregivers demonstrated the full complexity of treatment change processes. The research partners agreed that pain exposure treatment should be disseminated more, flexible, and transparent. These implications would not have been revealed if only traditional outcome and facility measures had been used. The clear and meaningful outcomes of this study strongly support the involvement of patients and caregivers in pain treatment manual developments and pain study designs.


To compare the efficacy and side effects of sufentanil and morphine titration for patient-controlled subcutaneous analgesia (PCSA) in severe advanced cancer pain management.A retrospective analysis was performed on the patients who were treated by two cancer centers with PCSA for severe advanced cancer pain at the Fourth Hospital of Hebei Medical University and Baoding No.1 Hospital between 2018 and 2021. These patients were divided into a sufentanil group and a morphine group. The drug dosage of the two groups was recorded. The pain intensity, sleep quality and adverse event rate (AER) were compared and analyzed between the two groups.PCSA was successful in 95.2% (120/126) of the patients. In all cases, titration was successful within 24 hour, followed by oral administration of sustained-release opioid medications at 208.4 ±75.1 mg in the sufentanil group and at 207.9±66.3 mg in the morphine group. There was a significant difference in pain intensity and sleep quality before and after titration (P <0.05). Both groups exhibited a decline in their heart rates during titration. Compared with the baselines before titration, the mean heart rates were significantly reduced in both groups (P <0.05). The sufentanil group had an AER lower than that of the morphine group.Short-term use of sufentanil supports PCSA for patients with severe advanced cancer pain can achieve effective and rapid pain management, it is worth clinical implementation and application. With the number of cancer patients increasing, cancer pain has become a major public health concern around the world.5Morphine is a typical opioid drug usually used in the studies of other opioid medications as the control drug and is commonly used for rapid titration and maintenance therapy in advanced cancer pain management. However, morphine may sometimes produce strong adverse reactions, such as respiratory depression and hypotension.The retrospective analysis involved 126 patients who received PCSA for advanced cancer pain at the Fourth Hospital of Hebei Medical University and Baoding No.1 Hospital during 2018 and 2021. Patient data including demographic data, diagnosis of primary cancer, pre-PCSA use of opioid medications and baseline dosage were retrieved from electronic medical record systems. This study was approved by the Medical Ethics Committees of the Fourth Hospital of Hebei Medical University and Baoding No.1 Hospital on November 10, 2018 (No. [2018]108), and written informed consent was obtained from all participants or their family members.Patients confirmed to have malignant solid tumors based on pathological or cytological diagnosis;Persistent, severe pain with a score of 7 and above at the onset based on the 11-point numeric rating scale (NRS), where ‘0’ represented ‘no pain’ and ‘10’ stood for ‘worst pain imaginable’.10All eligible patients were free of cognitive impairment and acted cooperatively in pain and satisfaction rating.Patients who received PCSA for less than 24 hours or whose clinical data were meaningless;Titration failure due to any reasons.A total of 120 patients with successful titration were recruited for subsequent analysis, including 62 receiving PCSA titration with sufentanil and the rest 58 undergoing PCSA titration with morphine.Titration method: All forms of opioid medications were discontinued before titration to calculate the dose of opioid and convert to an equivalent dose of subcutaneous morphine or sufentanil (N0). Dose determination dependent on pain intensity: I. Mild (1 <NRS <4): increase by 25%; II. Moderate pain (4 ≤NRS <7): increase by 50%; III. Severe pain (NRS ≥7): increase by 75% to 100%. An estimated increase in the dose (N1) was determined. Parameter setting: The ratio of loading dose to background dose was 1.5. Background dose: (0.5-1) (N0+N1) / 24 h. PCA dose: (1-1.2) times the background dose. Lock-on: 15 minutes. Extreme limit: (1/4) (N0+N1)/h. The actual dose of subcutaneous titration for 24 hour (N2) was calculated and converted to the equivalent dose of controlled- or sustained-release opioid medications. Following the 24-hour titration, the PCA pump was used for another 12 hour and was not withdrawn until the controlled- or sustained-release opioid medications fully took effect.Continuous subcutaneous infusion (CSCI) was converted to oral opioid medications at the ratio of 1:2 - 2 mg of oral morphine was substituted for CSCI with 1mg of morphine. The potency ratio of morphine to sufentanil was 1:1000.(1) Pain intensity and sleep quality assessment: Pain intensity and sleep quality were evaluated before PCAS via titration using the NRS and the Pittsburgh Sleep Quality Index (PSQI), with the global PSQI score ranging from one to 21 and a higher score suggesting worse sleep quality. The following outcome measures were recorded at different time points : mean NRS score, blood pressure, heart rate, and PSQI score at different time points; adverse reactions such as respiratory depression, bradycardia, hypotension, drowsiness, nausea or vomiting, urinary retention, constipation, and itching.2) test, with the significance level at P <0.05.The software SPSS19.0 was used for statistical analysis. Measurement data were expressed by “mean ± standard deviation (-χ±SD)”, examined by the paired sample t-test. Enumeration data were represented by percentage (%) and examined by the chi-squared  . The preBoth groups reported poor sleep quality before titration. The two groups exhibited a remarkable improvement in sleep quality at 24 hour after titration, which continued to improve after switching to the oral administration of controlled- or sustained-release opioid medications , represeThere was no significant difference in heart rate between the two groups before titration. After titration and switching to controlled- or sustained-release opioid medications, heart rates tended to decrease in both groups , and yet the two groups showed no statistically significant difference . ResultsIn China, about 4 million patients are newly diagnosed with cancer every year, and 60% to 70% experience cancer pain during the advanced stage.13,14 Clinicians mostly follow the WHO three step analgesic