Over two-thirds of the patients in the low-impact group did not require opioids postoperatively. Two factors were predictive of lower postoperative opioid consumption: low-impact laparoscopy  and a mean intraoperative peritoneum below 10 mmHg . Total hysterectomy by low-impact laparoscopy is feasible in an outpatient setting and is associated with a marked decrease in opioid consumption compared to conventional laparoscopy.Our objective was to evaluate postoperative pain and opioid consumption in patients undergoing hysterectomy by low-impact laparoscopy and compare these parameters with conventional laparoscopy. We conducted a prospective study in two French gynecological surgery departments from May 2017 to January 2018. The primary endpoint was the intensity of postoperative pain evaluated by a validated numeric rating scale (NRS) and opioid consumption in the postoperative recovery unit on Day 0 and Day 1. Thirty-two patients underwent low-impact laparoscopy and 77 had conventional laparoscopy. Most of the patients (90.6%) who underwent low-impact laparoscopy were managed as outpatients. There was a significantly higher consumption of strong opioids in the conventional compared to the low-impact group on both Day 0 and Day 1: 26.0% and 36.4% vs. 3.1% and 12.5%, respectively ( Around 33,000 hysterectomies are performed each year in the UK, which means that one in five women will undergo this major gynecological surgery at some point . In the Nevertheless, surgeons need to be sure that their patients will not experience any pain once home. Pain typically leads to the over-prescription and over-consumption of opioids. In a cohort of 40,000 patients who had undergone surgery, Clarke et al. reported that 49% were discharged with an opioid prescription, and that 3% were still using opioids 90 days after the operation . The opiLaparoscopic surgery has evolved significantly since the first laparoscopic hysterectomy by Reich in 1989 ,11, therThe main objective of our study was thus to evaluate postoperative pain and opioid consumption in patients undergoing a hysterectomy by low-impact laparoscopy. Our second objective was to compare these parameters with those of patients undergoing a conventional laparoscopic hysterectomy.We conducted an analysis of patients prospectively included, from May 2017 to January 2018, in two French surgical gynecology departments . All consecutive adult patients undergoing laparoscopic hysterectomy were included in the study. Patients with additional procedures were excluded from the analysis. The research protocol was approved by the Institutional Review Board (IRB) of the French College of Obstetrics and Gynecology (CEROG 2021—GYN—0101).All the low-impact laparoscopic procedures were performed by two senior surgeons. Conventional laparoscopy was performed by other surgeons in the departments.Patients in the low-impact group were all prescribed analgesics including paracetamol, a non-steroidal anti-inflammatory drug (NSAID), and a weak opioid (tramadol) at their preoperative appointment. All the low-impact laparoscopy hysterectomies were planned as outpatient procedures.A formalized anesthesia protocol was applied for patients who underwent low-impact laparoscopy. Anesthesia was achieved by a remifentanil/propofol rapid induction technique, and curarization by rocuronium bromide (quick-acting). All the patients received an infusion of ketamine (0.15 mg/kg) at the beginning of the surgery and were administered an antiemetic (dexamethasone) during the procedure. Peroperative analgesia also included paracetamol and nefopam. Vascular filling was restricted to 2 to 3 mL/kg/h.A bladder catheter was inserted systematically for both procedures.® 5 mm valve-free trocar—which provides stable pneumoperitoneum even under constant suction—was then introduced [For the low-impact procedures, pneumoperitoneum was created at the umbilicus using a Verress needle up to 15 mmHg. An AirSealtroduced ,14. We t® device. Three other 5 mm ports were introduced under direct visual control in the right and left iliac fossae and medially. The pressure was then lowered to 10–12 mmHg.For the conventional laparoscopic procedure, a 10 mm optical lens was introduced through the umbilicus. The first insufflation was at 15 mmHg. It was then mediated either by a conventional insufflator or by an Airseal® Harmonic forceps and coagulation using a bipolar grasp. At the end of surgery, the ports were infiltrated by ropivacaine (75 mg) at the surgeon’s discretion.The operative technique was similar in the two groups. Hysterectomy was performed using UltracisionPostoperative management was similar in the two groups, especially in terms of pain evaluation and administration of analgesics. The nurses in the postoperative recovery unit (PACU) and outpatient/gynecologic unit were completely blinded to the surgical approach used.The bladder catheter was removed at the end of surgery for the outpatients and on Day 1 for inpatients. The primary endpoint was opioid consumption for postoperative pain. Pain was evaluated in the PACU on Day 0 and Day 1 by a validated numeric rating scale (NRS) ranging from 0 to 10 (where 0 is no pain and 10 the worst imaginable pain) ,16,17,18Appropriate analgesics were administered according to the NRS. Postoperative analgesic prescriptions included paracetamol, nefopam, NSAIDs, and tramadol to be used only if the other drugs were not sufficient for pain relief. According to the NRS: paracetamol was used for light pain (NRS < 4), ibuprofen or weak opioids (Tramadol) were used for moderate pain (4 ≤ NRS < 7), and morphine was used for intense pain (NRS ≥7).The outpatients were all called on Day 1 as standard protocol to ensure the absence of uncontrolled pain.Databases were managed using Excel , and statistical analyses were performed using R studio software .n(%) unless otherwise specified. Statistical analysis was based on Student’s t test for continuous variables and the χ2 test or Fisher’s exact test for categorical variables. All the factors that could influence postoperative pain and analgesic consumption were then investigated in univariate analysis. Values of p < 0.05 were considered to denote significant differences.After descriptive analysis, the patients in the low-impact laparoscopy group were compared to those in the conventional laparoscopy group. Data are presented as p > 0.05). During the study period, of the 109 patients who had a hysterectomy by laparoscopy, 32 underwent a low-impact laparoscopic procedure and 77 a conventional laparoscopy. The data are shown in p = 0.01). The size of the uterus was comparable in the two groups with 63 (21.3) mm and 65 (22.5) mm and in the low-impact and conventional groups, respectively (p = 0.61).Surgical variables are displayed in p < 0.001).Patients in the low-impact group had more complementary surgery such as ureterolysis (15.6% (5/32) versus 1.3% (1/77)), or omentectomy/appendicectomy (p = 0.03). None of the patients of the total cohort experienced significant perioperative bleeding.There was no significant difference in the duration of surgery, but the duration of anesthesia was greater in patients the conventional procedure group  but similar on Days 0 and 1 postoperatively . NSAIDs were used for two patients (2.6%) in the conventional group and for one (3.1%) in the low-impact group. The maximum pain evaluated in the PACU was significantly higher in the patients that had conventional laparoscopy (No patient (0.0%) consumed weak opioids in the PACU or on Day 0 in the low-impact group.p = 0.02 and p <0.01). Of note, more than two-thirds of the patients who underwent a low-impact procedure did not use any opioids in the postoperative period. Postoperative opioid consumption and pain evaluation are plotted in There was a significantly higher consumption of strong opioids in the conventional group vs. the low-impact group on Day 0 and Day 1: 26.0% (20/77) and 36.4% (28/77) vs. 3.1% (1/32) and 12.5% (4/32), respectively (p = 0.002) and a mean intraoperative peritoneum pressure below 10 mmHg (OR 1.25 95%CI 1.03–1.51). None of the other parameters, including uterus size and duration of pneumoperitoneum, had an influence of postoperative opioid consumption, , umption, .We report here that patients who underwent a hysterectomy by low-impact laparoscopy experienced less postoperative pain and used significantly fewer opioids than those who had conventional laparoscopy. More than two-thirds of the patients who underwent a low-impact procedure did not use any opioids postoperatively. Low-impact laparoscopy was successfully managed in an outpatient setting for around 90% of the patients. Two factors were predictive of lower postoperative opioid consumption: low-impact laparoscopy, and a mean intraoperative peritoneum pressure below 10 mmHg.The implementation of low-impact procedures in our centers was motivated by the double objective of achieving outpatient management and reducing (and even completely suppressing) postoperative opioid consumption.