Prevalence, risk factors and medical management of persistent pain symptoms after critical care illness have not been thoroughly investigated.We performed a prospective multicentric study in patients with an intensive care unit (ICU) length of stay ≥ 48 h. The primary outcome was the prevalence of significant persistent pain, defined as a numeric rating scale (NRS) ≥ 3, 3 months after admission. Secondary outcomes were the prevalence of symptoms compatible with neuropathic pain (ID-pain score > 3) and the risk factors of persistent pain.Eight hundred fourteen patients were included over a 10-month period in 26 centers. Patients had a mean age of 57 (± 17) years with a SAPS 2 score of 32 (± 16) (mean ± SD). The median ICU length of stay was 6 [4–12] days (median [interquartile]). At 3 months, the median intensity of pain symptoms was 2 [1–5] in the entire population, and 388 (47.7%) patients had significant pain. In this group, 34 (8.7%) patients had symptoms compatible with neuropathic pain. Female (Odds Ratio 1.5 95% CI [1.1–2.1]), prior use of anti-depressive agents (OR 2.2 95% CI [1.3–4]), prone positioning (OR 3 95% CI [1.4–6.4]) and the presence of pain symptoms on ICU discharge (NRS ≥ 3) (OR 2.4 95% CI [1.7–3.4]) were risk factors of persistent pain. Compared with sepsis, patients admitted for trauma (non neuro) (OR 3.5 95% CI [2.1–6]) were particularly at risk of persistent pain. Only 35 (11.3%) patients had specialist pain management by 3 months.Persistent pain symptoms were frequent in critical illness survivors and specialized management remained infrequent. Innovative approaches must be developed in the ICU to minimize the consequences of pain.Trial registration. NCT04817696. Registered March 26, 2021.The online version contains supplementary material available at 10.1186/s13054-023-04491-w. Chronic pain is a major public health issue. On an individual level, chronic pain is associated with significant impairment of quality of life and major societal costs with loss of work productivity . SeveralThe ALGO-REA study was a prospective multicentric longitudinal study  and completed the ID-Pain score along with anatomical location of symptoms in order to screen symptoms compatible with neuropathic pain . DiagnosPrimary outcome was the rate of persistent pain defined as a pain score with an NRS ≥ 3/10, 3 months after ICU admission. Patients with an NRS < 3 were classified as having no or mild pain.Secondary outcomes were the intensity of pain symptoms on ICU discharge evaluated via NRS, the characteristics of symptoms compatible with neuropathic pain on discharge and at 3 months after admission assessed via ID-Pain score , evolutiThe following baseline characteristics were collected: gender, age, weight, height, comorbidities  and chronic medication before admission . We collected the simplified acute physiology score (SAPS II) and the reason for admission: traumatic brain injury, trauma without brain injury, burn, major cardio-thoracic surgery, sepsis/septic shock, COVID-19, acute respiratory failure not related to COVID-19, other major surgery and other causes of admission (miscellaneous). Regarding ICU management, we collected the following data: the type and total number of surgical interventions , use of continuous intravenous morphine, use of continuous intravenous ketamine, use of continuous intravenous remifentanil, use of antihyperalgesic drugs, use of continuous intravenous local anesthetic agents such as intravenous xylocaine and the use of loco-regional anesthesia techniques. We also recorded general complications such as the occurrence of acute respiratory distress syndrome, prone positioning, the use of neuromuscular blocking agents, the duration of invasive mechanical ventilation and length of ICU stay.All patients were treated according to international guidelines and local protocols. Patient analgesia and sedation management in the ICU, according to previously validated scales  and guist–3rd quartile] and discrete outcomes as absolute and relative (%) frequencies. We compared baseline demographic and follow-up data between groups with or without significant pain symptoms. Normality and heteroskedasticity of continuous data were assessed with Shapiro–Wilk and Levene’s tests, respectively. Continuous outcomes were compared with unpaired Student's t-test or Mann–Whitney U test according to data distribution. Discrete outcomes were compared with chi-squared or Fisher’s exact tests accordingly. The alpha risk was set at 5% and two-tailed tests were used. Based on our local experience of post-ICU follow-up during which we screened approximately 20% of the patients with pain at 6 months (unpublished data), we intended to include and perform follow-up in 700 patients. We therefore assumed that 140 patients would display persistent pain in order to perform a relevant multivariable logistic regression analysis and explore the risk factors of persistent pain 3 months after discharge. First, the groups with or without persistent pain were compared in univariate analysis. A specific model was elaborated according to the parsimonious rule. Variables associated with persistent pain in univariate analysis with a p value ≤ 0.15 were kept in the model. A backward selection process was then applied to elaborate the final model. Since we collected multiple causes of admissions, we pooled medical causes, surgical causes, and left trauma and burn patients alone. Sepsis was pooled in medical cause of admission and was set as the reference in the model owing to previously published data , had more history of anxiety and depression symptoms  and more chronic antidepressant agent medication . There were no significant differences in the use of analgesics before admission.At 3 months, the median intensity of pain symptoms was 2 [1–5] in the entire population. At 3 months, 388 (47.7%) patients presented persistent pain, defined as a NRS ≥ 3. There were 284 (34.9%) patients with NRS ≥ 4. In univariate analysis, patients with persistent pain were significantly more frequently female , underwent more frequently orthopedic  and spinal surgery . There were no other significant differences between groups regarding ICU management  , % CI 1.3–, p = 0.0In our prospective multicentric cohort, we found that almost half of the patients experienced significant pain 3 months after admission in an ICU. Among them, roughly 8% presented symptoms compatible with neuropathic pain and 11% had specialized follow-up., Kemp et al. [Pain symptoms have been little described after critical care admission. In a reviewp et al.  noted thp et al. … Moreovep et al. . In a rep et al. , Battle p et al. , the autp et al. . In an ip et al. , the autp et al. , 16, 18.We upheld the diagnosis of persistent pain with an NRS ≥ 3, but our definition is questionable. In the context of postoperative pain, a threshold ≥ 4 is commonly used , but somThe risk factors of chronic pain after critical illness deserve cautious interpretation to this day. As stated before, the definitions and time-point of evaluation are not congruent across studies –16. MoreFemales presented significantly more symptoms than males. Koster-Brouwer et al. also found that females were at higher risk . A possiThe transition from acute to chronic pain is a complex phenomenon which involves an interaction between the host inflammatory response and the central nervous system . There aWe did not use the Brief Pain Inventory in our study. However, owing to the lack of a gold standard, we used an NRS in this evaluation which has been largely used in the surgical context. Also, we did not perform face-to-face interviews to assess pain symptoms for logistic reasons. A face-to-face versus a remote evaluation could influence the evaluation of pain symptoms . Given tPersistent pain could be a common health problem after critical illness care. Our data also suggest that there is a lack of specific follow-up after ICU discharge. Given the major consequences on patient quality of life, the social implications and health-care costs, it appears to be important to design innovative interventions to minimize the consequences of pain after critical care illness.Additional file 1: STROBE checklist.Additional file 2: Table S1. Univariate analysis of patients with and without lost to follow-up.Additional file 3: The ALGO-RÉA study group.