ladder to achieve satisfactory pain control by oral administration of controlled- or sustained-release opioid medications. For rapid relief of severe pain, clinicians should consider parenteral opioids via subcutaneous or intravenous injection. Titration is preferred to reduce side effects and ensure optimal pain control through dose adjustment. PCSA is suitable for patients with advanced cancer pain as it offers a convenient administration route in cancer pain management and nursing care, without seriously affecting daily activities or causing aeroembolism.15,16 PCSA is reported to yield a plateau concentration in 12-24 hour.5 In this study, mean NRS scores were remarkably reduced in both groups receiving PCSA titration with sufentanil or morphine, while higher patient satisfaction levels were observed; moreover, opioid-related adverse reactions were not evident, and catheter- or pump-related adverse events did not occur throughout the treatment course.Injectable morphine is currently the clinical mainstay of titration or maintenance therapy for advanced cancer pain management. Morphine binds to glucuronide to produce morphine-3-glucuronide (M3G) and morphine-6-glucuronide (M6G). As a highly hydrophilic metabolite, M6G displays strong analgesic properties; in contrast, the other metabolite M3G appears to be associated with morphine-related neurotoxicity, which cannot bind to opioid receptors or stimulate analgesic activities.17 Additionally, injectable morphine can induce severe adverse reactions such as respiratory depression, dizziness, nausea, vomiting. In this study, 58 patients were treated by PCSA titration with morphine and 62 by PCSA titration with sufentanil. PCSA titration was successful in all cases within 24 h and then switched to sustained-release oral opioid medications. This demonstrated the feasibility and practicability of short-term PCSA titration with sufentanil or morphine to achieve satisfactory analgesia, where adverse reactions occurred less frequently in the sufentanil group as compared with the morphine group.Sufentaniln is a 4-Anilinopiperidine derivative like fentanyl. The opioid analgesic sufentanil is one thousand times more potent than morphine and surpasses morphine in safety and analgesic threshold.11 Pharmacokinetics demonstrates that sufentanil is especially effective in treating cancer patients with renal impairment.18 Sufentanil is reported to work faster in cancer pain management, where patients are less likely to develop opioid resistance.19 The statistical analysis in this study showed that sufentanil titration did not increase opioid use or induce drug accumulation or poisoning by 24-hour rapid titration. In short, sufentanil is comparable to morphine in PCSA titration for rapid pain control. Meanwhile, adverse events occurred less frequently in PCSA titration with sufentanil as compared with PCSA titration with morphine, conforming to the findings reported by Wan CF et al.8 Intense pain is known to trigger physical stress that induces increased pulse rate, blood pressure and respiratory rate. The study results demonstrated reduced heart rates in both groups after titration probably because of effective pain control.This retrospective study has its own limitations as no data is available to investigate the effects of PCSA on anxiety, depression and quality of life in cancer patients. In addition, this study did not cover the difference in hospital costs between rapid titration with wireless analgesic pump and conventional titration.Short-term use of sufentanil supports PCSA for patients with severe advanced cancer pain to achieve effective and rapid pain management with a relatively low AER and can be successfully switched to controlled- or sustained-release opioid medications.DL designed this study. prepared this manuscript, are responsible and accountable for the accuracy and integrity of the work.LC collected and analyzed clinical data.WL Data analysis, significantly revised this manuscript.


The acute clinical repercussions of SARS-CoV-2 infection have been widely studied. However, the possible late repercussions of long COVID have not yet been well defined in the literature.To identify the presence of pain and musculoskeletal disability in patients with Long COVID and also to identify predictive factors for pain intensity in this population.In this cross-sectional and retrospective observational study individuals with Long COVID symptoms were included. It was collected musculoskeletal disability measures, data from patient-related outcome measures and variables from a COVID-19 outpatient service database. Associations and sub-group analyses were performed considering the variables pain, disability and hospitalization. Linear regression was performed to identify predictive factors for pain intensity in Long COVID patients.r = 0.21; p = 0.003); days in intensive care unit  and days in invasive mechanical ventilation . Hospitalized individuals showed a higher chance of presenting late musculoskeletal pain (OR = 1.42: 95%CI 1.09–2.04). Days in intensive care unit  and days in invasive mechanical ventilation (β = 0.764: P = 0.001) were predictors of pain intensity .We evaluated 195 patients and most of them (57%) presented musculoskeletal pain in one area of the body. Pain sub-group presented worse disability indices and worse clinical course during hospitalization. Hospitalized patients presented worse disability indices comparing to non-hospitalized. Significant correlations were found between pain and days of non-invasive oxygen support (Individuals with Long COVID presented musculoskeletal pain and disability. Hospitalized patients showed a greater chance of having musculoskeletal pain. Days in intensive care unit and days in invasive mechanical ventilation were predictors of late musculoskeletal pain intensity. The acute clinical repercussions of SARS-CoV-2 infection have been widely studied since the beginning of the pandemic scenario –3. HowevMusculoskeletal manifestations in COVID-19 have being studied by different researches groups , 16–19. The investigation of the possible variables associated with musculoskeletal pain in Long COVID patients is still incipient and the causal relationships for musculoskeletal pain in these patients are not yet well established in the literature. The discussion about variables that may help in the construction of explicative models for pain occurrence in Long COVID patients should be stimulated in different populations. Thus, the aim of this study were to identify the presence of pain and Musculoskeletal disability in patients with Long COVID and also to