® Harmonic forceps energy in the 5 mm umbilical port or even larger bipolar forceps in the case of uncontrolled hemorrhage or large uterine pedicles. Mini-laparoscopy has been used by general surgeons for various procedures, such as cholecystectomy, with good outcomes. Casarin J. et al. in a recent review concluded that mini-laparoscopy could be a valid alternative to conventional laparoscopy in gynecologic surgery including major surgical and oncological procedures [It is now accepted that hysterectomy by laparoscopy is associated with lower morbidity and a shorter hospital stay than hysterectomy by laparotomy or by the vaginal route, for both cancerous and benign indications ,20. For ocedures . In our p < 0.001). The use of opioids did not differ by surgical indication . The use of non-opioid medication was also significantly lower in the low-impact group. Several authors have studied the performance of hysterectomy by mini-laparoscopy but with a focus on feasibility and complications as well as cosmetic results [A recent report from the West Sussex NHS Trust highlighted that the UK is now heading toward a US, opioid-style crisis with five people dying every day from opioid overdose . There i results ,29,30. A results , and som results , our wor results ,34,35,36D’Angelis et al. reported that low-impact laparoscopy in the setting of cholecystectomy provided improved postoperative outcomes and less pain . Some auOur study has some limitations. Two experienced surgeons performed all the low-impact procedures, which might have resulted in an overestimation of the benefit of the technique, since surgical duration and gestures performed are based on a surgeon’s skills. However, in their experience, the main barriers for undertaking a low-impact procedure were concerns about lacking adequate visibility with low pressure and 3 mm optical lens, and concerns about mastering the mini-instruments. It deserves to be mentioned that the transition in our centers from conventional to micro-instruments was responsible for some material difficulties, and the operative room staff were unfamiliar with the new instruments for the first few cases. These data are not registered in this work. Another limitation is the short follow-up for postoperative pain. We only evaluated pain on Day 0 and Day 1 postoperatively, and some patients might experience prolonged or delayed pain. However, acute pain requiring opioids is usually the most intense on the first two days following surgery. Another limitation of our work was the inability to evaluate the impact of peroperative bleeding on postoperative pain, since none of the patients experienced significant bleeding. This could be explained by two factors: (1) the experience of the surgeons that performed the surgeries or (2) the relatively limited sample size. Another limitation was the lack of data regarding anesthetic management especially pulmonary recruitment maneuver that could significantly reduce the need for postoperative opioids. These data were not part of our data collection initially and should be included in the future RCT that will be conducted. Finally, bladder catheterization ablation on postoperative day 1 versus immediately at the end of surgery in the low-impact group may be a confounding factor, as it is a source of discomfort for patients.The most appropriate method to formally assess the benefit of low impact procedures would be to conduct a randomized controlled trial. In Our study shows that, for women undergoing total hysterectomy, low-impact laparoscopy and an intraperitoneal pressure of <10 mmHg are the main determinants of reduced postoperative pain and analgesic consumption. Total hysterectomy by low-impact laparoscopy is feasible and can be performed in an outpatient setting. Low-impact procedures could constitute the best option for reducing (and possibly eliminating) opioid consumption in the postoperative period. A randomized controlled trial should now be performed to definitely assess the potential benefit of low-impact procedures.


Distal symmetric diabetic peripheral polyneuropathy (DPN) is the most common form of neuropathy in the world, affecting 30 to 50% of diabetic individuals and resulting in significant morbidity and socioeconomic costs. This review summarizes updates in the diagnosis and management of DPN. Recently updated clinical criteria facilitate bedside diagnosis, and a number of new technologies are being explored for diagnostic confirmation in specific settings and for use as surrogate measures in clinical trials. Evolving literature indicates that distinct but overlapping mechanisms underlie neuropathy in type 1 versus type 2 diabetes, and there is a growing focus on the role of metabolic factors in the development and progression of DPN. Exercise-based lifestyle interventions have shown therapeutic promise. A variety of potential disease-modifying and symptomatic therapies are in development. Innovations in clinical trial design include the incorporation of detailed pain phenotyping and biomarkers for central sensitization. Diabetic peripheral polyneuropathy (DPN) affects about 50% of patients with diabetes mellitus and is the most common cause of neuropathy worldwide5. DPN is also the precipitating risk factor for diabetic foot complications, including diabetic ulcers, Charcot arthropathy, and lower limb amputations. These sequelae are independently associated with increased mortality risk6. Associated healthcare costs related to diabetes mellitus and its complications increased from $232 billion in 2007 to $760 billion in 2019 worldwide7, and up to 27% of these costs are attributed to DPN8.Diabetes mellitus is a worldwide pandemic, affecting 537 million adults9. DPN develops in the context of a system of metabolic derangements, including hyperglycemia, increased polyol flux, oxidative stress, and lipid alterations, in addition to other cardiovascular risk factors12. The Toronto consensus criteria provide a framework for DPN diagnosis, which is based on the combination of neuropathy symptoms and signs and can be confirmed using nerve conduction studies (NCSs)13. NCSs are normal in small fiber neuropathy, which is usually associated with significant neuropathic pain. In this setting, a validated measure of unmyelinated small-diameter axonal injury may be used to confirm the diagnosis14. The most used diagnostic tool for small fiber neuropathy is a skin biopsy with quantification of intraepidermal nerve fiber density (IENFD)14.Diabetic neuropathies may be classified into generalized and focal/multifocal forms. The most common diabetic neuropathy is a length-dependent, symmetrical sensory-motor peripheral polyneuropathyIn this article, we highlight five areas of recent updates in DPN: evolving biomarkers for early and accessible diagnosis, metabolic risk factors, innovations in clinical trials for painful diabetic neuropathy, genetic modifiers of disease risk, and recent therapeutic developments.16. Thus, there is a need for more increasingly sensitive and responsive biomarkers as screening and diagnostic tools and surrogate end-point measures17. Accurate diagnosis of different DPN phenotypes, including small fiber neuropathy, is necessary for clinical trial design and to facilitate targeted therapeutic intervention. The 2020 Analgesic, Anesthetic, and Addiction Clinical Trial Translations, Innovations, Opportunities, and Networks (ACTTION) criteria are standardized diagnostic criteria for idiopathic large, small, and mixed fiber neuropathies for research use: at least one small or large fiber symptom and sign and abnormal IENFD or sensory NCS (or both) for small fiber, large fiber, and mixed polyneuropathies, respectively18. Publication of specific aligned criteria for DPN is expected in 2022. IENFD remains the gold standard pathological confirmation of small fiber neuropathy, but the test is minimally invasive, and the biopsy specimen needs to be processed and evaluated at highly experienced laboratories to avoid false-positive results that can occur from suboptimal handling18. The development of less invasive and more easily performed biomarkers is necessary to facilitate diagnosis and design of clinical trials for disease prevention or early intervention. A summary of the biomarkers discussed below is shown in A major criticism in the screening process for DPN is that by the time neuropathy becomes detectable by current assessments; nerve injury is well established and difficult to reverse19. A confocal laser scanning microscope noninvasively visualizes small-diameter unmyelinated axons in the cornea. Patients with DPN have reduced corneal nerve fiber density and length compared with normal controls19. In a cohort of 143 patients with diabetes20, corneal fiber density correlated with neuropathy signs on examination. Comparison of corneal nerve fiber length and density against neuropathy exam findings  in controls (n = 30), painful diabetic neuropathy (n = 78), and painless diabetic neuropathy (n = 62)21 suggested that inferior whorl fiber changes preceded changes at the central whorl in a length-dependent fashion and correlated with decreased cold and warmth perception thresholds in those with painful diabetic neuropathy21. More investigation and validation studies are needed before corneal confocal microscopy can be considered as an alternative measure of small-caliber nerve fiber loss.Corneal confocal microscopy is a noninvasive technique that can detect and quantify small nerve fiber loss in DPN and other forms of neuropathy22, acting as a surrogate of axonal membrane dysfunction before axonal damage occurs and NCS findings are evident24. The hope is that NET may detect early changes in axonal function in DPN before axonal degeneration becomes irreversible, as demonstrated in oxaliplatin-induced neurotoxicity25. Patients with mild DPN  had abnormal axonal excitability profiles compared with healthy controls: longer duration of the relative refractory period, lesser prominent change of superexcitability, and smaller threshold changes to 50% depolarizing current26. Limitations of this technology include (1) this technique requires specialist training and equipment and is not widely available, (2) NET is more reliable and reproducible in motor nerves than sensory nerves27, (3) it does not provide information about the status of small fiber nerves, (4) no clinically relevant normative ranges are defined, and (5) NET still needs to be validated as an alternative biomarker for diabetic peripheral neuropathy22.Nerve excitability testing (NET) may show promise as an emerging experimental neurophysiological biomarker of early axonal dysfunction. NET measures axonal firing thresholds in response to submaximal and supramaximal current delivered via noninvasive electrodes28. NfL is increased in DPN patients compared with controls, and MPZ mRNA transcript levels are reduced28. The latter may predict future axonal loss 24 months in advance28. Reduced MPZ mRNA levels predicted a hypoalgesic phenotype as opposed to increased NfL levels, which predicted a hyperalgesic phenotype28. NfL has been proposed as a biomarker of many neurodegenerative conditions, including motor neuron disease, degenerative movement disorders, dementia, and hereditary amyloidosis29. Serum NfL levels have also been shown to correlate with treatment response in patients with hereditary transthyretin amyloid  polyneuropathy30. Patients with ATTRv polyneuropathy had higher levels of serum NfL than healthy controls , and after 18 months, serum NfL levels increased with placebo (36.3 mg/mL increase) and decreased with transthyretin (TTR) silencer patisiran treatment (-23.3 pg/mL), correlating