Central sensitization (CS) is becoming increasingly recognized as a significant factor in many chronic pain conditions, including knee osteoarthritis (KOA) and chronic low back pain (CLBP). Yet it presently remains unclear how strong is the involvement of CS in KOA and CLBP and which factors are involved in CS in these two chronic disabling diseases.This is a cross-sectional study in which included a total of 178 patients with KOA and 118 patients with CLBP. Inclusion criteria for eligible participants for the KOA group were a confirmed diagnosis of KOA according to the American College of Rheumatology criteria, and for the CLBP group a chronic low back pain for more than 3 months. Subjects were excluded if they presented with a diagnosed psychiatric disorder or if they lacked the capacity to provide informed consent, understand study questionnaires or perform physical performance tests. In each group, were assessed; CS-related symptoms using the Central Sentization Inventory (CSI); demographic and clinical characteristics such as disease duration, pain intensity on a visual analog scale, self-reported function using the Lequesne index for KOA patients and the Oswestry Disability index for CLBP patients, and physical performance with the 6 minutes’ walk test; as well as psychosocial risk factors using the Patient Health Questionnaire for depression (PHQ-9), the Generalized Anxiety Disorder (GAD-7) and the Pain Catastrophizing Scale (PCS).CSI scores significantly correlated with pain intensity and disability in KOA and CLBP patients, and were highly correlated with self-reported symptoms of depression, anxiety and pain catastrophizing. Depression significantly predicted the CSI score in both groups.These findings provide further evidence for the impact of CS on pain, function and physical performance in KOA and CLBP patients. Psychosocial symptoms such as pain catastrophizing, anxiety and depression should also be considered as they are also associated with CS. Knee osteoarthritis (KOA) and chronic low back pain (CLBP) represent a major cause of pain and disability worldwide, with high costs for the patient, his family, and the society , 2. HoweOne reason for this disparity and the unproportionally high pain experience is neuroplastic changes that occur in the peripheral and central nervous system and result in pain sensitization enhancing the nociceptive drive from a damaged structure and hence causing more pain than can be accounted for by the damage –14. In sIf direct electrophysiological recordings from central neurons have proved the existence of CS in animal studies, these methods cannot be performed in humans . HoweverThe Central Sensitization Inventory (CSI) was developed as a screening tool to assess CS-related symptoms in a number of chronic pain conditions , includiThe aim of the present study was twofold: (1) to analyze the associations between the CSI score, and pain-related symptoms, self-reported function, physical performance and psychosocial factors in KOA and CLBP patients, (2) to explore potential factors that contribute to CS in these two patients’ groups.This is a cross-sectional study carried out in the department of rheumatology of Tangier’s university hospital in Morocco, between February 2022 and September 2022. Data was prospectively collected from the outpatient department. The study was approved by the ethics committee of Tangier’s university hospital (n 01/2022), and all procedures performed on this study were in accordance with the ethical standards of the 1964 Helsinki declaration. Written informed consent was obtained from all subjects prior to the study.Inclusion criteria for eligible participants for the KOA group were a confirmed diagnosis of KOA according to the American College of Rheumatology criteria, and for the CLBP group were a chronic low back pain for more than 3 months. Subjects were excluded if they presented with a diagnosed psychiatric disorder or if they lacked the capacity to provide informed consent, understand study questionnaires or perform physical performance tests.Personal variables as age, sex, body mass index (BMI) and education level were collected.Duration of disease was measured as the number of years of disease progression. Radiographic evidence of KOA was graded according to the Kellgren-Lawrence scale. The number of co-morbidities was defined. Pain intensity was rated on a visual analog scale (VAS). The Arabic version of the Lequesne index was used to assess function in KOA group , while tPain sensitization was assessed using the Arabic version of the Central Sensitization Inventory (CSI). The CSI consists of two parts: A and B . Part A Patients completed a number of validated self-reported questionnaires for measuring depression, anxiety, and pain catastrophizing using the Arabic version of the Patient Health Questionnaire-9 (PHQ-9) , the GenPhysical activity was assessed using the Arabic version of the International Physical Activity Questionnaire (IPAQ)  and by iα = 0.05), a minimum sample size of 85 patients in each group was required for this study [Using an expected correlation coefficient of 0.3 between CSI and the different predictors –46, withis study .p < 0.05.Descriptive characteristics are expressed using percentages (%) for categorical variables, means ± standard deviation (SD) for normally distributed continuous variables, and median first and third quartile  otherwise. To analyze the correlation of pain intensity, self-reported function, physical performance and psychosocial factors with the CSI score, we performed univariate correlation analysis using Pearson correlation coefficients in each group. Simple linear regression was used to identify variables that significantly predicted the CSI. Relationships between candidate variables and the CSI score were tested using multiple linear regression. The results are expressed in terms of unstandardized beta coefficients with 95% confidence intervals  and p values. All analyses were conducted using SPSS V.21. The level of significance was set at In this study, 178 patients with KOA and 118 patients with CLBP were included.The participants’ characteristics are summarized in Table Table Using simple linear regression, sex, number of co-morbidities, pain-intensity, depression, anxiety and pain catastrophizing score were found to have a significant regression coefficient in both KOA and CLBP groups Table . LequesnFor each group, only variables found to have a statistical significance in the univariate analysis were included in the multivariable linear regression, which determined that depression significantly predicted CSI score in both KOA  p < 0.001), and CLBP patients  p < 0.001). Number of co-morbidities was also found to significantly predict CSI score in the KOA group  p: 0,014)  in clinical practice during the initial evaluation, the rehabilitation program, as well as the regular follow-ups may help identify KOA and CLBP patients at risk of a greater pain severity and who may potentially need pain medications targeting the central nervous system . SeSeveral limitations should be considered when interpreting this study’s findings. First, the design was cross-sectional; therefore, it is not possible to draw conclusions regarding causation or predictive validity. Second, the majority of surveys in this study relied on self-reported questionnaires, which raises the possibility of recall bias or overestimation of the indices being measured. Future studies will require more objective and quantitative methods for further verification. Third, the relationships between CSI and the somatosensory function measured by QST are still unknown in this population. In fact, the lack of consensus regarding the correlation between the CSI and QST in the existing literature suggests that the CSI may not reflect a direct measurement of CS . TherefoOur study found that central sensitization, as assessed by CSI, has a significant impact on pain, function and physical performance in KOA and CLBP patients. This outcome endorses the relevance of early CS assessment and management in KOA and CLBP patients in order to prevent transition into a chronic pain state. Moreover, the highly significant correlation of depression, anxiety and pain catastrophizing with CSI should be interpreted as a call for better understanding of these psychosocial factors affecting the patients’ pain experience to allow for a more focused and individualized treatment.Further research would aid in providing evidence of the utility of CSI as a treatment-outcome assessment tool after addressing the underlying factors involved in CS in KOA and CLBP patients, and explore whether improvements in CSI scores are associated with reduced pain and improved functioning in these patients.


A clinical survey based on the visual analog scale of pain and a brief pain inventory (BPI) was performed during the study period. The average age was 60.55 ± 13.18 years-old with a male-to-female ratio of 6:5. The median current pain decreased from 10.0 to 7.0 (p = 0.021), median average pain decreased from 8.5 to 6.0 (p = 0.027), and median maximum pain decreased from 10.0 to 8.0 (p = 0.008) at 4 weeks after treatment. Additionally, the sum of daily life interference based on BPI was improved from 59.00 ± 11.66 to 51.91 ± 9.18 (p = 0.021). There were no side effects such as burns, headaches, or seizures, and no significant changes in follow-up brain magnetic resonance imaging. Low-energy tcNgFUS could be a safe and noninvasive neuromodulation technique for the treatment of chronic neuropathic painNeuromodulation using high-energy focused ultrasound (FUS) has recently been developed for various neurological disorders, including tremors, epilepsy, and neuropathic pain. We investigated the safety and efficacy of low-energy FUS for patients with chronic neuropathic pain. We conducted a prospective single-arm trial with 3-month follow-up using new transcranial, navigation-guided, focused ultrasound (tcNgFUS) technology to stimulate the anterior cingulate cortex. Eleven patients underwent FUS with a frequency of 250 kHz and spatial-peak temporal-average intensity of 0.72 W/cm Neuropathic pain is a complex chronic condition with a major impact on quality of life . NeuropaAlthough the mechanism of DBS is still unclear and the outcomes are variable, DBS for neuropathic pain has gradually gained consensus approval worldwide ,5,6. DeeThe anterior cingulate cortex (ACC), which is involved in many motor and psychological functions and plays an important role in pain and empathy, has emerged as an alternative target for neuropathic pain ,14. PainRecently, there has been a paradigm shift towards less invasive methods of brain stimulation, and transcranial focused ultrasound (tcFUS) is one such method . BecauseBuilding upon these findings, our hypothesis posited that low-energy sonication could provide a safer means of neuromodulation without irreversible brain-tissue damage. In this exploratory clinical trial, grounded in the aforementioned research, we conducted transcranial navigation-guided focused ultrasound (tcNgFUS) using low-intensity sonication in patients with intractable neuropathic pain. Our objective was to establish the safety and efficacy of this treatment approach. This was a prospective, single-center, single-arm, open-label, exploratory trial with a 3-month follow-up. The study was conducted in accordance with the 1964 Helsinki Declaration and its later amendments and was approved by the Institutional Review Board of our institute (GCIRB2020-030). This study was registered as a clinical trial in the Clinical Research Information Service of South Korea (KCT 0007894).This clinical trial aimed to explore the efficacy and safety of low-energy tcNgFUS for pain relief in patients with uncontrolled neuropathic pain. The primary endpoint was efficacy based on pain relief measured using the visual analog scale (VAS). The secondary endpoint included the effectiveness of treatment from a subjective patient’s viewpoint and improvement of daily life interference based on the Korean version of the Brief Pain Inventory (K-BPI) .Safety was estimated by investigating any procedure-related adverse events or changes in follow-up brain MRI after treatment. The final follow-up period was up to 3 months, and the study was conducted over 18 months.TcNgFUS stimulation was performed according to detailed protocols for 2 weeks, three times a week. A clinical survey was conducted before the procedure and immediately, 2 weeks, and 4 weeks after the procedure. The final follow-up was conducted 3 months after the procedure for safety evaluation and follow-up brain magnetic resonance imaging (MRI) . The number of samples was calculated as follows: Based on the results of previous clinical trials of neuromodulation ,26,27,28Participants were recruited from the outpatient clinic of a neurologist or neurosurgeon specializing in spine disease, stroke, or functional brain surgery.All potential participants were screened to determine their eligibility according to the following inclusion and exclusion criteria. The inclusion criteria were as follows: (1) adults aged 19–75 years; (2) persistent neuropathic pain for more than 6 months, as determined by International Classification of Disease-10 codes of T060, T061, T093, T913, S141, S241, S246, S341, S342, M890, M961, G500, G530, G546, G564, G631, G632, G5780, G5880, and G5881; (3) intractable pain despite a minimum of 4 weeks of medication and any intervention such as nerve block, epidural block, or spinal cord stimulation; (4) severe pain that interferes with daily life, defined as a VAS pain level ≥ 5 and pain disability index ≥ 30 ; (5) a s®  with a 1 mm isovoxel and brain MRI using Skyra 3T®  with 1 mm isovoxel to confirm the skull and brain anatomical structure. All imaging was performed after the attachment of a multimodal sticker  for the fusion of both CT and MRI images and the planning of image guidance. Through acquired brain image processing, the brain anatomical/functional target of the ACC area for each participant was identified, and image-guided FUS was designed [After patient selection and informed consent, all patients underwent pre-procedure brain CT using Somatom forcedesigned .