identify predictive factors for pain intensity in this population.This cross-sectional and retrospective observational study included musculoskeletal disability measures, patient-related outcome measures and database analysis. The study has been carried out following the Helsinki Declaration and obtained approval from the Research Ethics Committee at Centro Universitário Augusto Motta (UNISUAM). It was approved under the number CAAE 48074921.7.0000.5235. The informed consent was presented to all patients, and it must be signed before data collection. This research report followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement.Participants were recruited through face-to-face assessments. Patients who attended the Post-COVID-19 Outpatient Service of the Rio de Janeiro Military Police Physiatrics and Rehabilitation Center (CFRPM-RJ) between July 2020 and March 2022 were invited to participate. Patients were referred after a medical consultation at the Central Hospital of the Rio de Janeiro Military Police (HCPM-RJ). The CFRPM-RJ is a Military Police health unit that has an outpatient service and monitors all patients who had at least one medical consultation due to COVID-19 symptoms with or without a hospitalization history.The following inclusion criteria were considered: (1) individuals over 18 years old; (2) more than 90 days of positive COVID RT-PCR test, considering the moment of enrollment; and (3) individuals who had any musculoskeletal pain complaint that did not exist before the diagnosis of COVID-19. Exclusion criteria were: (1) patients with any surgical intervention for at least 3 months before diagnosis; (2) individuals undergoing current cancer treatment; (3) individuals with a history of walking limitations before diagnosis; and (4) individuals with cognitive or functional alterations that made it impossible to perform the tests.The sample size calculation considered a model for regression analysis with 3 possible predictors of pain intensity (main outcome) in the GPower 3.1 Software. Because there is no consensus in the literature regarding the possible associated or predictive variables of late pain in this patient profile, the sample size calculation considered an effect size of 0.10, with a statistical power of 80% and an error of 5%. The calculation showed the necessity to include 176 participants in the research. The sample size calculation for the other analyses of possible associations between the variables required entering a smaller number of participants than the number of patients that were included for regression analysis.The outpatient evaluation collected sociodemographic and clinical data from the participants . The patients were asked at the moment of the assessment if they had been hospitalized and the patient’s medical record was consulted in the hospitalization sector. The following data related to hospitalization were collected: days of hospitalization, days in non-invasive oxygen support, days in intensive care unit (ICU) and days in invasive mechanical ventilation (MV).The following measurement instruments were applied in order to identify pain intensity and musculoskeletal disability: the Numerical Pain Rating Scale (NPRS); Fatigue Pictogram; Berg Balance Scale; the Post COVID Functional Scale (PCFS) and the 10-meter Walk Test. All evaluations were performed by a single evaluator, a physiotherapist, with more than 15 years of experience in the area of musculoskeletal rehabilitation, under the supervision of a senior researcher with experience in clinical research.Pain assessment was performed using the Numerical Pain Rating Scale (NPRS). This is a simple 11-point scale with data that is easy to document and interpret and is very useful in pain assessment, graded from 0 (zero)—no pain, to 10 (ten)—worst pain , 26.Fatigue assessment was performed using the Fatigue Pictogram . PictogrRegarding the assessment of balance and risk of falling, we used the Berg Balance Scale . The insThe Post-COVID-19 Functional Status Scale was also applied to investigate disability . This inThe 10-meter Walk Test was also applied. It consists in timing a free ten meters of walking in the usual speed . StartinThe Shapiro-Wilk tests suggested a normal distribution of variables. The clinical profile and characteristics of the sample were described using means and standard deviation or occurrence frequency (percentage).t-test for two independent samples was applied for these analyses.Two subgroup analyses were performed: one comparing disability and pain intensity means from hospitalized and non-hospitalized individuals; and another one comparing disability and data hospitalization means from patients with and without pain. The Student´s Possible associations between disability variables, hospitalization data and pain intensity were evaluated. Pearson’s coefficient correlation was applied to identify possible correlations between continuous variables. The odds ratio was used to quantify associations for categorical variables.To identify predictive factors for pain a linear regression analysis was performed. The model considered pain intensity as a dependent variable and days of hospitalization, days in intensive care unit and days in invasive mechanical ventilation support as independent variables. The model was built using the backward regression method, starting from a model with all variables and eliminating non-significant variables. Data were analyzed using the JASP Version 16.3 assuming a significance level of 5%.2 (DP 4.8). We observed that 121 (62%) participants presented systemic arterial hypertension, 87 (45%) were diabetic, 35 (18%) were smokers, and most of the sample (n = 165) was hospitalized due to COVID-19 (85%). Most patients, 112 (57%), reported musculoskeletal pain in one region of the body at the moment of the evaluation and 83 patients (43%) presented pain complain in 2 or more body areas. The average of data collect presented 120 days (SD 2) after COVID-19 diagnosis. A total of 195 participants were included in the study. The population had a mean age of 54.74 years (SD 11.12), 137 (70%) were males, 58 (29%) were females and the BMI mean was 35.31 kg/mn = 165) and non-hospitalized patients (n = 30) significant differences were also found in the means of pain intensity and disability variables collected. The results showed that the hospitalized patients presented worse disability indices and more pain. The means of these both groups are shown in Comparing the sub-groups of hospitalized patients (n = 112) versus patients without pain (n = 83) significant differences were found in disability variables means