with clinical progression in the placebo group versus the treatment group30. While nonspecific, this correlation with treatment response suggests that NfL holds promise as a biomarker for disease progression and treatment response in neurodegenerative diseases, including DPN.Neurofilament light chain (NfL) protein, a marker of axonal degeneration, and circulating myelin protein zero (MPZ) mRNA transcripts show promise as blood biomarkers for diabetic neuropathy31. High levels of TNF-α and IL-6 were associated with the development of DPN over time32. An increase in systemic inflammatory markers TNF-α and IL-6 was associated with DPN in type 2 diabetes, but these markers were also increased in painful neuropathies of various etiologies over nonpainful neuropathies31. Cytokine activation is associated with the generation of neuropathic pain33, but cytokine-specific antagonists (such as TNF-α inhibitors) failed to treat neuropathic pain34, suggesting that cytokines and chemokines function more as a network than single proteins in mediating painful polyneuropathies31.In contrast with diabetic patients without neuropathy, patients with DPN in type 2 diabetes showed elevated inflammatory markers C-reactive protein (CRP), tumor necrosis factor-alpha (TNF-α), intercellular adhesion molecule 1 (ICAM-1), and interleukin 6 (IL-6)38. In animal models, interventions that enhance or reduce spinal inhibition resulted in respectively decreased39 or increased40 behavioral indices of pain41. Additionally, advanced imaging shows cortical changes that may serve as promising biomarkers in painful DPN, which we will discuss below.There is increasing evidence that changes in the brain and spinal cord reflect and modulate neuropathic pain in DPN42, whereas type 2 diabetes is due to insulin resistance in association with metabolic risk factors, including obesity and dyslipidemia43. Multiple pathophysiologic pathways contribute to the development of diabetic peripheral neuropathy, including microvascular injury and ischemic stress to the peripheral nerve, inflammation, oxidative stress, and mitochondrial injury41. Multiple animal studies and cross-sectional, observational, and case-control studies across multiple continents spanning 40 years strongly suggest that metabolic syndrome and its component features are associated with an increased risk of developing polyneuropathy in type 2 diabetes and idiopathic neuropathy as well as in long-standing type 1 diabetes44. Metabolic syndrome is defined by the presence of at least three out of five criteria: elevated serum triglycerides, reduced high-density lipoprotein cholesterol, central obesity, hypertension, and diabetes or prediabetes45.While both type 1 and type 2 diabetes are characterized by hyperglycemia, type 1 diabetes is caused by autoimmune injury to pancreatic beta cells resulting in reduced insulin and C-peptide levels44. The association between metabolic syndrome and sensory polyneuropathy is present independent of glycemic status in multiple studies49, suggesting that the other components of the metabolic syndrome may play a greater role in modulating the development of neuropathy in type 2 diabetes. In type 1 diabetes, aggressive glucose control significantly reduces the risk of neuropathy, but this effect is much more attenuated in type 2 diabetes (the relative risk reduction in type 1 is over 75% but is less than 10% in type 2 diabetes)51. Both dyslipidemia and prediabetes are also independently associated with the development of idiopathic peripheral polyneuropathy44. A meta-analysis investigating the association of dyslipidemia and diabetic neuropathy in 2021 examined 39 clinical trials containing 32,668 patients with either type 1 or type 2 diabetes and found that higher triglyceride and low-density lipoprotein levels were associated with an increased risk of diabetic neuropathy52. Tissue-specific dyslipidemia profiles distinguished diabetic nephropathy, retinopathy, and neuropathy, each with a distinct set of lipid species affected53. In a diabetic mouse model, overall lipid species were increased in kidneys and nerves, while lipid content was decreased in retinas. In human sural nerve biopsies, progressive and stable diabetic neuropathies had distinct transcriptomic profiles54. Of the three diabetic complications, diabetic neuropathy is most associated with dyslipidemia, which in turn induces mitochondrial deficits and accumulation of lipotoxic species to axons leading to axonal degeneration55.Both idiopathic peripheral polyneuropathy and diabetic polyneuropathy manifest with length-dependent sensory loss, with preferential injury to small nerve fibers. In addition, the presence of metabolic syndrome is a significant risk factor for developing polyneuropathy in both type 1 and type 2 diabetes56. More individuals with obesity had neuropathy compared with lean individuals, and the presence of neuropathy has been associated with abdominal obesity, hypertension, and elevated triglycerides56. Additionally, obese patients without neuropathy had reduced intraepidermal nerve fiber densities and worse pain, quality of life, and depression scores in contrast with lean controls57.Growing evidence suggests that obesity alone without hyperglycemia is a significant risk factor for neuropathy58. Similarly, the Look AHEAD study demonstrated that intensive lifestyle modifications significantly decreased DPN symptoms, which were associated with a degree of weight loss 1 to 2.3 years after termination of active intervention59. Multiple clinical trials are under way to examine the effect of lifestyle interventions on diabetic neuropathy (NCT04813146 and NCT01565317). The Topiramate as a Disease Modifying Treatment for Cryptogenic Sensory Neuropathy (TopCSPN) trial (NCT02878798), funded by the National Institutes of Health, is examining whether 100 mg of topiramate daily slows the progression of idiopathic neuropathy based on weight loss and its effects on metabolism. Results are expected later this year.The impact of aggressive management of metabolic syndrome features has yet to be determined; however, clinical and preclinical data suggest that this approach may have promise. Lifestyle interventions over 12 weeks, including strategies for glucose control, physical activity, weight loss, and diet modifications, reduced the severity of DPN symptoms62. There is increasing interest in whether the pain phenotype may help characterize the underlying pathophysiology and thereby suggest a more tailored treatment approach. Characterization by quantitative sensory testing (QST) of over seven types of neuropathic pain syndromes  showed that the pain phenotypes were incredibly heterogeneous and that different patients with the same disease can have different phenotype profiles 63. In studies characterizing subjective pain descriptors, two types of neuropathic pain have been described: ongoing burning pain and electric shock-like sensations64. While there was no clear relationship between burning pain and specific patterns of abnormal sensory modalities on QST, the level of burning pain was inversely related to laser-evoked potentials, which primarily measure Aδ fibers64. In contrast, electric shock-like sensations were associated with abnormal non-nociceptive Aβ-fibers based on somatosensory-evoked potentials or NCS abnormalities64. Four theoretical mechanisms61 underlie ongoing burning neuropathic pain: (1) sensitization of “irritable” nociceptors where distal nerve terminals are spared and IENFD may be normal, (2) hyperexcitable “regenerating sprouts” in ongoing regeneration with reduced IENFD, (3) functional deafferentation due to distal axonal degeneration manifesting as distal numbness and proximal hypersensitivity, and (4) anatomical denervation in processes such as ganglionopathy or root lesions where the pain is felt in the same region as hypoesthesia64.About 30% of patients with DPN have neuropathic pain, which is a significant cause of patient morbidity65. Demant et al. (2014) categorized 97 patients with neuropathic pain64 as having an irritable nociceptor versus nonirritable phenotype66. These patients were randomly assigned to treatment with oxcarbazepine or placebo. The numbers needed to treat for a more than 50% reduction in total pain score were 3.9 in the irritable nociceptor group and 13 for the nonirritable nociceptor group67, suggesting that sodium channel antagonists may be effective in the irritable nociceptor phenotype.Sodium channel blockers have been explored as a potentially efficacious therapy for the irritable nociceptor phenotype68. In this technique, a microelectrode is inserted into the nerve fascicle and records action potentials from a single axon, thus measuring the degree of spontaneous activity from the peripheral nerve. Patients with painful polyneuropathy demonstrate a higher proportion of spontaneously active or mechanically sensitized C-nociceptors in contrast to patients with painless polyneuropathy and also showed less activity-dependent slowing suggestive of a peripheral sensitization69. However, microneurography is a time-consuming process performed at a few institutions and requires special expertise by the investigator and collaboration from the awake patient. Furthermore, there are no normative data in healthy subjects, and C-type nociceptor hyperactivity and sensitization may not be specific to patients with peripheral neuropathy, as this has also been demonstrated in patients with other etiologies of pain, including fibromyalgia70, erythromelalgia71, or complex regional pain syndrome72. While these limitations prohibit its use in bedside clinical practice, it may be a promising option in identifying the subset of patients with irritable nociceptor phenotype that might be more responsive to treatment, demonstrated in the randomized control trial of ABT-639  on spontaneous C-type nociceptor activity in patients with painful diabetic neuropathy73. Although the trial showed no differences in C-nociceptor activity or pain in 34 patients, microneurography may still hold promise in identifying irritable nociceptor phenotypes for future drug trials in painful polyneuropathy.Microneurography may serve as a biomarker for the irritable nociceptor phenotype and as an objective, quantifiable measure of subjective painet al. (2019)74 demonstrated a relationship