® . Treatment was carried out three times a week for 2 weeks . The visitation period for each treatment was 2 days within the planned date of treatment, and if the attendance rate was less than 80%, the patient would drop out. TcNgFUS was performed using an NS-US100The stimulation target was Brodmann area 24 , which was a white matter located 20 mm posterior to the anterior tip of the frontal horns of the lateral ventricles . During 2, and volume of target of 5280 mm3 was used. To increase the transmittance of ultrasound across the skin, ultrasound was applied after the hydrogel had spread to the scalp of the participant . The total stimulation time, including the rest period, did not exceed 30 min in all patients. Additionally, the device was used within a range that does not exceed a Mechanical Index of 1.9 (in situ peak rarefaction pressure less than 0.95 MPa according to the Food and Drug Administration safety standards for ultrasonic imaging devices). Low-energy FUS had a frequency of 250 kHz, spatial-peak temporal-average intensity of less than 0.72 W/cmDrug treatment was maintained as usual as the pre-procedure state for all patients.Demographic data, including age and sex, and baseline characteristics, including diagnosis and symptom duration, were recorded. Clinical data, including VAS and K-BPI, were obtained before the procedure, immediately after completion of the procedure, and at 2 and 4 weeks after the procedure in all patients. The degree of current pain, average pain during the last 24 h, and maximum pain during the last 24 h were surveyed using VAS scores ranging from 0 to 10 points. Pain-related quality of life was assessed using K-BPI [Procedure-related complications, such as the burning of the scalp, headache, seizure, and aggravation of pain, were observed during the follow-up period of up to 3 months after the procedure in all patients. In addition, a post-procedure brain MRI was performed 3 months after the procedure to check for any adverse events in the structure around the stimulated target. t-test were used according to the characteristics of the factors. Data management and statistical analyses were performed using SPSS . The non-parametric Friedman test, one-way analysis of variance (ANOVA), and paired p-values < 0.05. The results were expressed as mean ± standard deviation, median with range, or mean and corresponding 95% confidence interval (CI) depending on whether the data were normally distributed or not. Statistical significance was set at Among the 12 registered patients, one patient was excluded because of withdrawal of consent due to simple change of mind during follow-up. The 11 final study participants comprised 6 men and 5 women, with an overall mean age of 60.55 ± 1.18 years . Patients were classified based on their diagnosis as four patients with spinal cord injury, three with compressive myelopathy, three with post spinal surgery syndrome, and one with cauda equina syndrome. The median symptom duration was 4.33  years .p = 0.039, non-parametric Friedman test). The pre-procedure to 2 weeks post-procedure and pre-procedure to 4 weeks post-procedure differences in current VAS scores were significant ; however, the difference during follow-up after the procedure was not significant , and this decreased to 8.0  immediately post-procedure, 7.0  at 2 weeks post-procedure, and 7.0  at 4 weeks post-procedure . The pre-procedure to 2 weeks post-procedure and pre-procedure to 4 weeks post-procedure difference in maximum VAS scores were significant ; however other differences between each period were not significant , and this decreased to 9.0  immediately post-procedure, 9.0  at 2 weeks post-procedure, and 8.0  at 4 weeks post-procedure . The pre-procedure to immediately post-procedure and pre-procedure to 4 weeks post-procedure differences in sum of interference of daily life were significant   . p = 0.429, non-parametric Friedman test)  at pre-procedure, and 50.0  after the procedure (an test) . No procedure-related complications, such as a burning sensation of the scalp, headache, or seizure, were observed during the follow-up period. Additionally, no specific changes in the structure of the target, such as inertial cavitation, edema, or hemorrhage, were observed after sonication according to the follow-up brain MRI. The ACC has been revealed as a key structure of the affective component among three integrated aspects including sensory, affective, and cognitive aspects of chronic neuropathic pain. Anatomically, the ACC is a part of the cingulate gyrus and consists of Brodmann areas 24, 25, 32, and 33  Several The stimulation of the ACC was supposed to improve the affective component of pain, whereas stimulation of the thalamus or periventricular gray region was shown to reduce the intensity of pain ,38. ConsHowever, DBS requires the invasive surgical implantation of electrodes and causes fear/inconvenience and surgery-related complications. According to a previous study, complication rates were reported with a remarkable probability, including 16.7% for infection, 8.3% for broken lead, and 16.7% for seizure, after DBS surgery of the ACC for neuropathic pain [To overcome the limitations of invasive implantation surgery, several new trials based on advanced technology have been developed in the last decade, and tcFUS is one of the most promising methods. FUS is a precise, noninvasive, and radiation-free technique in which ultrasound single waves reach the target without acoustic reflection, refraction, and distortion through trajectory ,44,45,46Classic high-energy FUS has two main bioeffects: the local thermal effect and inertial cavitation. Protein denaturation and cell death, which result from local heat generation, and inertial cavitation, which is caused by the collapse of gas bubbles owing to the pressure exerted by the ultrasonic field, induce irreversible tissue ablation . HoweverAccordingly, there has been a growing interest in the reversible biological effects of FUS, and many researchers have tried to improve the neurological and histological effects of low-energy FUS ,51. The TcFUS has been approved for the treatment of refractory essential tremors and is being studied for other neurological indications, including dyskinesias and tremors in Parkinson’s disease, dystonia, obsessive-compulsive disorder, epilepsy, brain tumors, and traumatic brain injury ,58,59,602 to prevent heat generation or inertial cavitation [2 generates a pressure wave of mechanical energy, unlike high-intensity FUS, which generates heat [MRI-based tcNgFUS device is an advanced technology using low-energy FUS. According to the standards of the Ministry of Food and Drug Safety, ultrasonic waves should be used within a range of less than 3 W/cmvitation ,65. FUS tes heat . The patients who underwent low-energy FUS in this clinical trial showed a mean current pain relief profile across time, from 21.22% (from 9.00 to 7.09) at 2 weeks to 2.54% (from 7.09 to 6.91) at 4 weeks after treatment. The improvement in the maximum pain during the last 24 h was similar, as 15.94% (from 9.41 to 7.91) at 2 weeks and 3.41% (from 7.91 to 7.64) at 4 weeks. Furthermore, an improvement in interference with daily life based on BPI was observed to be as significant as 24.45% (from 59.00 to 51.91) at 4 weeks after the procedure. Because the primary effect of low-energy FUS is not pain alleviation like high-energy FUS, patient satisfaction based on subjective pain-relieving effect may appear insignificant. However, patients tend to describe that pain is still present but that it is less stressful. In other words, the improvement in pain and life quality is statistically significant, although the degree of improvement is slightly lower than the results of the previous literature at 30–40% improvement ,50,57,61The present study had several limitations. First, owing to its single-arm design, direct comparison with the sham group was not possible. Therefore, the placebo effect cannot be disregarded. Second, the number of enrolled patients was small. Nonetheless, regarding the purpose of this study as a preliminary exploration, it provides sufficient evidence to prove the safety and efficacy of low-energy tcNgFUS. Third, the follow-up period was relatively short. Improvement in early phase can diminish over time owing to reversible lesioning and the possibility of brain plasticity . A fourtThe trend of the results of this study was not superior to that in the previous literature based on DBS or high-energy FUS for neuropathic pain. However, we believe that the obtained results are valuable because this is the first pioneering study of low-energy FUS for chronic neuropathic pain. We suggest that further large-scale, randomized controlled trials with long-term follow-up for direct comparison between case and control groups should be conducted to confirm our results.This prospective exploratory study showed that low-energy tcNgFUS could be used effectively in patients with chronic neuropathic pain. Low-energy FUS avoids procedure-related complications and irreversible brain-tissue damage. In addition, portable real-time navigation guidance is accurate for planning targeting and comfortable for the patient. However, further clinical investigations are necessary to confirm its clinical safety and long-term efficacy.


Chronic pain is common in cirrhosis; however, the mechanistic classifications are not well characterized. Nociplastic pain, for instance, is associated with comorbid nonpain symptoms and responds to different treatments than nociceptive pain.N = 238) to evaluate pain widespreadedness, associated nociplastic symptoms, and pain intensity.We conducted a survey study in February 2022 of adult patients with cirrhosis at the University of Michigan (Pain and pain widespreadedness were associated with mood and cognitive disturbance, fatigue, sleep difficulty, and physical and social functioning. Patient-reported Outcomes, such as body maps, can be useful to phenotype patients for pain mechanisms. Chronic pain is common in cirrhosis, reported by up to 79% of patients.Surveys were sent to 2000 adult (aged 18 y or above) patients through email in February 2022. Participants had an established diagnosis of cirrhosis and were followed by a hepatologist at the University of Michigan. We excluded patients with liver transplants. Participants were paid 10 dollars for completing the survey. The study was approved by the University of Michigan Institutional Review Board, and all respondents provided informed consent.The widespreadedness of pain (a key feature of nociplastic pain), as well as associated nociplastic symptoms, was assessed using the American College of Rheumatology 2011 Fibromyalgia Survey Criteria.N=238) was comprised of 40.8% of men with an average age of 58.8 years . Most (60%) had a college degree or more and were primarily White (89.5%). The commonest etiology of cirrhosis was NAFLD. Most were compensated, with 12.6% and 16% reporting ascites and HE, respectively. Overall, 21% were taking opioids. The most common pain region reported was the axial region (65.5%).Overall, 238 patients responded to the survey (response rate 11.9%). Our study sample .There was no consistent association between pain region and associated symptoms or pain intensity  like body maps can be useful to phenotype these patients for pain mechanism and help predict treatment responses.Identifying patients with features of nociplastic pain is important because first-line treatment is nonpharmacologic, incorporating patient education, self-management strategies, lifestyle interventions , and psychological treatments , which can be useful in patients with cirrhosis, for whom pharmacologic therapy is complex.In addition, PROs can identify patients with characteristics of nociplastic pain and help to predict the presence of nonpain symptoms that can guide therapy. For instance, in addition to nonpharmacologic therapy, low-dose tricyclic compounds can address multiple symptoms and are first-line for nociplastic pain.Similarly, PROs can predict treatment response. Conventional analgesics  are not generally useful for nociplastic pain, and opioid use is strongly discouraged.Our study has various limitations, significantly the small sample size and primarily White, educated sample, which restricts the generalizability of our results.Overall, nociplastic pain seems to be an important pain phenotype in patients with cirrhosis, for which treatment centers on nonpharmacologic therapies, as well as the improvement of nonpain symptoms and functioning.