and also in the hospitalization data collected. The results showed that the group with pain presented worse disability indices and worse clinical course during hospitalization. The means of both groups are show in Comparing the sub-groups patients with pain . Thus, individuals with a longer duration of mechanical ventilation had greater pain intensity. A negative correlation was also observed between the value obtained on the Berg Scale and pain . Thus, a lower index on the Berg Balance Scale was associated to pain intensity. A correlation was also identified between the value on the scale and pain intensity . The higher the value on the PCFS score , the greater the pain intensity. The pain intensity also showed a correlation with the fatigue pictogram . Correlation analyses are described in The correlation analysis showed a positive correlation between mechanical ventilation duration and pain intensity .R2 = 0.342; P = 0.13]. A second model considering the variables days in the intensive care unit and days in invasive mechanical ventilation support found statistical significance . The independent variables showed low level of correlation but the model didn’t present multicollinearity. It was identified that the variables “days in intensive care unit”  and “days in invasive mechanical ventilation support”  were predictors of pain intensity.The regression analysis used first an exploratory model, including pain intensity as a dependent variable and days of hospitalization, days in intensive care unit, and days in invasive mechanical ventilation support as independent variables. However, this model did not show statistical significance [F = 11.357; The findings indicate that musculoskeletal pain had a high prevalence in the observed population with Long-COVID and participants with pain presented worse disability indices and worse disease clinical course during hospitalization. Hospitalized patients also presented worse disability indices. The odds ratio analysis in our sample showed that hospitalized patients had more chance to present late musculoskeletal pain when compared to non-hospitalized ones. Days in intensive care unit and days in invasive mechanical ventilation support were predictive variables for pain intensity.The findings about the prevalence of late musculoskeletal pain in Long-COVID patients corroborate with studies in different populations from different parts of the world. A systematic review conducted by Akbarialiabad et al. reported a prevalence of 51% for late musculoskeletal pain in patients with more than 6 months after COVID-19 diagnosis . Soares Our findings high lightened the importance of continuous assessment of COVID-19 patients even after hospital discharge. The impact of Long-COVID on aspects such as gait, balance, and daily life activities should also be considered by health professionals. Similar findings were reported by Giardini et al. that found worse performance on static and dynamic balance measures in post-COVID-19 patients compared to healthy individuals . Pant etThe finding regarding the predictive variables of musculoskeletal pain intensity is another important message for clinicians , 36. It Our study has some limitations. We should face that the lack of a control group (non-COVID) does not allow us to isolate the real impact of COVID-19 on the participants. Data collection occurred in only one healthcare center and data analysis comparing different sample size sub-groups could have decreased the statistical power. However, the findings of some pain predictive variables in this study can collaborate with discussions about musculoskeletal complaints in Long-COVID and intensive care syndrome patients.Musculoskeletal pain had a high prevalence in the observed population with Long-COVID. Patients with pain presented worse disability indices and worse clinical course during hospitalization. Hospitalized patients showed more chance to present late musculoskeletal pain comparing to non-hospitalized ones. Days in intensive care unit and days in invasive mechanical ventilation support were predictive variables for pain intensity.


Objective: Chronic low back pain in children is a condition that should be investigated. In this study, we examined the effects of agricultural work on imaging results, risk factors, night pain, and vitamin D levels in children and adolescents with chronic low back pain.Material and methods: The study included 133 patients who presented to the Physical Medicine and Rehabilitation and Neurosurgery outpatient clinics with low back pain that had lasted more than three months. The patients were evaluated based on the duration of their low back pain, the presence of night pain, a family history of low back pain, their employment status, local or radicular pain, and their body mass index (BMI). A physical examination was carried out to look into the etiologies of low back pain. Appropriate imaging, such as x-ray radiography, magnetic resonance imaging (MRI), and computed tomography (CT), was performed for the patients. Blood samples were collected from patients to assess inflammatory pathologies and vitamin D levels.Results: The 133 patients in the study ranged in age from seven to 16 years, with a mean age of 14.3 + 1.9 years. Further, 60.2% (n = 80) of the cases were male, while 39.8% (n = 53) were female. Imaging revealed findings in 59.4% of the patients. In 97.7% of the participants, D hypovitaminosis was detected. There was no significant relationship between the patients’ imaging findings and vitamin D deficiency, family history, BMI, and employment status . The relationship between family history, employment status, and night pain was statistically significant (p < 0.001). There was no statistically significant relationship between night pain and vitamin D deficiency (p = 0.667).Conclusion: Mechanical strain due to agricultural work and family history was found to be associated with night pain in patients with chronic low back pain in our study. The most important finding of this study is that night pain, which is considered a red flag, can occur in both inflammatory pathologies and situations causing mechanical low back pain, and risk factors should be thoroughly investigated. Studies with patients who have sufficient vitamin D will help to clarify the relationship between chronic low back pain and vitamin D. Low back pain is a common condition in children that worsens with age. While it occurs at a rate of 1% in early childhood, it can reach 50% in adolescence. Moreover, 80% of people have at least one occurrence before the age of 20. Low back pain in childhood also increases