between brain volume and functional changes in the somatosensory cortex correlating with the severity of peripheral neuropathy as demonstrated by functional magnetic resonance imaging (fMRI)75. Patients with the greatest severity of neuropathy characterized by NCS correlated with the greatest reduction in sensory cortical thickness as well as a widening of the S1 functional representation of the foot and thigh, suggesting deafferentation affecting the sensory neurons with the recruitment of nearby functioning neurons74.Selvarajah et al.76 examined the impact of IV lidocaine on pain severity, sensory phenotype , and fMRI somatosensory cortical response in 29 patients with DPN compared with 26 healthy controls74. Responders were defined by a 30% decrease in pain intensity, lasting for at least 3 weeks74. Patients with an irritable nociceptor phenotype were more likely to respond to IV lidocaine than patients with a nonirritable nociceptor phenotype74. fMRI in nonresponders had lower S1 cortical volumes and functional connectivity compared with responders and healthy controls74. These results suggest that pain phenotypes can help predict treatment response  and that treatment response may be characterized by connectivity between primary somatosensory cortex on fMRI.In 2020, Wilkinson 77 found a genetic locus on Chr2q24, which was more frequent in diabetic patients without peripheral neuropathy than in patients with diabetic neuropathy. This is a novel locus associated with the risk of diabetic peripheral neuropathy, and its function has not yet been clearly defined77. It has been suggested to be associated with higher tibial nerve expression of the SCN2A gene, which is located nearby as well as potentially influencing glucose metabolism and insulin resistance78. microRNAs, which regulate up to 30% of human genes, are emerging from animal models of neuropathy risk as possible biomarkers of risk and pathogenesis in diabetic neuropathy in humans79. Diabetic sensory neurons demonstrate a unique pattern of microRNA alterations in preclinical models of neuropathy in type 1 diabetes80. In type 2 diabetic neuropathy, epigenomic factors such as DNA methylation and post-translational histone modifications are considered possible contributors to the development of “metabolic memory” and risks of developing diabetic complications81.A genome-wide association study of the ACCORD and BARI 2D cohorts82. This pathway was discovered when a colony of C57Bl/6J mice spontaneously developed the WldS mutation, which resulted in dramatically slowed Wallerian degeneration83. WldS mice are resistant to axonal degeneration due to nerve injury and other neuropathic insults, including neurotoxic chemotherapy85. Subsequently, SARM1 was noted to be required for axonal degeneration in fruit flies and mice86. Structure and functional studies showed that SARM1 is a critical enzyme in initiating axonal death87. Upstream from SARM1 activity, survival factor NMNAT2 is an endogenous enzyme in healthy axons and restrains SARM1 degenerative activity88. The absence of NMNAT2 induced axonal degeneration, but since this pathway is dependent on SARM1 activity88, degeneration could be prevented in preclinical models by knocking down SARM1 or inhibiting its function pharmacologically89. Deletion of SARM1 prevented the development of neuropathy in the streptozotocin mouse model of type 1 DPN90. SARM1 is emerging as a potential treatment target for multiple forms of neuropathy. It is also possible that genetic variation in SARM1 can predict disease risk91. While data are not available for DPN, recent studies suggest that naturally occurring variation in the SARM1 gene may increase the risk of amyotrophic lateral sclerosis92.In recent years, a mechanistic model of axonal degeneration demonstrated that the balance between pro-survival factors and pro-degenerative molecules drives axonal metabolism and self-destruction. SARM1 is a pro-degenerative molecule and represents a key step in a program for axonal degeneration following injury 100. Low-intensity exercises improved quality of life as well as reduced pain and tingling symptoms101. Indeed, in diabetic patients without neuropathy, weekly exercise for one year significantly increased distal IENFD compared with those without exercise, suggesting that presymptomatic injury to small unmyelinated fibers may be reversible102. Similar results were demonstrated in patients with metabolic syndrome without clinical neuropathy103. A clinical trial examining the combination of bariatric surgery and high-intensity exercise in the prevention and treatment of diabetic neuropathy is underway (NCT03617185).An evolving literature supports the utility of lifestyle-based therapies for patients with DPN and neuropathy associated with prediabetes . Short-t104 have explored the effects of vitamin supplementation in diabetic neuropathy: oral alpha lipoic acid105, vitamin E107, vitamin D108, EMA401109, and sodium channel blocker PF-05089771110; these studies have mostly been negative or inconclusive.In the past few years, a handful of small cohort clinical trials111 in 95 patients in the treatment group. Long-term follow-up results from a smaller trial were published in 2018, noting treatment success in 55% of spinal cord stimulation in patients with painful diabetic neuropathy after 5 years112. Patients with more severe neuropathy (Michigan Diabetic Neuropathy Score [MDNS] 3) had a higher risk of long-term treatment failure at the 5-year follow-up, resulting in device removal112. In contrast, a higher baseline nocturnal pain score was associated with decreased risk of treatment failure112. Complications include infection (5%) and pocket pain (25%), and about half required adjustments or replacements in equipment, such as lead revision (10%) or battery replacement (33%)112.Several recent studies have explored neuromodulation as a therapeutic strategy for painful DPN. In 2021, results from the SENZA-PDN trial  showed significant pain relief sustained over 6 months114. Pulse-dose electrical stimulation for 4 weeks in 10 patients showed a reduction in pain at the end of treatment and for 4 weeks after discontinuation of treatment116. Frequency-modulated electromagnetic neural stimulation (FREMS) showed pain reduction and increased tactile perception117. Pulsed electromagnetic field therapy in painful diabetic neuropathy showed mixed results120. Acupuncture showed a decrease in pain during a 12-week intervention period, but this response was not sustained after treatment stopped121. The ACUDPN trial (NCT03755960) started in 2018 and examined the effect of acupuncture over 8 weeks on pain severity and nerve conduction parameters; results are pending.Attempts at peripheral neurostimulation have been largely unsuccessful. Bioelectronic therapies were explored in small cohorts of patients with painful diabetic neuropathy: transcutaneous electrical nerve stimulation (TENS) in a retrospective study showed an average use of 1.7 years, with 76% of patients reporting subjective improvement in pain122. Four classes of medications are recommended in the treatment of painful DPN: gabapentinoids, tricyclic antidepressants, sodium channel blockers, and serotonin and norepinephrine reuptake inhibitors; opioids are not recommended122. If a trial of one medication class achieves partial pain control, adding on a second class is recommended. If one class has no effect on pain control, a trial of a different medication class is recommended over attempting a second agent from the same class. Clarifying expectations of pain management is essential in achieving patient satisfaction: while patients often expect complete pain resolution, a 30% reduction in pain level is considered successful in clinical trials, and the goal of pharmacotherapy is to reduce but not necessarily eliminate neuropathic pain122. Evaluation for comorbidities such as sleep and mood disorders is recommended. These are more prevalent than in the general population, and both affect pain experience, and treatment can be more effective in improving pain control and quality of life122.The American Academy of Neurology updated guidelines for the management of painful DPN in 2022123 have been suggested as potential pharmacologic targets for the prevention of diabetic neuropathy, given their role in off-loading mitochondrial respiratory demand. Benfotiamine was explored as a potential therapy via reducing excess glucose metabolism down the pentose phosphate pathway, which in turn forms advanced glycation end-products, resulting in increased oxidative stress124. A 3-week placebo-controlled trial in 2005 showed a reduction in neuropathic pain but no improvement in vibratory sensation125. This was confirmed in a phase III trial in 2008, and long-term benfotiamine supplementation showed improvement in NCSs and inflammatory markers such as TNF-α, IL-6, and IL-18126. A small study has been proposed to evaluate the effect of benfotiamine on IENFD and diabetic neuropathy (NCT01868191). Omega-3 polyunsaturated fatty acids are also of interest in preventing the progression of neuropathy with early preclinical evidence of preserving nerve function127, and multiple clinical trials  are under way. Early Phase Pain Investigation Clinical Network (EPPIC-Net) is currently funding two clinical trials for DPN: the development of NRD135S. E1, a nonopioid oral analgesic that downregulates purinergic receptors involved in the central nervous system processing of pain (NCT02345291), and a phase 2 study on the efficacy of topical pirenzepine, a muscarinic antagonist which showed promise in mouse models for painful DPN (NCT04786340)128.A number of potentially disease-modifying therapies are in preclinical development. Sirtuins such as resveratroleffective symptomatic treatments targeting neuropathic pain and disease-modifying and preventative therapies, recent advances promise to accelerate therapeutic development. Refined diagnostic criteria and characterization of specific pain phenotypes will inform clinical trial design, and developing biomarkers promise to facilitate earlier diagnosis and design of clinical trials for patients early in the disease course. Preclinical studies of metabolic and genetic risks for neuropathy are being translated into clinical trials.DPN is a highly prevalent disorder associated with significant patient morbidity and healthcare costs. While there is an urgent need for more