No significant change in coronal or sagittal parameters was observed in this single-institution long-term radiological outcome study of adults following HR instrumentation removal and watchful waiting of residual spinal deformity.The study aimed to assess long-term radiological outcomes in patients from our institution who were primarily treated for adolescent idiopathic scoliosis with surgical correction using Harrington rod (HR) instrumentation, and afterward with watchful waiting of residual spinal deformity after HR removal, whereby no patient consented to spinal deformity correction. A single-institution case series of 12 patients was retrospectively evaluated. Preoperative and most recent post-instrumentation removal radiographic measurements were compared, along with baseline characteristics. The average age of patients  at the time of HR instrumentation removal was 38 ± 10 years . The mean follow-up from the HR instrumentation implantation to the HR instrumentation removal was 21 ± 10 years , with a further mean of 11 ± 10 years  of follow-up following HR instrumentation removal and watchful waiting. No significant change in radiological parameters was observed: LL ( Instrumentation with Harrington rod (HR) used to be the standard of care for scoliosis treatment in children in the past . Such a ASD can be managed either with nonsurgical methods or surgical treatment. The nonoperative treatment is regarded as the first-line response, whereas surgical intervention has recently become the mainstay of treatment, since it may yield more favourable outcomes than nonsurgical methods for improving the function of patients with ASD and achieving good pain improvement and deformity correction ,3,5. HowThe purpose of this study was to assess long-term radiological outcomes in patients from our institution who were treated primarily for adolescent idiopathic scoliosis with surgical correction using HR instrumentation, and afterward with conservative management (watchful waiting) of residual spinal deformity after HR removal, whereby no patient consented to adult spinal deformity correction.We performed a retrospective, institutional review board-approved (No. 2/2022) analysis of a single-institution case series of 12 consecutive patients with adolescent idiopathic scoliosis, treated primarily with surgical correction using HR instrumentation a betweenThe upper instrumented vertebra (UIV) was in five cases Th5, in two cases Th4, and in one case Th2, Th3, Th6, Th7, and Th10. The lower instrumented vertebra (LIV) was in one case Th12 and L1, in two cases L3, and in eight cases L4. The indication for instrumentation removal was metal hypersensitivity in one case, instrumentation failure in one case, progressive back pain and/or radiculopathy in six cases, and an indication for a diagnostic head magnetic resonance imaging (MRI) in four cases. Other patients who underwent concomitant instrumented fixation without deformity correction at the time of HR removal (7 patients) were not included in the analysis.Demographic data collected included age, sex, body mass index (BMI), and the American Society of Anesthesiologists (ASA) physical status score. Radiological measurements included lumbar lordosis (LL), thoracic kyphosis (TK), pelvic tilt (PT), sacral slope (SS), pelvic incidence (PI), pelvic incidence–lumbar lordosis (PI–LL), sagittal vertical axis (SVA), C7-central sacral vertical line (C7-CSVL), spinosacral angle (SSA), T1 pelvic angle (TPA), and coronal Cobb angle  before HR instrumentation removal and most recently after HR instrumentation removal and watchful waiting.t-test and Wilcoxon signed-rank test. No multiple comparison corrections were applied to statistical significance testing. Statistical analyses were performed in R software 4.1.3 . p < 0.05 was considered significant.The Shapiro–Wilk test was used to assess for normal distribution. Pre- and post-instrumentation removal radiographic measurements were performed in Agfa Impax version 6  and Surgimap version 2.3.2.1  software, and compared using two-tailed paired Student’s The average age of patients  at the time of HR instrumentation removal was 38 ± 10 years , the average BMI was 25 ± 6 , and the average ASA score was 2 ± 1 . No postoperative complications were observed. The mean follow-up from the HR instrumentation implantation to the HR instrumentation removal was 21 ± 10 years , with a further mean of 11 ± 10 years of follow-up  following HR instrumentation removal and watchful waiting, and a minimum of 2 years of follow-up after HR instrumentation removal for each patient . The aveThis study aimed to assess long-term radiological outcomes in patients from our institution who were treated primarily for adolescent idiopathic scoliosis with surgical correction using HR instrumentation a, and afIn recent years, the importance of a well-aligned spine has been increasingly recognized, regardless of the spine pathology . MeasureIn our study, we analyzed the long-term effect of the potential progression of radiological spinal parameters in the interval from the HR instrumentation removal to the last follow-up after HR instrumentation removal and watchful waiting. We observed a progression of SVA from the mean 18 mm to the mean 33 mm, loss of LL from the mean 39° to the mean 35°, PI–LL progress from the mean 11 to the mean 16, PT progress from the mean 18° to the mean 23°, which may be within  the recommended ideal target values for sagittal alignment ,11,12. IThe surgical treatment for ASD has become increasingly common, despite concerning surrounding complications, revision rates, and cost-effectiveness . Major bThe level of evidence regarding the effectiveness of conservative treatment in patients with ASD is low; however, patients with mild disability and pain are often encouraged to try the conservative treatment modalities before the surgical ones . This maThis study has some limitations. One limitation is that we only assessed the long-term radiological outcome, which revealed no significant deformity progression after a mean of 11 years of follow-up. However, patient-reported outcome measures would have gauged also the clinical outcome of the same follow-up and allowed for further statistical comparison, whether there is any impact on quality of life. Another limitation is a small case series, but our study reports on a long-term radiographic outcome of ASD treatment in a specific population from a single-institution following HR instrumentation removal. Multicentric studies are needed for clarification.No significant change in coronal or sagittal parameters was observed in this single-institution long-term radiological outcome study of adults following Harrington rod instrumentation removal and watchful waiting of residual spinal deformity. Further studies are needed for clarification.


BackgroundTransforaminal epidural steroid injections (TFESIs) are widely used as a minimally invasive treatment for lumbar radicular pain. This study presents an alternative approach for lumbar TFESI, the Kumar Technique, which utilizes a more lateral and inferior needle starting point to better align the trajectory of the needle with the neural foramen. We hypothesize the Kumar Technique will result in safer and more effective outcomes than the traditional approach to TFESI. This article was previously presented as a poster at the 2023 University of Florida College of Medicine Celebration of Research on February 27-28, 2023, and as an abstract and poster at the 2023 University of Florida Department of Anesthesiology Celebration of Research on March 29, 2023.MethodsThe charts for 1,424 patients who received lumbar TFESIs were retrospectively reviewed, and patients were stratified into groups receiving either the traditional approach or the Kumar Technique. Outcomes measures included numerical pain scores, measures of functional status and activity limitations, duration of pain relief, and procedural complications.ResultsCompared to the group undergoing the traditional approach, patients receiving the Kumar Technique reported a significantly greater decrease in average pain (-2.3 (95% CI: -3.0 to -1.6) vs -1.1 (95% CI: -1.4 to -0.7)) and maximum pain (-2.4 (95% CI: -3.2 to -1.6) vs -1.3 (95% CI: -1.8 to -0.9)). Patients receiving the Kumar Technique had a significantly greater likelihood of reporting any pain relief  compared to those undergoing the traditional approach. In addition, a greater percentage of patients receiving the Kumar Technique experienced at least one month of pain relief compared to the traditional approach . The occurrence of complications did not significantly vary between the modified (4.1%) and the traditional (3.0%) approaches.ConclusionsThe Kumar Technique is a modified TFESI approach that allows for improved access to the nerve roots through a more lateral and inferior needle entry point. The analysis supports the benefits of the Kumar Technique with patients experiencing a greater reduction in pain and longer durations of pain relief without increasing the risk of complications. Low back pain is one of the most commonly reported problems in pain medicine with a lifetime prevalence of 65% to 80% -3. PatieEpidural steroid injections are a nonsurgical treatment option for patients with radicular lumbar pain who have failed conservative therapy . The effThe TFESI procedure involves directing a spinal needle posterolateral to the epidural space at the outer border of the intervertebral foramen, often under fluoroscopic guidance ,13. CortThis study introduces a novel lumbar TFESI method with a modified angle of approach. In this modified approach, which we name the “Kumar Technique,” the needle starting point is more lateral and inferior to the traditional approach. Therefore, the needle trajectory better aligns with the neural foramen, improving access into the ventral epidural space. In addition to allowing better access to the ventral epidural space, traditional complications of epidural injections may be minimized by the needle tip staying ventral to all neurovascular structures. Thus, we hypothesize that patients will have greater symptomatic relief and fewer complications compared to the traditional approach.Study design and overviewThis study retrospectively evaluated the charts for 1,500 patients who underwent lumbar TFESI procedures at the University of Florida Health Pain Medicine Gainesville between December 2018 and September 2020. The protocol was approved by the University of Florida Institutional Review Board, and individual written informed consent was waived. Patients included in the study were at least 18 years of age who underwent lumbar TFESI. Exclusions included patients whose cases were cancelled or erroneously tagged as having undergone a TFESI during this time. The final number of patient charts analyzed was 1,424.Patients were deidentified for the purpose of database entry. A retrospective chart review was performed to extract basic demographic information, the lumbar TFESI method, and the identified outcome measures. For data analysis, procedures were stratified into two groups based on the method utilized to perform the lumbar TFESI: those using the traditional approach and those using the Kumar Technique. The procedural method used was determined based on the standard approach of