the likelihood of having low back pain in adulthood . FurtherAccording to studies, obesity, female gender, increased screen exposure, sedentary lifestyle, depression, catastrophe, low socioeconomic level, child labor, accompanying systemic diseases, postural disorders, non-ergonomic study and sitting positions, sleep disorders, and hypermobility have all been linked to chronic low back pain .Llow back pain 80%) in children is caused by muscle spasms, which are easily treated and are referred to as non-specific low back pain. However, in pediatric patients, conditions such as disc pathologies, spondylolisthesis, spondylolysis, scoliosis, vertebral alignment disorders, Scheuermann's disease, juvenile fibromyalgia, infections, tumoral formations, and ankylosing spondylitis, which can be diagnosed and treated, can be classified as specific low back pain -7. Chron0% in chiWhen evaluating a pediatric patient presenting with low back pain, conditions such as night pain, pain lasting more than four weeks, constant pain, weight loss, incontinence, immunosuppression, trauma, and neurologic deficits, which we call red flags, should be questioned. As a rule, applications from patients under the age of seven should be evaluated as a red flag and a detailed examination should be performed ,9.During the patient examination, which begins with an inspection, conditions such as posture, gait disturbance, and skin pigmentation changes should be examined. A thorough neurological examination should be performed on the patient, and the range of motion of the joint should be measured in all directions. Starting with the painless area, palpation should be performed. The Adam test should be used to assess patients for scoliosis. Sciatic and femoral nerve stretching tests should be performed on eligible patients ,10.In cases where non-specific low back pain is considered, imaging is not required in the initial evaluation. Patients who have red flags should begin with x-rays and, if necessary, advanced examination techniques such as magnetic resonance imaging (MRI) for soft tissue and disc pathologies, computed tomography (CT) and scintigraphy for bone pathologies. Blood tests should be performed on patients who require them, and treatment should begin immediately ,6,11,12.Vitamin D deficiency is a common condition in society and among children. The 25-(OH)D3 form is frequently measured in routine laboratory tests. 25-(OH)D3 values are evaluated as ≤20 ng/mL deficiency, 21-29 ng/mL deficiency, and ≥30 ng/mL adequate. Moreover, vitamin D deficiency in children has been linked to low back pain, and chronic low back pain has been associated with D hypovitaminosis -16. In tThis study included 133 children and adolescents who presented to Şanlıurfa Training and Research Hospital with a complaint of chronic low back pain and who presented to the Physical Medicine and Rehabilitation and Neurosurgery outpatient clinics with low back pain lasting more than three months between April 1, 2020 and October 31, 2020, and whose informed consent form was obtained from their parents.The patients were evaluated based on the duration of their low back pain, the presence of night pain, a family history of low back pain, their employment status, local or radicular pain, and their body mass index (BMI). For the etiology of the patients, appropriate imaging such as x-ray, MRI, and CT was performed. Blood samples were collected from patients to assess inflammatory pathologies and vitamin D levels. After fasting for 8 h, blood was drawn from the cubital vein. The 25-(OH)D3 chemiluminescence immunoassay method was used to determine vitamin D levels. Since only three of the patients had sufficient vitamin D levels in the examinations, the patients were divided into two groups: those with vitamin D deficiency and those without (insufficient and sufficient). At the end of the study, it was determined whether the patients’ night pain, low back pain in the family, employment status, and etiology were related to vitamin D.The Harran University Faculty of Medicine Clinical Research Ethics Committee approved this study . The study was planned in accordance with the Helsinki Declaration.http://www.medcalc.org; 2013) was used for the analyses.To define continuous variables in statistical analysis, descriptive statistics are mean (mean), standard deviation (sd), minimum (min), median (med), and maximum (max). The descriptive statistics of categorical variables were calculated using frequency and percentage values. The Mann-Whitney U test was used to compare independent and non-normally distributed continuous variables. Chi-square or, where appropriate, Yates correction for continuity was used to compare categorical variables. The statistical significance level was set at p < 0.005. MedCalc Statistical Software version 12.7.7  of the cases were male, while 39.8% (n = 53) were female. Table The patients were classified based on the etiological diagnosis they received following imaging. Findings were found in 59.4% (n = 79) of the patients who underwent imaging. Disc pathology was detected in 78.5% (n = 62) of the patients with imaging findings. Patients with disc pathologies account for 46.6% of all patients. Disc bulging was detected in 90.3% (n = 56) of patients with disc pathology, while disc protrusion was detected in 9.7% (n = 6). The levels of patients with bulging were L4-5 and L5-S1. After disc pathologies, structural pathologies are the second most common imaging finding, and scoliosis was found in seven patients after a positive Adam test, and spondylolisthesis was found in four patients. Three of the patients with spondylolisthesis were female, with their lumbar levels ranging from L5 to S1. The etiology of low back pain was found to be sacroiliitis in five patients, accounting for 3.8% of all patients. After a five-month trauma, a fracture in the L1 vertebra was discovered in one patient. Immunosuppression, cancer, and infection were not found in any of the patients.Moreover, 44.4% (n = 59) of the patients were employed. In 97.7% (n = 129) of the patients, the pain was localized to the lumbar region. In four patients, the pain was radicular. There were no motor deficits among the patients in the study. In two patients, the sciatic nerve stretch test (Straight Leg Raise Test and Lasegue) was positive.A family history of low back pain was discovered in 51.1% (n = 68) of the study participants. Night pain was detected in 66 patients, accounting for 49.6% of the total. According to BMI, three patients were obese, 12 were overweight, 10 were underweight, and 108 were within normal weight limits.In