Laparoscopic cholecystectomy is the gold standard surgical procedure for treating gallstone disease. Despite it being minimally invasive, various medications and methods are used to alleviate postoperative pain, and some patients still experience moderate-to-severe pain. This is a crucial problem that must be solved to avoid chronic pain. As part of postoperative multimodal analgesia, regional block is being increasingly applied in surgery under ultrasound guidance. We aimed to evaluate the analgesic effect of erector spinae plane block in adult patients undergoing laparoscopic cholecystectomy.PubMed, Cochrane Library, EMBASE, and Web of Science were searched for randomized controlled trials investigating the efficacy of erector spinae plane block on postoperative pain after laparoscopic cholecystectomy. The primary outcome was the postoperative pain score. The secondary outcomes were the cumulative intraoperative and postoperative opioid consumption at 24 h, incidence of postoperative nausea and vomiting, and shoulder pain after surgery. The results were pooled using the fixed- or random-effects model with Review Manager 5.3.p < 0.00001) and 24 h . Cumulative opioid consumption was lower in the erector spinae plane block group than in the control group at postoperative 24 h . The erector spinae plane block group also experienced a lower incidence of postoperative nausea and vomiting than the control group. Opioid consumption and the incidence of postoperative nausea and vomiting were similar between the erector spinae plane block group and other block groups, including the oblique subcostal transversus abdominis plane block and quadratus lumborum block groups.Fifteen randomized controlled trials involving 947 patients were included in the analysis. Postoperative pain score in the erector spinae plane block group was lower than that in the control group at postoperative 12 h (MD − 0.81, 95% CI − 1.1 to − 0.51, Ultrasound-guided erector spinae plane block provides effective postoperative analgesia in adults undergoing laparoscopic cholecystectomy.The online version contains supplementary material available at 10.1186/s12871-023-01969-6. Laparoscopic cholecystectomy (LC) is the most commonly performed surgical procedure for cholelithiasis management. Although it is minimally invasive and is associated with a shorter hospital stay and faster recovery than open surgery, some patients still experience moderate-to-severe postoperative pain –3. AcuteLately, under ultrasound guidance, regional blocks have been performed more accurately, providing better postoperative analgesia management , 8. The In the past 6 years, an increasing number of studies have been published to support the efficacy of ESPB, including case reports, clinical trials, and meta-analyses involving different surgical types , 15. HenCRD42022336837).The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) was followed to perform this meta-analysis . This meAll randomized controlled trials (RCTs) comparing ESPB with no block or other regional blocks in adults undergoing LC were included. Electronic databases including PubMed, Cochrane Library, EMBASE, and Web of Science were comprehensively searched for RCTs published before May 30, 2022. Literature search was conducted using a combination of medical subject headings and entry terms, including “(Laparoscopic or Celioscopic) and Cholecystectom*”, “erector spinae plane block”, “erector spinae plane”, “ESPB”, “ESP”, and “ESB”. A detailed search strategy for each database is available in Additional File Two experienced authors (Xiaoli Yang and Yu Zhang) independently screened the titles and abstracts of each article to eliminate repeated and irrelevant studies. The full texts of potentially eligible studies were then reviewed, and articles that meet the eligibility criteria were included. The data were extracted by two independent authors (Xiaoli Yang and Yu Zhang). Disagreements were resolved through discussion. If necessary, a third reviewer participated in the discussion to reach a consensus. The following data were extracted: first author, year of publication, sample size, type of surgery, ESPB target spine level and local anesthetics, control group technique, intraoperative opioid consumption, postoperative analgesia protocol, postoperative pain score and opioid consumption, postoperative nausea and vomiting(PONV), shoulder pain, and block-related complications. Data presented in the form of graphs were extracted using Plot Digitizer, a graph digitizing software.Two reviewers (Xiaoli Yang and Yu Zhang) independently assessed the quality of included trials using the Cochrane Collaboration tool . Each inPostoperative pain score at postoperative 12 and 24 h.Cumulative intraoperative and postoperative opioid consumption at 24 h, incidence of PONV, shoulder pain, and other block-related complications after surgery.I2 statistical test was used to assess the statistical heterogeneity of the pooled results [I2 between 0 and 25% was interpreted as no heterogeneity, 25–50% as low heterogeneity, 50–75% as moderate heterogeneity, and 75–100% as high heterogeneity. The fixed- or random-effects model was selected according to the level of heterogeneity. If I2 was < 50%, the fixed-effects model was selected, whereas if I2 was > 50%, the random-effects model was selected. A trial sequential analysis of the primary outcome was performed to confirm whether the sample size was sufficient and the results were stable or not [P < 0.05.The meta-analysis was conducted using Review Manager . For dichotomous variables, the risk ratio (RR) and 95% confidence interval (CI) were calculated. For continuous variables, the mean difference (MD) and 95% CI were calculated. If continuous variables were expressed as median and range (minimum to maximum or interquartile range), Luo and Wan’s formula was used to estimate the mean and standard deviation , 19. If  results . I2 betwe or not . StatistA literature search identified 195 records based on the eligibility criteria, and 74 articles were excluded for duplication. After screening the titles and abstracts, 96 studies were excluded, and the full text of the remaining 25 potentially eligible studies was reviewed. Among them, five studies were excluded because of the pediatric population, two articles were excluded due to retrospective study, two for commentary, and one for conference abstract. Therefore, 15 RCTs involving 947 patients were included in this systematic review and meta-analysis –36, and p < 0.00001) and 24 h . Low-to-moderate level of heterogeneity was observed . High heterogeneity was observed . High heterogeneity was observed  and POV . No heterogeneity was observed among the studies. In one study included in this meta-analysis, no patient experienced PONV. Two studies reported that PONV showed no significant differences between the two groups , and four RCTs reported postoperative vomiting (POV). The results showed that ESPB reduced the incidence of PON  groups, and one study assessed this outcome between the ESPB and quadratus lumborum block (QLB). Pooled results suggested that no significant difference in the requirement of opioids between the ESPB and OSTAPB groups (MD − 3.77, 95% CI − 7.7 to 0.16, All included studies were carefully reviewed, except for one study that reported intraoperative bradycardia in two patients in the ESPB group and in one patient in the OSTAPB group, with no significant difference. Other intraoperative and postoperative adverse reactions or complications, including bleeding, hematoma, subcutaneous emphysema, pneumothorax, local anesthetic toxicity, and pruritus, were not reported. This may have resulted from the widespread use of ultrasound. Ultrasound facilitates the accurate identification of the target fascial planes and precise delivery of local anesthetics for safer conduct of the block.Our meta-analysis demonstrated the clinical role of ESPB in postoperative pain control in adults undergoing LC. Postoperative pain scores at 12 and 24 h and opioid consumption during the first 24 h were lower in the ESPB group than in the control group. Evidence indicates that ESPB also reduced the incidence of PONV compared with the control group. However, although ESPB was implemented, intraoperative opioid consumption was not reduced during surgery compared with that in the control group. In addition, more evidence is needed in the future to compare the analgesic effects of ESPB and OSTAPB in LC.The prevention and management of postoperative acute pain have been a worldwide issue worthy of attention that need to be addressed. Over the last few decades, opioids have been widely used in the management of surgery-related acute pain. Although opioids relieve pain in humans, they also cause problems. Addiction, chronic pain, prolonged length of hospital stay, related morbidity and mortality, and many adverse reactions to opioids strongly force us to face and look for new ways to manage pain . VariousPostoperative nausea and vomiting are two common adverse events, with an estimated incidence of 30%; in high-risk patients, it can be as high as 80% . The manCompared with other blocks such as OSTAPB and QLB, no significant difference was observed between ESPB and OSTAPB in terms of postoperative opioid consumption, which is consistent with the findings of Koo’s study . AlthougThis meta-analysis has some limitations that should be considered when interpreting the results. First, ESPB was conducted after anesthesia induction in some studies; therefore, any possible block failure could not be identified. Second, different block levels from T7 to T9, the concentration of different local anesthetics, and different types of analgesics may have influenced the results, and further studies are required to determine the optimal concentration, volume, and type of local anesthetic. Third, the heterogeneity cannot be ignored.ESPB plays an important role in the management of acute postoperative pain. To achieve opioid-sparing anesthesia, regional blocks such as ESPB should be advocated as part of multimodal analgesia for enhanced recovery after surgery. Further studies comparing ESPB, OSTAPB, and QLB are required to confirm their analgesic effects in LC.Additional file 1. Search strategy.