the physician performing the case and confirmed by reviewing the fluoroscopic procedural images.The Kumar TechniqueThe Kumar Technique starts with a true anteroposterior (AP) fluoroscopic view of the lumbar spine in which the spinous processes of the vertebral bodies are lined up in the midline, equidistant from both pedicles Figure . The C-AOutcome measuresTo assess subjective pain relief, pain scores measured using a self-assessed numerical rating scale of 0 to 10 were extracted via chart review from the pre-procedure visit, post-procedure at discharge, day-1 follow-up phone call, and the post-procedure follow-up appointment. Measures of functional status included general activity level, walking ability, ability to perform tasks of daily living, enjoyment of life, mood, and sleep. These were extracted from the history of the present illness and review of system sections in the post-procedure follow-up notes. Additionally, PROMIS29 and Oswestry Disability Index (ODI) measurements were documented pre-procedure and post-procedure for each patient. Procedural complications were divided into intraoperative and postoperative complications. Intraoperative complications were extracted directly from the operative report, and these included indications of structural damage during the procedure such as dural punctures and intravascular contrast spread. Post-procedure complications were extracted from postoperative follow-up visit notes and phone calls. These included dural rent, reports of worsening pain or functionality, and new complaints of headaches, weakness, or other complications.Statistical analysisContinuous measures were summarized as means with standard deviation, and categorical measures were summarized as counts and percentages. T-tests and chi-square tests were used to assess differences in demographic and clinical characteristics. Group differences in pain were assessed in multiple ways. Linear regression analyses were used to examine group differences in change among both average and maximum pain (before and after the procedure). For these models, group and before-procedure pain were included as independent factors and after-procedure pain was included as the dependent factor. By including before-procedure pain measurements, the model estimates a “residual change score” for pain. A statistically significant effect of group can then be interpreted as an association between group and change in pain. Pain was also assessed by subjective patient reports of pain relief. For this outcome, logistic regression analysis was used, with group as the independent variable and pain relief (yes/no) as the dependent variable. A similar analytic approach was used for post-procedure complications (yes/no). Ordinal logistic regression was used to evaluate group differences in pain relief duration . Regression analyses were also repeated to adjust models for relevant covariates. Effects from linear regression models were quantified as regression efficient (B) with 95% confidence intervals (95% CI). Effects for logistic regression models were quantified as odd ratios (OR) with 95% CIs. P < 0.05 was considered statistically significant. All analyses were performed in JMP Pro 16 .Overall, n = 1,424 patients were included in the study. Table Table A TFESI involves the injection of steroids under fluoroscopic guidance into the epidural space through a neural foramen at vertebral levels that correspond to a patient’s pain distribution . PatientProper TFESI technique delivers steroids at the site of pathology while minimizing the risk of nerve or vessel damage. The traditional supraneural approach to TFESI utilizes the “safe triangle” for injection, which avoids trauma to the exiting nerve root by placing the needle in the anterosuperior aspect of the intervertebral foramen ,23. A raThe Kumar Technique, when performed properly, should have a lower incidence of these traditional complications because the needle tip remains ventral to all neurovascular structures when approaching the neural foramen. In addition, the needle does not traverse towards the intervertebral disc, minimizing the risk of inadvertent disc penetration. While dural puncture is always a primary concern during epidural procedures, the Kumar Technique curtails this risk as well. The lumbar spine typically has progressively smaller vertebral bodies from L5 to L1, and the dural sac becomes more lateral in the spinal canal closer to the higher levels of the lumbar spine. Despite better alignment of the needle with the neural foramen seeming to increase the risk of dural puncture, the natural decrease in size of the vertebral bodies at higher levels requires an increased needle angle to reach the desired target. In turn, this ensures that the dura is avoided, even when it is more lateral in the spinal canal at the higher levels. Thus, the Kumar Technique is valid for all the lumbar spine levels (L5-S1 through L1-2 levels) and presents a low risk of all major complications resulting from improper needle tip placement.Under fluoroscopic guidance, contrast injected in the epidural space by the traditional approach quickly dissipates due to the surrounding vasculature. Thus, some of the injectate is “wasted” in the traditional approach as it is not delivered to the site of pathology in the spinal canal and does not remain on the exiting nerve root. Conversely, the trajectory in the Kumar Technique takes the needle safely ventral to the dura and nerve root and lands the tip at the posterior longitudinal ligament (PLL), which is usually an avascular structure except in chronic inflammatory conditions like old disc herniations, where the PLL can get inflamed with neovascularization. The lack of vascularity ensures that the injected steroid remains in place adjacent to the affected nerve root for a longer period, as evidenced by minimal contrast washout on repeat fluoroscopic images. In addition, many lumbar radiculopathies stem from disc bulges/herniations which displace the densely adhered PLL. Delivery of steroids at the PLL ensures precise delivery of medication at the site of pathology with less waste, thereby increasing injection efficacy.The theoretical benefits of the Kumar Technique are supported by the results of this analysis. Patients treated with the Kumar Technique had significant reductions in immediate post-procedure pain and average pain when compared to patients treated with the traditional TFESI approach. In addition, patients treated with the Kumar Technique experienced pain relief for a longer duration than the traditional approach.In our retrospective chart review of 1,424 procedures, we sought to determine whether the Kumar Technique was more effective in providing relief from radicular back pain than the traditional approach. We found that patients who received the Kumar Technique had an average immediate post-procedure pain reduction of 2.3 points on a self-reported pain score from 0 to 10. However, patients receiving the traditional approach had an immediate post-procedure pain reduction of just 1.1 points on the same 11-point scale. Results were similar with respect to reduction in average self-reported pain, with patients who received the Kumar Technique experiencing an average reduction of 2.4 points compared to 1.3 points for the traditional approach. Moreover, patients who received the Kumar Technique were 2.2 times more likely to report pain reduction immediately after the procedure.Another metric of efficacy is the duration of pain relief. The transient nature of pain relief associated with TFESI is well documented and often cited in arguments against the utility of lumbar TFESI. The results of this study found a marked improvement in the duration of pain relief when using the Kumar Technique as compared to the traditional approach. While the majority of patients receiving the traditional approach experienced less than one month of pain relief, 54% of those receiving the Kumar Technique experienced pain relief for greater than one month. Even more notably, 23% of patients receiving the Kumar Technique reported pain relief three months after the procedure.Our results show that the Kumar Technique is likely a more effective treatment for radicular back pain in most patients than TFESI via the traditional approach. The Kumar Technique allows for improved access to the nerve roots in the epidural space via the neural foramen of the affected vertebral level, thereby decreasing major risks of neurovascular trauma and intravascular injection and minor risks including headache, flushing, and increased back pain ,27-29. WThere are several potential limitations to our study. The average age of patients in this analysis was 58.5 years for the Kumar Technique and 60.5 years for the traditional approach; other TFESI efficacy studies evaluate slightly younger patient populations that average 50 to 55 years old ,23. HoweIn addition, differences in the volume and concentration of steroids injected were not accounted for in our study. Typically, 4 mg of decadron along with 2 cc of normal saline  is injected at each level for patients having two- to three-level TFESIs performed. However, if a single-level TFESI is performed, 8 mg of decadron is sometimes used; in addition, in severely stenotic patients, sometimes the total volume of injectate is less than 3 cc. However, these differences are the practice standard and should be consistent between the groups performing the traditional approach and the Kumar Technique.The study is further limited due to the novelty of the technique. Although the Kumar Technique has been mainly used by younger proceduralists at our institution who graduated from our Pain Medicine Fellowship Program, the results may be skewed by the random manner in which patients were chosen to undergo this novel technique versus the traditional technique. Further adoption of the Kumar Technique and future evaluation of the technique across a broader patient population could address this limitation. This emphasizes the importance of the discussion of this new technique as its efficacy can only truly be evaluated when the method is disseminated amongst providers.Future research could evaluate a younger patient population and control for rates of disc herniation, central stenosis, and foraminal narrowing between each intervention group. In addition, ensuring the same dose of steroids and volume of injectate could be controlled for in future studies. A prospective multicentric randomized control study would be an effective tool for further efficacy and safety evaluations as well as cost analysis of the Kumar Technique.TFESI is a widely used treatment for lumbar radicular pain. However, refinements in technique are needed to improve the consistency and efficacy of the procedure. The Kumar Technique is a modified TFESI approach that allows for improved access to the traversing nerve roots and ventral epidural space, through a more lateral and inferior needle entry point. A multicentric, prospective, randomized control study would provide more clear evidence of any objective benefits of this modified approach. This limited current analysis supports the benefits of the Kumar Technique with patients experiencing a greater reduction in pain and longer durations of pain relief without increasing the risk of complications.