three of the patients, the vitamin D level was ≥30 ng/mL, which was sufficient. Vitamin D levels were insufficient (between 21 and 29 ng/mL) in 90 patients and deficiency (≤20 ng/mL) in 40 patients -16. VitaWhile medical therapy, physical therapy, and rest are recommended for 96.2% of patients, surgery is recommended for five patients due to spondylolisthesis and fracture.There was no significant difference between the groups when the patients were examined as those with and without imaging findings, based on their working status (p = 0.605). There was no statistically significant correlation between imaging findings and whether there was a family history of low back pain (p = 0.147) Table .Between the patients' vitamin D levels and imaging was no statistically significant correlation . When the patients were divided into groups based on their vitamin D status, there was no significant difference in terms of night pain (p = 0.667).While 63.6% of those suffering from night pain work, 36.4% do not. This ratio differs statistically significantly (p < 0.001) Night pain affects 73.5% of those with a family history of low back pain, but only 24.6% of those without a family history. There was a statistically significant link between family history and night pain (p < 0.001)  as well as between the patients' vitamin D status and gender (p = 0.169). While 72.9% of working patients are male, 50% are non-working patients. Male employees make up a larger proportion of the workforce. The difference is statistically significant (p = 0.012).Low back pain is a common condition in children that can lead to serious complications. Since chronic pain is one of the red flags in pediatric patients, its etiology should be determined quickly and treated with a multidisciplinary approach if necessary ,5,7,8.Having a family history of low back pain, being under emotional stress, and leading a sedentary lifestyle all increase the risk of low back pain becoming chronic ,18. A faImaging findings were discovered in 59.4% of the patients in our study. Moreover, the most common etiologies were disc pathologies and scoliosis. In a study by Yang et al., the most common diagnoses in adolescents with spasms and strain in the low back muscles were disc pathology and scoliosis . Our finAlthough studies have found that low back pain is more common in females in children and adolescents, other studies have concluded that there is no relationship with gender . There wThe patients in our study were younger than 18 years old, the pain lasted longer than three months, and night pain was all red flags. In the literature, night pain, in particular, has been shown to occur in serious conditions such as malignancy, metastatic malignancy, infection, and spondyloarthropathy ,9,21. InVitamin D hypovitaminosis affects 97.7% of our patients. Moreover, 67.7% of the patients were vitamin D deficient. In the literature, due to differences in data from countries, the level of vitamin D in children and adolescents varies between 19% and 60%, and the level of deficiency varies between 7% and 68% . StudiesThe limitation of our study was the small number of participants who had adequate vitamin D levels.When the results of our study were examined, it was discovered that night pain was associated with work status and family history, implying that mechanical strain and family history in our patients could be risk factors for nocturnal low back pain. It is important to remember that the underlying cause of night pain, which is one of the red flags, could be an inflammatory pathology. However, we have determined in our study that night pain can also occur in conditions such as disc degeneration and structural disorders. Due to the small number of participants with adequate vitamin D levels, the statistical difference between vitamin D status and night pain may have been insignificant. Studies with a large number of participants and a patient group with adequate vitamin D levels will help to shed light on these issues.


Aim and Objective: To compare the analgesic effectiveness of the patient-controlled inhaled nitrous oxide (Entonox®) with intravenous opioids (pethidine/midazolam) in reducing pain during minor gynecological operative procedures, including manual vacuum aspiration (MVA), fractional curettage and dilatation and curettage. Materials and Methods: Patients undergoing minor gynecological procedures from August 2021 to December 2022 were randomized to receive nitrous oxide or intravenous pethidine (50–75 micrograms) plus midazolam (2 mg). Pain scores during and post-procedure, satisfaction level, and side effects were assessed and compared. Results: A total of 106 patients met the inclusion criteria, including 53 in the pethidine/midazolam group and 53 in the nitrous oxide group. Baseline characteristics were comparable . Pain scores during, immediately and 30 min after procedures were not significantly different in two groups . However, the rate of side effects was significantly lower in the nitrous oxide group . Additionally, the discharge scores showed a significantly faster recovery time in the nitrous oxide group at 60 and 90 min after the procedure; median (IQR): 10 (9–10) vs. 9 (8–10) and 10 (10–10) vs. 10 (8.5–10); p-value 0.002 and 0.029, respectively). Conclusions: Nitrous oxide is as effective as pethidine/midazolam for pain relief in minor gynecological operative procedures but associated with significantly lower side effects and significantly faster recovery time. Minor gynecological operative procedures, including dilatation curettage, fractional curettage, or manual vacuum aspiration, are commonly performed in daily gynecologic practice. Typically, the device is inserted through the cervical canal into the uterine cavity to obtain the tissue for diagnosis or treatment. Common indications for such procedures include abnormal uterine bleeding, termination of early pregnancy, evacuation of miscarriages, and retained pieces of the placenta or conceptive products. Although these are brief procedures lasting for 10–15 min and can be performed in an outpatient setting, the procedures are often associated with significant pain or uterine cramps during curettage, similar to labor pain. Therefore, pain management is an important component of the procedures for successful outcomes without complications.