The physical examination confirms the central sensitization of female patients with CPPS, helps us to determine the therapeutic management of the patient, and can be considered as a prognostic factor of the disease.(1) Background: The objective was to compare the exploration of chronic pelvic pain syndrome (CPPS) patients in different locations and establish the role of physical examination in CPPS patients. (2) Methods: We reviewed clinical data from 107 female patients with CPPS unresponsive to conventional therapies at Puerta de Hierro University Hospital Madrid, Spain, from May 2018 to June 2022. Patients were classified into three groups: (a) pelvic pain; (b) anorectal pain; or (c) vulvar/perineal pain. (3) Results: Although the demographics of patients with CPPS were different, their physical examinations were strikingly similar. Our study observed a comorbidity rate of 36% and 79% of central sensitization of pain. Seventy-one percent of patients had vulvar allodynia/hyperalgesia. Pain on examination was identified in any pelvic floor muscle, in any pelvic girdle structure, and neuropathic pain in 98%, 96%, and 89%, respectively. Patients with vulvar and perineal pain were more different from the other groups; these patients were younger and had fewer comorbidities and less central sensitization, less anorectal pain, more pain during intercourse, and greater nulliparity ( Chronic pelvic pain syndrome (CPPS) is a multifactorial pain condition primarily affecting the anatomic pelvis, anterior abdominal wall, infraumbilical, umbilical, and lumbosacral back area, and the buttocks ,3,4,5,6.According to the latest research on CPPS ,11,12,13Although there is an absence of specific recommendations for these phenotypes’ diagnosis, CPPS should be established through anamnesis and physical examination of the patient, yet it still seems that the standard examination for gynecologic patients might be insufficient.Unfortunately, most studies on CPPS lack phenotype stratification, so evidence on prognostic and treatment outcomes is not individually addressed. Nevertheless, phenotypic distinction is known to be beneficial in counseling women with tier 2 pain, as well as in guiding them toward multimodal and prolonged pain management.The aim of this study is to compare CPPS exploration in groups of women stratified according to their pain locations and establish the clinical usefulness of physical examination in the diagnosis, advice, and management of the CPPS patient. The medical records of 382 consecutive female patients with CPPS who sought consultation at the Puerta de Hierro Majadahonda University Hospital in Madrid, Spain, from May 2018 to June 2022, were reviewed. Ethical approval for this study was granted by the Puerta de Hierro Majadahonda University Hospital Institutional Review Board.The main inclusion criteria were female patients with CPPS that had been ongoing for at least three months (a time period that was selected in order to encompass the criteria for vulvodynia patients) and who had not responded to conventional therapy. Patients were classified into three groups according to the pain location as a reason for consultation: (a) pelvic pain  ,3,4,5,6;The data collected included a complete medical history , comorbidities, pain in neighboring organs , duration of pain (estimated by the patient as the number of years between the onset of symptoms and the date of first consultation), pain location, and intensity of the pain as measured via the visual analog scale (VAS), in which zero was defined as no pain and ten as the worst pain ever experienced. Comorbidities were defined as the concomitant presence of several clinical hypersensitivity syndromes, such as irritable bowel syndrome, fibromyalgia, interstitial cystitis, migraine, endometriosis, anxiety and depression, neuropathies, temporomandibular joint dysfunction, chronic fatigue syndrome, and/or a history of multiple chemical sensitivity .Clinical criteria of central sensitization for patients with chronic pelvic and perineal pain (Convergences PP Criteria Score) were calculated for each patient and a score ≥5/10 was considered suggestive of central sensitization .(1)An S2–S4 neurological examination:(a)Cotton swab testing of the S2–S4 dermatome and vestibule. The absence of signs and symptoms during the physical examination confirms the integrity of the C-fibers.(b)An evaluation of the motor response of the nerve using the clitoris, bulbospongiosus, and perineal reflexes. Normal motor activity at S2–S4 is indicated by anal sphincter contraction.(c)Tinel’s sign in the sciatic spine area to evaluate the third segment of the pudendal nerve. Pain is reproduced with transrectal compression of the third segment of the PN (Tinel sign) in the sciatic spine and Alcock’s canal.(d)Tinel’s sign at the clitoris to evaluate the dorsal nerve of the clitoris. The clitoris was compressed to locate painful spots.(2)Exploration of the pelvic girdle: bilateral palpation in order to identify painful spots—retropubic, ischiopubic ramus, ischium, sacrospinous ligament, sacrum, and coccyx area.(3)Exploration of pelvic floor muscles :(a)Levator ani muscle (LAM): assessment of painful palpation of the pubococcygeus muscle.(b)Obturator internus muscle (OIM): contracture of the OIM with flexion and external rotation of the hip in the supine decubitus position and transgluteal examination of OIM segments—pelvic (ischium), medium (midpoint between trochanter and coccyx), and gluteal (hip).(c)Piriformis muscle (PM): simultaneous hip external rotation and abdominal flexion is encouraged to reproduce the pain. PM is palpated transgluteally five centimeters above the OIM middle segment.Data from the examination were collected according to the pain mapping method reported in previously published works ,20, inclPatients were asked to rate their level of pain on a scale from 0 (no pain) to 10 (worst pain ever experienced) during the assessment.p ≤ 0.05 was considered statistically significant. The statistical analysis was performed using R. (R version 3.6.3 (29 February 2020) Copyright (C) 2020 The R Foundation for Statistical Computing).Dichotomous or categorical variables were expressed as absolute values and percentages; continuous variables were expressed as the mean and median. The chi-square test was used to estimate the relationship between variables and pain. The relative risk (RR) was calculated. Differences in distributions of dichotomous variables were analyzed using Fisher’s exact test. Differences in distributions of continuous variables were analyzed using the Kruskal–Wallis test. A value of We identified 382 medical records in our hospital’s electronic database of female patients who sought consultation between May 2018 and June 2022. After excluding 275 cases that had missing data needed for the study, a total of 107 patients met all inclusion criteria and were selected for evaluation.The median age of the cohort was 41 years (range: 16–72). The median pain duration was 1.5 years (range: 0.3–26), and the median VAS score was 7/10 (range: 1–10). The most common symptoms in neighboring organs were pain during sexual intercourse (83%) followed by urological pain (48%) and proctalgia (39%). A total of thirty-eight patients (36%) had associated comorbidities: endometriosis (30), anxiety and depression (13), irritable bowel syndrome (10), fibromyalgia syndrome (10), interstitial cystitis (6), migraine (5), neuropathies (4), temporomandibular joint dysfunction (1), chronic fatigue syndrome (1), and a history of multiple chemical sensitivity (1). Detailed demographic data on the patients included in each group and the correlations between them are shown in p = 0.031).The Convergence PP Criteria score was calculated in 101 patients. Scores of five or more points, suggestive of sensitization to pelvic pain, were found in 80 patients (79%). The median duration of pain since the onset of symptoms for patients with central sensitization was three years (range: 0.3–26), whereas, for patients without central sensitization, the median duration was 1.5 years (range: 0.3–10). The difference between the two groups was statistically significant , followed by the coccyx (67%) and sacrospinous ligament (65%).There were 105 patients (98%) with pain in any pelvic muscle , 103 patients (96%) with pain in any pelvic girdle structure, and 95 patients (89%) with neuropathic pain. The clinical and examination findings of each group and the correlations between them are shown in p = 0.022; p = 0.040; p = 0.048; p = 0.000; p = 0.006; p = 0.005). The results are shown in Demographic differences were found between the patient groups, possibly related to their specific characteristics. The group with vulvar and/or perineal pain had the demographic characteristics that were the most different in our population; these patients were younger and had fewer comorbidities, less central sensitization, less anorectal pain, more pain during intercourse, and greater nulliparity  and neuropathic pain. According to the opinion of a formal consensus of experts , the diaThe examination of patients with central sensitization seems to confirm the patient’s phenotype (tier 2), reveals the affected compartments, and allows for the proposal of multidisciplinary procedures for pain management . Pain ceFurthermore, the diagnosis of central sensitization predicts a poor, transient response to conventional treatment and can be considered a predominant risk factor for postoperative pain ,22,23. I(a)Pain perception occurs through afferent pain pathways. When tissue damage occurs, the release of local inflammatory mediators occurs, which are detected by nociceptors in response to a noxious inflammatory stimulus. C-fibers can become sensitized if C-fiber nociceptors are activated and, thus, they no longer remain silent, even after resolution of the inflammation . In norm(b)Central sensitization ,26 beginIn routine clinical practice, many patients seek a diagnosis for long-standing persistent pelvic pain. However, it seems to be that after taking a detailed case history and performing a physical examination, many possibilities still remain. With many years of knowledge on CPPS, the answer may lie in understanding the pathophysiology of CPPS, particularly in regard to the following.