Quantitative measurement of perisurgical brain function may provide insights into the processes contributing to acute and chronic postsurgical pain.We evaluate the hemodynamic changes in the prefrontal cortex  and the primary somatosensory cortex/S1 using functional near-infrared spectroscopy (fNIRS) in 18 patients (We examined the (a) hemodynamic response to surgery and (b) the relationship between surgery-modulated cortical connectivity (using beta-series correlation) and acute postoperative pain levels using Pearson’s We show a functional dissociation between mFPC and S1 in response to surgery, where mFPC deactivates, and S1 activates following a procedure. Furthermore, the connectivity between (a) left mFPC and right S1 (original Our findings suggest that greater functional dissociation between mFPC and S1 is likely the result of inadequately controlled nociceptive barrage during surgery leading to more significant postoperative pain. It also supports the utility of fNIRS during the perioperative state for pain monitoring and patient risk assessment for chronic pain. Such ongoing nociceptive afferent signals have been shown to reach the brain under general anesthesia,,–,,,We have previously reported the use of functional near-infrared spectroscopy (fNIRS) to measure evoked and ongoing nociception under general inhalational anesthesia;,,,–Furthermore, a body of evidence indicates that several perisurgical factors may contribute to increased pain and analgesic requirements in the early postsurgical time and, importantly, to the condition of CPSP.To this end, we performed continuous fNIRS scanning during the pre-, intra-, and postoperative states in 33 patients scheduled to undergo knee arthroscopy for anterior cruciate ligament repair. The psychological outlook of the patient toward pain was evaluated prior to surgery using fear of pain and pain catastrophizing questionnaires. We examined the (a) cerebral hemodynamic changes in response to surgical procedures and (b) surgery-modulated cortical FC using beta-series correlation after accounting for their preoperative psychological state. We then computed the relationship between cortical FC and acute postoperative pain levels in these patients. We hypothesized that the cortical activity in pain-related brain regions is reflective of the afferent nociceptive barrage that was not mitigated or eliminated by analgesia/regional anesthesia during surgery; and greater nociceptive barrage during surgery will contribute to greater levels of acute postoperative pain. Additionally, we examined baseline brain changes before and after surgery to understand how brain state postsurgery relates to postoperative pain levels and presurgical outlook toward pain.22.1Data were collected from 33 participants undergoing arthroscopic knee surgery under general anesthesia. Eligible individuals were between 12 and 25 years of age. Individuals were excluded if they had structural brain disorders, significant medical disorders, such as diabetes, cardiac disease, autism, developmental delay, or cancer, or a history of smoking. Patients from whom reliable NIRS measures could not be obtained during an initial signal test, who could not keep their head still for 200 consecutive seconds, or who could not cooperate or understand the nature of the study were also excluded. Informed consent was obtained from the participants or their parent/guardians prior to the study, and assent was obtained from minor children. All study procedures were approved by the Institutional Review Board of Boston Children’s Hospital, Harvard Medical School, Boston, United States.2.2,,Preoperative and postoperative pain intensity was assessed on an 11-point numeric rating scale, where 0 = no pain and 10 = worst possible pain.2.3The fNIRS recording was sampled at a frequency of 25 Hz using a continuous wave fNIRS system  at 690 and 830 nm wavelengths. A custom-designed head probe consisting of 9 sources, 14 long-separation detectors (placed at a distance of 3 cm), and 9 short-separation detectors (placed at a distance of 0.8 cm) were used to record signals from the bilateral prefrontal and somatosensory cortices . A chann2.4The first fNIRS recording was performed while the patient was being prepared for surgery in the preoperative room. Once the clinicians completed their routine preoperative procedures, head probes were placed on the patient’s scalp, and optode-scalp contact was confirmed by a heart rate signal in every channel. Following the installation, a 10-min resting-state scan was collected. The patients were instructed to stay awake, silent, and remain as still as possible. The anatomical location of the optodes was maintained between recordings by transferring the patient to the operating room while still wearing the head probe secured to the fNIRS system.,In the operating room, the quality of the data was once again evaluated prior to anesthetic induction by establishing the heart rate signal in the different cortices. The patients were then induced using a standard anesthetic regimen, where patients were premedicated with intravenous 2 mg midazolam and induced using propofol (median 200 mg [min 150 mg to max 300 mg]) along with fentanyl or sufentanil. The detailed anesthetic protocol of this patient cohort is discussed in our prior papers.2.5hmrOD2conc function from the Homer2 toolbox.All data and statistical analyses were performed on the MATLAB R2019b platform using in-house scripts. First, the data were visually inspected to ensure acceptable signal quality. Acceptable signal quality was defined as a (1) minimum raw signal intensity of 2.62.6.1The resting-state FC during preoperative and postoperative states was computed using Pearson’s 2.6.2The block-averaged hemodynamic response of a cortical region, i.e., the changes in hemoglobin concentration to surgical procedures, was computed by averaging 30 s of time series after a surgical procedure  across all procedures a patient underwent during the surgery. Before averaging across the events, the time series following an event was normalized using the 5 s of timeseries before an event. This was performed for every region in each patient. The group averaged hemodynamic response using oxyhemoglobin and total-hemoglobin time series were obtained by averaging the block-averaged hemodynamic response across all patients for every cortical region.2.6.3,FC during surgery was computed using the Beta Series Correlation technique, where we calculate the pairwise correlation of trial-by-trial task activation measures of different brain regions.2.7The statistical analyses described below were performed separately for oxyhemoglobin and total hemoglobin time series.(1)Preoperative versus postoperative resting-state FC. The preoperative and postoperative FCs were compared to identify differences associated with the intraoperative state, likely emerging from effects of anesthesia, analgesia, and surgery. Before comparing the resting-state FC measures of the unique connections ((2)Intraoperative FC and acute postoperative pain levels. Relationship between intraoperative FC of each of the 66 connections and postoperative pain levels were determined using a simple Pearson’s 33.1Six of the 24 patients were excluded from the analysis due to poor data quality. The demographic information of the remaining 18 patients is provided in 3.2No significant relationship was found between acute postoperative pain levels and whether the patient received peripheral nerve block using ANOVA  intraoperative state: brain state modified by surgically induced nociceptive drive occurring during surgery. The approach allowed us to determine cortical changes during surgery that relate to acute postoperative pain levels, where patients with greater functional dissociation between mPFC-S1 in response to procedure had greater postoperative pain. We believe this could be due suboptimal or inadequate analgesic coverage during the procedure that could be overcome using an objective pain monitoring system such as fNIRS.Using fNIRS, we report cortical response and FC of S1 and prefrontal cortices during the following states: (1) 4.1,The resting-state FC before surgery was compared with the postoperative state. The FC of mFPC between and within the left and right hemispheres was significantly reduced during the postoperative state when compared to the preoperative awake state. Imaging studies have evidenced anterior prefrontal cortex to uniquely contribute to executive functioning depending on the subregion. For example, the mFPC is thought to play a key role in the default mode network (DMN) during unconscious processing, and internal modes of cognition, such as self-oriented thoughts/tasks and autobiographic memory retrieval.4.2,,,,Noxious surgical procedures under anesthesia were associated with deactivation of mFPC (immediate decrease in oxyhemoglobin concentration changes following stimuli) and activation of S1 (sustained increase in oxyhemoglobin concentration changes following stimuli). A similar response was also observed using the total hemoglobin measure . The cor4.3,,An estimated one in five individuals undergoing surgery is found to develop CPSP with significant implications on the quality of life and health care costs.4.4fNIRS technique, due to its noninvasive nature, ease of setup, portability, and flexibility is an excellent neuroinvestigative tool for surgeons and anesthesiologists. Concurrent physiological, autonomic, and cerebral hemodynamic monitoring (providing greater specificity of pain measures) is already made possible by newer systems in the market, such as NIRx Sport, NIRSIT, and NINJANIRS. These newer systems offer compact hardware, and superior scalp positioning, that can be easily implemented into routine surgical practice. Optodes may be placed on the forehead and scalp of patients without discomfort, or interference from head movement or other electrical medical equipment, similar to how a bispectral index is used for depth of anesthesia. Real-time data processing software, such as Turbo-satari by NIRSx or NINJANIRS provides platforms for neuroscientists/bioengineers to develop fNIRS-based applications, such as neurofeedback, brain computer interface, and bedside patient monitoring systems for various patient populations.4.5Numbers of patients. We recruited a total of 33 patients, however, due to the variability in optode location, and poor quality, or incomplete data, only 18 out of the 33 patients were used. (2) Nature of surgical and anesthesia paradigm. The anesthetic/analgesic regimen, the duration, nature, and complexity of surgery were unique to a patient. Accounting for these secondary factors is beyond the scope of this study. Future efforts from our group will include understanding the effect of regional anesthesia and the development of an analgesic index. (3) Secondary factors contributing to the perioperative state. The preoperative state may be confounded by procedures surrounding the patient, such as interactions with clinical staff. Intraoperative and postoperative states are bound to be confounded by the differing levels of surgical procedures between patients. However, these factors are often impossible to control during surgery. (4) Effects of biological sex. Due to the collinearity between sex and pain levels, where male patients report higher postoperative pain levels than female patients, the sex of the patient was not included as a regressor. One of our immediate future steps is to understand the effects of sex on perioperative brain state as female patients in general have been shown to have greater pain sensitivity and are at increased risk of severe pain.Physiological and autonomic factors. We do not evaluate for changes in the physiological and autonomic variables, such as blood pressure, heart rate, or respiration, during the intraoperative period. However, understanding the relationship between these factors with the fNIRS measures would be essential to fully model nociception and analgesia in the brain. (6) Other risk factors of CPSP. As such, the current study does not account for other risk factors such as genetic mutations, psychological vulnerability, and other comorbidities. (7) Technical issues. fNIRS due to its inherent limitations only allow recording of the superficial cortex with limited spatial resolution and noise introduced due to scalp hair, and movements during surgery. Multimodal systems with both fNIRS and electroencephalography (EEG) may be better suited for intraoperative monitoring as EEG allows measurement of depth of anesthesia and access to deeper brain regions.Methodological considerations. It is worth noting that no additional preprocessing, such as prewhitening or precoloring, was performed to account for structured or colored noise in the fNIRS data. fNIRS, due to its high sampling rate and susceptibility to physiological noise, may require additional steps to account for colored noise while performing ordinary least square estimates.This study is limited by a number of caveats: (1) 5–,To-date, ongoing monitoring of brain systems during the perisurgical period has been done using EEG-based systems to evaluate depth of anesthesia.