® is more convenient to administer than intramuscular injection of pethidine.Intravenous opioid derivatives and benzodiazepines are commonly used for pain management during a minor gynecological operative procedure. In addition, in our practice, we usually use pethidine (meperidine) for pain control as a method of choice because it is inexpensive, available, and has a rapid onset of action in about 5 min. Typically, pethidine combined with midazolam or diazepam, a benzodiazepine for anxiolysis, releases an effect in about 45 min with a duration of action of up to 2–4 h. Nevertheless, pethidine/midazolam is often associated with several side effects, such as respiratory depression, tachycardia, hypotension, and gastrointestinal symptoms. Additionally, Entonox®, a mixture of 50% nitrous oxide (N2O) and 50% oxygen, used as a self-controlled inhaled gas for pain control, has become widely available. Entonox® provides analgesic, anxiolytic, and amnesic effcts [® provided better pain relief for labor pain compared to a single dose of pethidine 30 min after intervention. Nevertheless, studies on nitrous oxide for pain relief in gynecologic procedures have been published in a very limited number. Del Valle Rubido et al. [®) with intravenous opioids (pethidine and midazolam) in reducing pain during minor gynecological operative procedures, including fractional curettage, dilatation and curettage and manual vacuum aspiration (MVA).Currently, Entonoxc effcts . Since is oxide NO and 50%c effcts , and colc effcts , and is c effcts  demonstro et al.  demonstrThis study is a single-center, prospective, randomized, open-label controlled trial in two parallel arms to compare the analgesic efficacy of the patient-controlled inhaled nitrous oxide with pethidine/midazolam at Maharaj Nakorn Chiang Mai hospital, Chiang Mai University, Thailand  between August 2021 to December 2022. The study was ethically approved by the Institutional Review Board (Research ID: OBG-2564-08098). The project was registered for clinical control trial study at the Thai Clinical Trials Registry (TCTR20230107003). All of the participants were invited to participate in the study and were systematically informed about the objective and intervention of the research. Written informed consent was provided by all participants. The study population was gynecologic patients undergoing minor gynecologic procedures in an outpatient setting. The women met the following inclusion criteria: (1) age of greater than 18 years; (2) indicated for minor surgical procedures including dilatation and curettage, fractional curettage, and manual vacuum aspiration (MVA); (3) understanding of the study and capable of self-controlled inhaled nitrous oxide administration. The exclusion criteria were as follows: (1) unstable hemodynamics; (2) contraindicated for medications used in the study, such as the history of severe respiratory or cardiac disease, thyroid disease, neurological disorder, renal disease, upper respiratory infections or sinus blockage, the recent history of middle or inner ear surgery, pneumothorax or intestinal obstruction, and ASA physical status III/IV; (3) patients with a history of a previous gynecologic procedure such as curettage.All participants were randomly allocated to one of the two groups: the group using nitrous oxide and the group using pethidine/midazolam for pain relief during the procedure. A randomization scheme was prepared and organized by one of the authors (NL) prior to the beginning of the study, and the code for each participant was kept in a sealed, black opaque envelope. The randomization was a ratio of one-to-one, using a computer-generated block randomization sequence with a random sequence with a block size of 4. This was an open-label controlled trial. The patients, care providers, and study investigators were not blinded to the study group. After randomization, the women could withdraw from the study at any time.Study protocol: Baseline characteristics, including obstetric and gynecologic history as well as indication for the procedures, were prospectively collected and recorded in a research form. After enrollment and randomized allocation, the participants in the pethidine/midazolam group were given 50 mg of pethidine and 2 mg of midazolam intravenously 5 min before starting the procedure, whereas those in the nitrous oxide group were instructed to begin inhalation via mouthpiece 2 min before starting the procedure and continued inhaling gas when she felt pain or until the end of the procedure. The participants in the nitrous oxide group were trained for the self-administration of Entonox® by the nurse who was in charge of that case. If the participants needed more pain control during the procedure, those in the intravenous sedation group received an additional 25–50 mg of pethidine, and those in the nitrous oxide group received 50 mg of intravenous pethidine and 2 mg of midazolam after discontinuation of the nitrous oxide. The participants who received both intravenous sedation and nitrous oxide were not excluded from the study and were included in the analysis as intention-to-treat.The minor gynecological operative procedures were performed by well-trained gynecologists. The procedures followed the clinical standard of care and were not altered for this study. All participants were assessed for pain scores during, immediately post-procedure, and 30 min post-procedure, satisfactory levels, and side effects. Immediately after the procedure and while still receiving the allocated medication, participants rated their maximum pain on the Numerical Rating Scale (NRS). The NRS is a 10-point scale with a score of 0 reflecting “no pain” and a score of 10 reflecting “maximum pain”. At 30 min post-procedure, participants completed another NRS, recalling maximum pain during the procedure and satisfactory level. Participants were monitored at 60, 90, and 120 min post-procedure or until they achieved a modified post-anesthesia discharge scoring system of 9 or greater, indicating recovery from sedation. However, according to our hospital protocol, all patients were discharged from the hospital at 2 h after the procedure.Outcome measures: The primary outcome measure was the difference between the two groups in maximum pain during, immediately post-procedure, and 30 min post-procedure as measured on NRS. The secondary outcomes were satisfactory level, side effects, and discharge time. The patient’s pain level during the procedure and post-procedure, along with the satisfaction levels and the presence or absence of side effects, were assessed after the procedure. Regarding the discharge time evaluation, the modified post-anesthesia discharge scoring system was used to assess at 60, 90, and 120 min post-procedure. A score of 9 or greater was considered as complete recovery and ready to discharge home.Statistical analysis: The data analysis was performed using the