(c)The splanchnic, pelvic, and pudendal nerve pathways innervate the female reproductive tract. This is an opportunity for cross-talk through shared neuronal pathways with other neighboring organs. Cross-organ sensitization occurs when sensitized afferents from one organ induce the sensitization of another. Patients may have symptoms ,28 rangi(d)Physicians are often confused by patients with a history of multiple medical conditions, including depression, anxiety, or post-traumatic stress disorder, as well as patients with common comorbidities, such as fibromyalgia, migraine, tension headache, or chronic fatigue syndrome .The case history for a patient with central sensitization can be complex and misleading. Indeed, the perception of pain can be misinterpreted by both the patient and the physician. Symptoms include burning, tingling, prickling, hyperalgesia, and perineal allodynia. Both the physical examination and case history of these patients can also be unclear. Multiple tender points may be identified, such as a pain response to pelvic nerve stimulation; muscle trigger points; or pain from visceral, perineal, and/or vulvar compression.In this work, the demographic characteristics of each group differed. Patients with vulvar and perineal pain were most unlike the other groups. This may be due to three factors: (a) a shorter median duration of pain given that the inclusion criterion was pain that had been ongoing for three months, which was defined in order to include patients with vulvodynia in this study; (b) the correlation between youth, pain during sexual intercourse, and nulliparity ; and (c)Another interesting aspect was the high rate of comorbidities (36%). Comorbidities suggest a dysfunctional central mechanism ,30,31. Op = 0.031). In CPPS patients, perineal and/or vulvar pain may be triggered by the use of tampons or by wearing tight clothing or underwear. This study suggests that vestibular allodynia/hyperalgesia is present on the physical examination of patients with CPPS due to a non-gynecologic condition in a similar percentage as in gynecologic patients  . In these patients, the duration of pain (three years) was twice as long as in those who did not show these signs ( 60–77%) . Likewis 60–77%) . Further 60–77%) . DefinitProviding physical examination information and commonalities in women exhibiting chronic pain with central sensitization and suffering from different diseases is one of the major strengths to consider in this study, thus identifying women as a group of patients with a similar prognosis and with multimodal disease management. In contrast, the present study has several limitations, resulting from its retrospective nature and the small number of patients included in the anorectal pain group. A control group without CPPS might also improve the study outcomes, since the pain mapping method is not justified in patients without pain, where the finding of trigger points is not foreseeable. Finally, the study was conducted in a gynecology department, so its results imply a lack of generalizability to men. Future research should take into account the limitations described above.CPPS physical examinations can be remarkably similar, despite the underlying disease or condition causing the symptoms. Central sensitization and cross-organ sensitization are present in the vast majority of patients who do not respond to conventional therapy. Sign and symptoms such as vulvar or perineal allodynia and/or hyperalgesia, trigger points in the pelvic floor musculature, tender points in the structures related to the pelvic girdle, and neuropathic pain are frequent findings resulting from the pathophysiological process described in patients with CPPS. As a consequence, physical examination in patients with central sensitization identifies the co-existence of somatic, visceral, and neuropathic pain symptoms, thus allowing the recognition of the pelvic pain patient phenotype, which will be crucial for decision making regarding the management and prognostic factors of the disease.


Cardio-pulmonary function, symptoms and the quality of life (Short-Form-36 and St.George’s questionnaires) were evaluated pre- and 3-, 6-, 12- and 24-months postoperatively. Extrapleural pneumonectomy demonstrated lower pain at 12 months but a higher decrement of forced vital capacity at 24 months than pleurectomy/decortication. Both procedures revealed a 3-months improvement of many symptoms and the quality of life determinants. Improvement in physical, social and pain-related measured parameters lasted for a longer time-spawn in the extrapleural pneumonectomy group. No differences were found in chemotherapy compliance and survival between groups. Age-at-presentation (p = 0.02) and non-epitheliod histology (p = 0.10) were the only significant prognosticators. Surgery, despite poor survival results, improved symptoms and the quality of life in patients with mesothelioma with high symptom-burden at diagnosis. Therefore, extrapleural pneumonectomy demonstrated the most durable effects.Mesothelioma has a scant prognosis and a great impact on symptoms and the quality of life. Pleurectomy/decortication and extrapleural pneumonectomy are the two cytoreductive surgical strategies, with different invasiveness, but achieving similar oncological results. Hereafter, the two surgical procedures effects on symptoms and the quality of life are compared in a high symptom-burden population. Between 2003 and 2017, 55 consecutive patients underwent pleurectomy/decortication ( Malignant pleural mesothelioma is a rare and highly aggressive tumor with a poor prognosis ,2. Only Given life expectancy is generally low, the quality of life assumes a leading role. The impact and duration on the effects of surgery on patients’ quality of life seems to be morally crucial. An impaired quality of life has been associated with early chemotherapy discontinuation and reduced overall survival ,11. TherIn this retrospective study, we compared the effect of pleurectomy/decortication and extrapleural pneumonectomy on the symptoms and the quality of life in patients affected by malignant pleural mesothelioma with a preoperative high symptom-burden at fixed time point. The durability of the effects of surgery on respiratory function, the quality of life, and symptom control between the two procedures, in the two years after surgery, have been compared.From 2003 to 2017 inclusive, 55 consecutive patients, 49 men and 6 women (median age 61.8 ± 10.0 years), underwent intentional extended pleurectomy/decortication  or extrapleural pneumonectomy . Clinical and pathological features of the study group are summarized in All patients had undergone total body computed tomography (CT) scan. Mediastinoscopy was performed whenever CT evidenced enlarged upper mediastinal lymph nodes. Patients were staged according to the TNM-staging system by the International Mesothelioma Interest Group ,14. All Demographic and perioperative characteristics of the enrolled patients were collected in a prospectively organized database with standardized entries. Data on long-term outcomes including symptoms, the quality of life, and survival, were determined the day before cytoreductive surgery and 3-, 6-, 12- and 24-months postoperatively. A fully informed consent in order to manage clinical data for scientific purposes was asked for and signed by all patients.Extended pleurectomy/decortication involves the complete resection of both visceral and parietal pleura including, whenever necessary, pericardial and/or diaphragmatic resection after an intraoperative evaluation ,3. ExtraInclusion and exclusion criteria for either pleurectomy/decortication or extrapleural pneumonectomy was made according to medical and surgical criteria listed in 2) given at day 15, and gemcitabine (1 g/m2) administered on days 1, 8, and 15. Treatment was repeated every 4 weeks. Cisplatin was infused over 1 h after intravenous administration of 2000 mL saline plus potassium chloride. Gemcitabine was administered as a 30 min intravenous infusion diluted with 250 mL of saline. Pemetrexed replaced gemcitabine as it has become the standard of care in malignant pleural