To inform the development of an intervention, it is essential to have a well-developed theoretical understanding of how an intervention causes change, as stated in the UK Medical Research Council guidelines for developing complex interventions. Theoretical foundations are often ignored in the development of mobile health apps intended to support pain self-management for patients with cancer.This study aims to systematically set a theory- and evidence-driven design for a pain self-management app and specify the app’s active features.The Behavior Change Wheel (BCW) framework, a step-by-step theoretical approach to the development of interventions, was adopted to achieve the aim of this study. This started by understanding and identifying sources of behavior that could be targeted to support better pain management. Ultimately, the application of the BCW framework guided the identification of the active contents of the app, which were characterized using the Behavior Change Technique Taxonomy version 1.The theoretical analysis revealed that patients may have deficits in their capability, opportunity, and motivation that prevent them from performing pain self-management. The app needs to use education, persuasion, training, and enablement intervention functions because, based on the analysis, they were found the most likely to address the specified factors. Eighteen behavior change techniques were selected to describe precisely how the intervention functions can be presented to induce the desired change regarding the intervention context. In other words, they were selected to form the active contents of the app, potentially reducing barriers and serving to support patients in the self-management of pain while using the app.This study fully reports the design and development of a pain self-management app underpinned by theory and evidence and intended for patients with cancer. It provides a model example of the BCW framework application for health app development. The work presented in this study is the first systematic theory- and evidence-driven design for a pain app for patients with cancer. This systematic approach can support clarity in evaluating the intervention’s underlying mechanisms and support future replication. In patients with cancer, pain is one of the most devastating symptoms throughout the cancer stages, during which it increases in prevalence throughout and beyond cancer treatment ,2. ApproA systematic review revealed that mobile apps have been increasingly reported as delivering health behavior change interventions and showing promising results . SignifiAccording to the UK Medical Research Council (MRC) guidelines for developing complex interventions, a solid theoretical understanding of how an intervention causes change is required to inform its development . Indeed,pain self-management. This has led to heterogeneity in the focus and content of pain self-management support interventions for patients with cancer. Indeed, Howell et al [In relation to interventions for pain self-management for patients with cancer in particular, systematic reviews and meta-analyses have shown that such interventions are effective in supporting better pain management ,8,19-21.ll et al  emphasizA review of Cochrane reviews of the self-management of chronic condition interventions stated that, in practice, the term “self-management” has been used to describe both simple and complex interventions aimed to empower individuals to manage their own health. Such interventions focused on educating patients about their condition and providing them with basic skills to manage their disease symptoms daily . The latPain self-management interventions for patients with cancer have been described as complex interventions because they need to incorporate several interacting components, reflecting the complexity of cancer pain ,12,29. AThere are many theories and models for behavior change, such as the theory of reasoned action  and the The BCW is based on the capability, opportunity, motivation, and behavior (COM-B) model that suggests that interaction among 3 components, namely capability (C), opportunity (O), and motivation (M), produces behavior (B) that, in turn, influences them ,38. ThusThe BCW is an increasingly applied framework for designing and developing behavior change interventions in various health-related problems and contexts -42 . The MEDLINE database was searched using a combination of keywords and relevant Medical Subject Headings (MeSH) terms, such as There are 9 BCW intervention functions . They are education, persuasion, incentivization, coercion, training, restriction, environmental restructuring, modeling, and enablement ,38. The The BCW identified 7 policy categories that could effectively support the delivery of the intervention functions and provided a matrix for this process. The possible policy categories are communication and marketing, guidelines, fiscal measures, regulation, legislation, environmental and social planning, and service provision ,38. In tFurthermore, the BCW framework emphasizes the importance of considering the context of the intervention as all steps are implemented and selecting what is most appropriate for the intervention to ensure effectiveness ,38. In lThe contents of the intervention were identified in this step using the BCTTv1 . This waThe selected mode of delivery, as discussed earlier, is a mobile phone app. Therefore, this step of the framework was not considered.From a behavioral perspective, it was clear from the literature that the problem of unsatisfactory pain management is related to a combination of behaviors on the HCP, health care system, and patient levels -52.Pain self-management was selected as the target behavior for the app because it shows strong supporting evidence for better pain management -58.Patients need to self-manage their pain at home and during the period of experiencing pain by incorporating pain control strategies into daily life and communicating with HCPs.Five relevant review articles ,55-58 weMapping the intervention functions to the corresponding COM-B components indicated that all 9 intervention functions were appropriate for addressing the identified determinants for pain self-management behavior . HoweverA total of 65 candidate BCTs were derived from linking the selected intervention functions to BCTs. This set was refined based on considering the context and applying the APEASE criteria to the 18 BCTs listed in Much of the recent literature on evaluating pain apps has revealed the absence of any theoretical foundation and evidence-based features -18. ThisIn this study, the results of the fundamental phase of the BCW, the behavioral diagnosis based on the COM-B model, revealed that patients may have deficits in their capability, opportunity, and motivation that prevent them from performing pain self-management . ConsequThe app needs to use education, persuasion, training, and enablement intervention functions because, based on the analysis, they were found the most likely to address the specified factors. Incentivization, coercion, and modeling intervention functions were also suggested by the BCW, but they were excluded . This waEighteen BCTs were selected to describe specifically how the intervention functions can be presented to induce the desired change regarding the intervention context . In otheinformation about others’approval, information about emotional consequences, and information about social and environmental consequences, had no evidence of earlier use. Despite the lack of evidence of the effectiveness to support the exceptions, it was decided to include them in the design of the app to provide evidence about their effectiveness in a future work. Some of the BCTs  proposed by the BCW were found inappropriate to the context, such as biofeedback, identification of self as role model, and social comparison. Other promising BCTs  cannot be delivered through the app, such as goal setting, review behavior goal, and action planning; these are likely to require nurse coaching to be better implemented, which was beyond the scope of this study  had previously been applied in effective self-management interventions, whereas 3 (17%), namely is study ; for exaself-monitoring and feedback will not be effective if patients lose interest in using the app.The BCTs specified for the app need to be carefully translated and implemented as meaningful app features because no guidance is provided by the BCW in relation to this matter. It is crucial that the BCTs are delivered in optimal ways that ensure patients’ engagement; therefore, the user-centered design approach is recommended to be adopted for building the app in line with patients’ preferences. BCTs such as It is important to acknowledge that the application of behavior change theory in digital health is still an emerging area of research, with creation of an agenda to guide the development of research only started in recent years . The behOn the basis of the aforementioned particulars, this study provided a step-by-step theory- and evidence-based design for the intended app. Such clarity was considered minimal or even nonexistent in the practice of interventions claiming that they are guided by theory . CharactThe behavioral analysis was based on literature from only 1 database because the topic of patients’ barriers to cancer pain management seemed well investigated. Nevertheless, searching more databases and additional data from multiple sources, such as focus groups or interviews, could have revealed further insights and strengthened the understanding of cancer pain self-management behaviors. Consequently, this could have resulted in a more precise selection of BCTs and effective interventions. Another limitation was related to implementing the stepwise approach recommended by the BCW team . AlthougThere has been increasing emphasis on the need for underpinning theory and evidence for mHealth interventions to ensure their success and facilitate their appraisal. The work in this study demonstrated the application of the BCW framework in designing and developing an app for supporting pain self-management for patients with cancer. The app design will be based on education, persuasion, training, and enablement intervention functions that will be presented by 18 BCTs. To the best of our knowledge, this is the first systematic theory- and evidence-driven design for a pain app for patients with cancer. This systematic approach can support clarity in the evaluation of the underlying mechanisms of the intervention and support future replication.