statistical package for the social sciences (SPSS) software version 26.0 . The baseline demographic data were presented as mean + SD or median (IQR) for continuous variables as appropriate and as a percentage for the categorical variables. In comparisons of the data between both groups, Student’s t-tests, Mann–Whitney U, and Cchi-square were applied as appropriate. A p-value of less than 0.05 was regarded as statistical significance. According to the primary outcome, this study as a non-inferiority trial needed a sample size of at least 84 cases, 42 in each group, to gain a power of 90% at a 95% confidence interval when a reduction in visual analog pain score of 1 was considered clinically significant.p-value: 0.566).During the study period, August 2021 to December 2022, a total of 110 eligible women were enrolled in the study. Of them, four patients were excluded before allocation, as presented in p-value: 0.174, 0.634, 0.889) for pethidine/midazolam vs. nitrous oxide group, respectively as presented in Pain scores during, immediately and 30 min after procedures were not significantly different in the two groups , as presented in p-value 0.001), as presented in Satisfaction scores were comparable in both groups , whereas the scores at 120 min were comparable in both groups, as presented in Additionally, the discharge scores, assessed by the modified post-anesthesia discharge scoring system, showed a significantly faster recovery time in the nitrous oxide group at 60 and 90 min after the procedure (New insights gained from this research are as follows: (1) effectiveness of nitrous oxide and pethidine/midazolam is comparable for pain relief in minor gynecologic procedures; (2) patients’ satisfaction is also not significantly different between the two groups; (3) side effects of nitrous oxide is significantly lower when compared to those in pethidine/midazolam group; and (4) patients in nitrous oxide group had significantly faster recovery time. However, though the discharge scores were better with statistical significance in the group of nitrous oxide, one or two points of scores might not be clinically significant. Nevertheless, this study supports that inhaled nitrous oxide could be an alternative analgesic technique for minor gynecologic operative procedures, which would improve patients’ comfort and tolerance to the procedures and health care quality without serious side effects.To the best of our knowledge, this is the first study that evaluated the effectiveness and safety of nitrous oxide as pain relief during minor gynecologic procedures. Accordingly, this study could not be perfectly compared with other previous studies on the effectiveness of nitrous oxide. Nevertheless, our finding seems in agreement with that reported by Schneider et al. , who demp-value 0.013). They conclude that paracervical block could be used as another choice for pain relief during uterine curettage. Likewise, our findings supported that nitrous oxide may be another option for such a purpose. However, because both methods for pain relief were not excellent for analgesia in minor gynecologic procedures, as indicated by the mean pain scores of no lower than 5, though acceptable by the patients, suggesting that other techniques still need to be sought.Interestingly, both methods in this study were not highly effective in pain relief for minor gynecologic operations . Nevertheless, most patients expressed high satisfaction with the procedures. This might be associated with rapid recovery, no serious side effects, short operation time, and probably acceptability of moderate pain relief among our patients. In fact, our results are consistent with those reported by Thongrong et al. , who comThe strengths of this study include: (1) no selection bias at recruitment. This was due to the nature of randomized controlled trials in which known and unknown confounders were equally allocated to both groups, as confirmed by the similar baseline and clinical data; (2) as conducted in a single center, the same standard protocol of care was provided to all patients; (3) exclusion of the women who had a history of prior gynecologic procedure such as curettage because it might alter the pain threshold; and (4) all main outcomes were assessed using the well-validated metric tool; NRS as well as post-anesthesia discharge scoring system.The weaknesses of this study are as follows: (1) Because of the apparent difference in the methods of drug administration, both participants and care providers could not be blinded to the groups of study, possibly resulting in a bias in the subjective assessment of pain scoring and other outcomes. (2) The types of procedures were heterogeneous and did not include some other important gynecologic procedures such as loop electrosurgical excision procedure or hysteroscopic polypectomy, etc. (3) The sedative effects after the procedure might still persist and affect the capability in pain scoring. (4) Though the sample size was adequate for primary outcomes, it might be relatively small for some rare side effects of both medications. Of note, the pain scores in the nitrous oxide group seemed to be slightly higher, though not significantly different. Thus, it is possible that studies with larger sample sizes or high power of test might express a significance of such a small difference if it existed. Nevertheless, such a small difference, if it existed, was unlikely to have a clinical impact.Based on our findings, because of the comparable effectiveness to intravenous sedation for pain relief and its safety as well as rapid recovery, it is reasonable to use nitrous oxide for pain control during the uncomplicated short minor gynecological procedure. Advantages of nitrous oxide include its low cost and non-burdensome training of clinic staff. Additionally, nitrous oxide sedation has a rapid onset, quickly reversible with the administration of 100% oxygen, and delivery of the gas is noninvasive. However, because of some weaknesses mentioned above, larger randomized controlled trials are needed to confirm our results. In health systems that do not have the resources for analgesia sedation or anesthesia supervised by an anesthesiologist for such minor gynecological procedures, the use of nitrous oxide appears to be a second-rate alternative.Nitrous oxide is as effective as pethidine/midazolam for pain relief in minor gynecological operative procedures but associated with significantly lower side effects and significantly faster recovery time. Nevertheless, because of some limitations, further studies with larger sample sizes are needed to confirm our findings.