To examine the efficacy and safety of ozonated autohemotherapy (O3-AHT) combined with pharmacological therapy for comorbid insomnia and myofascial pain syndrome (MPS). N = 50) and the O3-AHT group (N = 53). Patients in both groups were given the same pharmacological management for three weeks. Patients in the O3-AHT group were treated with ozonated autohemotherapy  combined with pharmacological therapy. Primary (the insomnia severity index (ISI) and visual analogue scale (VAS)) and secondary outcomes , polysomnography data, the anxiety and preoccupation about sleep questionnaire (APSQ), the beck depression index (BDI), and the multidimensional fatigue inventory (MFI)) were examined at pretreatment, posttreatment, 1 month, and 6 months.  One hundred and eighteen patients were randomly divided into two groups: the control group (3-AHT group completed the study. In both groups, insomnia and pain symptoms were relieved significantly compared with pretreatment. Compared with the control group, the O3-AHT group had significantly improved sleep quality, pain, and negative mood at different time points. No adverse complications were observed in either group.  Fifty patients in the control group and fifty-three patients in the O Compared with pharmacological therapy alone, ozonated autohemotherapy combined with pharmacological therapy can ameliorate insomnia, reduce pain intensity, improve negative mood, and alleviate fatigue more effectively without serious adverse complications. Myofascial pain syndrome (MPS), defined as a kind of painful and aseptic skeletal muscle inflammation, is one of the main causes of chronic pain in clinics. This complicated syndrome is characterized by myofascial trigger points (MTrPs) within fascia and muscles, and pressing on MTrPs can induce localized and referred pain . MPS is Insomnia, defined as at least 3 months of difficulty in initiating and/or maintaining restorative sleep, is a common and debilitating comorbidity of musculoskeletal painful diseases . They agThe close relationship between insomnia and pain suggests the importance of effectively managing patients' sleep when treating patients with MPS. However, in clinical practice, pain physicians often focus on improving pain symptoms and ignore the potential harm caused by insomnia. The overall goals of treating patients with comorbid insomnia and MPS are improving sleep quality, alleviating pain, relieving negative emotions, and reducing the risk of insomnia-related disorders. Current strategies for the management of insomnia include cognitive behavioral therapy, medication, acupuncture, and other complementary therapies . Cogniti3-AHT) is a common pattern of ozone therapies during which autologous blood is ozonated and then injected back into the body [3-AHT on coronavirus 19 [3-AHT has shown significant advantages in diverse diseases such as psoriasis, age-related macular degeneration, and multiple sclerosis [3-AHT has been reported to relieve pain in fibromyalgia and postherpetic neuralgia [Recently, a multitude of studies has focused on the therapeutic value of ozone. In general, ozone's mechanism of action can be summarized as antioxidant capacity, vascular and hematological modulation, pathogen inactivation, and immune system activation . Ozonatethe body . Recentlvirus 19 . Besidesclerosis –15. In teuralgia , 17. In euralgia .3-AHT with pharmacological therapy can provide safe and effective relief of insomnia and pain in patients with comorbid insomnia and MPS. Therefore, we conducted a prospective, randomized, controlled study to evaluate the efficacy and safety of this combination therapy.As mentioned above, there is a complicated correlation between insomnia and pain, which poses a knotty challenge for management. We hypothesized that combining O3-AHT group or the control group using a computerized number generator.This study was approved by the Institutional Review Board and Ethics Committee of Shanghai East Hospital ChiCTR1900021602). The present clinical research was conducted in accordance with the Declaration of Helsinki. All authors had access to the study data and approved the manuscript. Written informed consent was obtained from all patients before the inclusion. From March 2019 to October 2021, we invited 176 patients to participate in our study on the basis of inclusion and exclusion criteria. The inclusion criteria are as follows: (1) age >18 years; (2) suffering from back pain for at least 3 months; (3) underwent a pain physician interview and a thorough physical examination to confirm the MPS diagnosis [00021602.3-AHT group after treatment. Therefore, the sample size calculation was based on a 45% effective rate in the control group and a 75% effective rate in the O3-AHT group. Assuming a two-sideda = 0.05 and a statistical power of 0.9, the sample size was calculated to be 38 for each group. Considering a 15% loss to follow-up, the sample size was at least 44 in each group.Because there was no reference for the effectiveness of ozonated autohemotherapy in patients with comorbid chronic insomnia and MPS, we conducted a preliminary trial before conducting the formal research. The preliminary trial indicated that the effective rate of treatment was 45% (9/20) in the control group and 75% (15/20) in the OAll patients included in the study underwent routine examinations after admission to the hospital, including a blood routine examination, coagulation function, liver function, and kidney function.Patients in both groups were given the same pharmacological management for 3 weeks. For insomnia management, patients were allowed to take 0.5–2 mg of estazolam if they found it extremely difficult to fall asleep. For pain management, patients with a VAS score <5 were given 60 mg of loxoprofen, with a maximum of 3 tablets per day. Patients with a VAS score of ≥5 were given tramadol 100 mg tablets, up to a maximum of 3 tablets per day.2-O3 mixture by the ozone medical apparatus  for 3 minutes. Afterward, the ozonated autologous blood was transfused back into the patient within 10 minutes. Patients received ozonated autohemotherapy three times a week for 3 weeks. The concentration of ozone for each week was as follows: 20 µg/ml in the first week, 30 µg/ml in the second week, and 40 µg/ml in the third week. 100 ml of the blood of patients in the control group was also collected without mixing with ozone, and then the sham infusion was performed. Only the special operator was aware of each patient's actual infusion condition.A special operator collected 100 ml of blood via the median cubital vein and injected it into a blood bag with an anticoagulant (10 ml of 3.8% sodium citrate). Blood was then mixed with a prepared 100 ml OThe insomnia severity index (ISI) was the primary outcome for evaluating the severity of insomnia in our study. This self-report questionnaire includes 7 items with a total score range of 0–28. Higher scores indicate more serious insomnia in the past two weeks.The visual analogue scale (VAS) was the primary outcome for evaluating the severity of pain in our study. One end of a 10 cm straight line is written “painless,” and the other end is “the most severe pain.” According to the degree of pain they felt, patients made a mark at a certain point on the straight line to indicate the intensity of pain and psychological impact. The distance from the starting point to the mark is the amount of pain, 0–10 points. The higher the scores, the heavier the degree of pain.The Epworth sleepiness scale (ESS) is a questionnaire used to evaluate the degree of subjective somnolence. Patients recalled their recent experiences of drowsiness and scored the severity of drowsiness in different situations, such as sitting still, lying flat, watching TV, and driving. Then, we evaluated the severity of daytime drowsiness according to the total score. The sum score was calculated (range 0–24), with higher scores indicating more dangerous somnolence. We used ESS as the secondary outcome to evaluate sleep quality.We utilized a polysomnography system  to record the sleep data of patients at four time points . At each time point, this instrument monitored the patient's sleep for 3 nights. Then, we collected the following data and took the following average: (1) total sleep time (TST)—sum of all asleep time in a night; (2) sleep onset latency (SOL)—time between going to bed and falling asleep; (3) wake after sleep onset (WASO)—sum of waking time in a night; (4) sleep efficiency (SE)—ratio of total sleep time to total time in bed; (5) number of awakenings (NOA)—times of awakening in a night.The anxiety and preoccupation about sleep questionnaire (APSQ) consists of 10 self-reports of insomnia patients about their distress and anxiety about sleep, each with a score of 0–10. Individuals compared the consistency between these self-reports and their own conditions in the past three days. The total score is the sum of the 10 answers, with a range of 0–100. Higher scores indicate worse anxiety and preoccupation in the past three days.The Beck depression inventory (BDI) contains 21 questions about the severity of depression in the past week, each with a score of 0–3. The total score ranges from 0–63, and higher scores indicate more severe depression.The multidimensional fatigue inventory (MFI) assesses the following 5 aspects of fatigue: general fatigue, physical fatigue, reduced activity, reduced motivation, and mental fatigue. There are 20 questions in this questionnaire, each with a score range of 1–5. Higher scores indicate worse fatigue.n)∗100%.The treatment effect was assessed 6 months after treatment according to the following criteria: “remarkable”—the symptoms, especially insomnia and pain, almost disappeared, with good quality of life restored; “valid”—the symptoms, especially insomnia and pain, were relieved, with quality of life improved; “invalid”—no improvement in the symptoms, signs, or quality of life. The effective rate (%) = /Possible complications, such as an allergic reaction, puncture point infection, hypotension, myocardial infarction, blood contamination, and abnormal blood potassium, were evaluated throughout the observation period.n (%). The independent-samplet-test was used for statistical analysis of the continuous data, and the chi-squared test was used for statistical analysis of the categorical data. The repeated-measures analysis of variance (ANOVA) test was used to compare data between the two groups before and after treatment. A P-value of <0.05 was considered to represent a statistically significant difference.All data were analyzed using SPSS 26.0  and GraphPad Prism 5.0 . The data were presented as the mean ± SD or 3-AHT group) completed each follow-up (P > 0.05)  .3-AHT group were significantly lower than pretreatment and showed the lowest at the 6-monthfollow-up. Meanwhile, the ISI score of the O3-AHT group was significantly lower than the control group at each time point after treatment , the most mature and widespread form of ozone therapy in clinical practice, combines precollected blood with O2-O3 in vitro and then administers ozonated blood back to the patient. O3-AHT has been well received because it allows for a predetermined amount of blood to be taken and a precise concentration of O2-O3 to be infused [3-AHT can efficiently alleviate pain and improve functional scores in patients with low back pain, causing only occasional and slight adverse reactions [Ozone therapy has been gradually applied in the field of medicine since its identification, although the process was circuitous and controversial . Ozonate infused . It has eactions .3-AHT in the treatment of comorbid insomnia and MPS. This clinical effect may involve the antioxidant, anti-inflammatory, oxygen supply, and microcirculation mechanisms of ozone. Ozone has a strong antioxidant capacity. To be specific, after being dissolved in the aqueous component of plasma, ozone can initiate transient oxidative stress and an increased release of microparticles from blood cells [Our study indicates the efficacy and safety of Ood cells . In respod cells . ROS andod cells . The antod cells . Owing tSleep restriction can elevate inflammatory markers, including interleukin-6 (IL-6), tumor necrosis factor (TNF), and C-reactive protein (CRP), which are considered to be related to the onset and mediation of pain , 34. Ozo3-AHT can promote the activity of glycolysis and increase 2, 3-diphosphoglycerate  in red blood cells [3-AHT on insomnia and pain is complicated and comprehensive, and further studies are needed to clarify its specific mechanisms.Ozone can improve the oxygen supply for tissues. Ood cells . 2, 3-DPod cells , so as tod cells . The imp3-AHT throughout the study. However, it is still necessary for researchers to carry out O3-AHT in a standardized procedure and actively notice any potential risk.Consistent with previous studies , 17, we There are also the following limitations to our study: (1) the patients were recruited from a single centre; (2) double blinding was not used in this research; and (3) the patients were only followed for 6 months after treatment. we did not comprehensively analyse the interaction between insomnia and pain during treatment. Therefore, it is necessary to be cautious about the results of this study and the explanation for our findings.In conclusion, our research demonstrated that ozonated autohemotherapy combined with pharmacological therapy was an effective and safe treatment for comorbid insomnia and myofascial pain syndrome. Compared with pharmacological therapy alone, this combination therapy can ameliorate insomnia, reduce pain intensity, improve related negative mood, and alleviate daily fatigue more significantly.