mesothelioma management [2) and Cisplatin (75 mg/m2) was administered on day 1. Treatment was repeated every 3 weeks. Bevacizumab and other immune checkpoints inhibitors were not used at the beginning of the study period. To avoid bias in the quality of life and symptoms parameters, patients undergoing immunotherapy as adjuvant therapy have been excluded from this study. Treatment was interrupted because of disease progression or intolerable toxicity. Adjuvant chemotherapy was started between 4 and 10 weeks after surgery depending on the postoperative recovery.Surgical procedure was followed by adjuvant chemotherapy in 40/55 cases (72.8%). Twelve patients received neoadjuvant chemotherapy  and three patients both neoadjuvant and adjuvant chemotherapy 3/55; 5.5%). Chemotherapy regimen usually consisted of four to six cycles of cisplatin  was always delivered to areas of gross residual disease or positive resection margins, and metastatic lymph nodes.Information was preferably retrieved by outpatient clinic or alternatively by medical records, general practitioner, or patients’ telephone call. Cross-sectional contact for all surviving patients was routinely performed every 3 months. Since imaging studies available at the beginning of the study period were not sensitive enough to accurately diagnose early recurrence, the disease-free interval was not evaluated. Therefore, the survival duration was measured from the date of surgery to the date of the patient’s last follow-up contact or death.Evaluation of acute pain was self-scored by the patients like a visual analogue scale (VAS)  during the study at timed intervals .Dyspnea was rated after clinical examination according to the modified Medical Research Council score  . Exercis® (SF-36) [® (SGRQ) [The quality of life was assessed using the Medical Outcomes Study Short Form 36-item (SF-36) ,19 and t® (SGRQ) ,21. SF-3SGRQ quantifies the impact of chronic airflow limitation on health and well-being. It contains 76 items organized into three sections investigating symptoms, activity, and the impact on mood of these limitations .The durability of the effects of surgery on symptoms and the quality of life was assessed. The results obtained at each time spawn for each measured parameter have been compared with the preoperative value. Surgery was considered to affect symptoms or the quality of life until a significant difference from the preoperative values could be retrieved. At the time point when no differences could be found, the value was considered to be returned to the pre-operative value. Therefore, the durability of the effect of surgery on that symptom or the quality of life parameter was considered expired.Questionnaire administration was approved by Institutional Ethical and Review Board of the single institutions. For ethical reasons, questionnaires were no longer administered in the case of evident neoplasm progression.The primary objective of this retrospective study was to compare the effects of pleurectomy/decortication and extrapleural pneumonectomy on symptom control and the quality of life at fixed post-operative times. Secondary outcomes were to evaluate differences between pleurectomy/decortication and extrapleural pneumonectomy on the durability of the effects of these surgical procedures in symptoms and the quality of life determinants. Finally, differences in chemo/radiotherapy administration and overall survival between the two groups were assessed.p-Value less than 0.05 was considered statistically significant.Statistical analysis was performed using the SPSS . Due to the small sample size, the non-parametric Wilcoxon test was used to compare the scores mean values before and after surgery. The internal consistency of the questionnaires was evaluated for global scores and specific domains using the Cronbach’s α test: considering the highest score possible for consistency equal to 1 and the lowest equal to 0. Cronbach’s α test greater than 0.7 was considered desirable.The comparison between pleurectomy/decortication and extrapleural pneumonectomy for the scores mean values before and after surgery was performed using the non-parametric Mann-Whitney U test, due to the small number of patients.The impact of continuous variables on survival was analyzed with the Kaplan-Meier curve and the log-rank test by dichotomizing the patients into groups according to the score above and below the median value. Factors significantly affecting survival at univariate analysis underwent a multivariate analysis by the Cox regression model.n = 9), cardiac arrhythmias (n = 8), bleeding requiring reoperation (n = 2), and deep venous thrombosis (n = 3). Some patients had more than one cause of morbidity. The median follow-up interval was 16.5 ± 10.4 months (range 1–44 months).Data of the study group patients are described in Chest pain or dyspnea were the presenting symptoms in 62.5% of cases. Symptom evolution is summarized in p = 0.005), and in forced vital capacity at 2 years, with a higher mean value for patients undergone pleurectomy/decortication (p = 0.003).As depicted in At intergroup analysis, patients undergoing pleurectomy/decortication demonstrated a significant improvement of pain at 3 and 6 months and a decrease after that, an improvement of dyspnea and forced vital capacity up to 6 months post-operatively, followed by a return to the pre-operative values. Nonetheless, the 6 min walking test was improved up to 12 months post-operatively and decreased at 24 months towards the pre-operative values .As regards extrapleural pneumonectomy, pain as well as the 6 min walking test and dyspnea index were improved consistently throughout the overall follow up period. Conversely, there was a continuous and statistically significant reduction of forced vital capacity after surgery .The presence of pericardial or diaphragmatic prosthesis did not affect symptom evolution in any of the parameters investigated. Data regarding SF-36 SGRQ are summarized in p < 0.0001 for pleurectomy/decortication and 14.1 ± 20.6 to 37.9 ± 14.1, p < 0.001 for extrapleural pneumonectomy) and physical role functioning  scored the greatest improvement. In the patients still alive after 6 months, only some physical domains persisted significantly greater than the baseline values. Thereafter, every domain slightly declined reaching or crossing the baseline value.No significant difference was found in any follow-up for both physical and mental SF-36 domains and for SGRQ domains . Body pap = 0.001 for pleurectomy/decortication, 28.4 ± 11.3 to 37.1 ± 9.9, p < 0.001 for extrapleural pneumonectomy) during the first 3 months after surgery and values persisted for 6 months, whereas the mental component presented only a mild and time-limited amelioration.The physical component summary significantly improved  and activity . Thereafter, we experienced a progressive worsening of all parameters with the restoration of the preoperative status at 24 months.As regards SGRQ, a significant improvement was found in 2 of 3 domains at 3 months postoperatively: symptoms  were able to receive the planned cycles of the treatment regimen. Seventeen patients did not complete the planned chemotherapy: 11 refused further treatment after two cycles and another six patients after three cycles. Radiotherapy did not produce significant morbidity unless a slight basal lung fibrosis in nine patients.p = 0.44).No differences could be found in chemotherapy administration between the two groups. Particularly, adjuvant chemotherapy was administered, with no delay, in 22 (21 patients had only adjuvant treatment and one patient had both neoadjuvant and adjuvant treatment) in the pleurectomy/decortication group and in 21 (19 patients had only adjuvant treatment and two patients had both neoadjuvant and adjuvant treatment) in the extrapleural pneumonectomy group (p = 0.007) and age > 65 years old (p = 0.001) significantly influenced the prognosis. On the contrary, the type of surgery (p = 0.54) (p = 0.002) and the nonepithelial histology  were selected as the sole significant prognosticators.Overall median survival was 14 months. A total amount of 37 patients (67.3%) died within 2 years from the operation. Nonepithelial histology ( = 0.54)  and any Surgery has a pivotal role in the multimodal management of malignant pleural mesothelioma. Nevertheless, the best surgical strategy in the management of this aggressive disease is currently a topic of discussion ,3,6,9. PDespite the encouraging results obtained with multimodal treatment, including surgery and chemo-radiation therapy, the disease has still a scant prognosis and significantly affects the quality of patients’ life ,3,4,7. TIn this report, the effects of pleurectomy/decortication and extrapleural pneumonectomy in malignant pleural mesothelioma on symptoms and the quality of life have been compared at 3-, 6-, 12- and 24-months after surgery. At the beginning of the study period, extrapleural pneumonectomy was considered as the standard of care for surgically resectable mesothelioma, but during the years the standard of care changed towards pleurectomy/decortication. Thus, patients enrolled later in the study were more likely to undergo pleurectomy/decortication than patients enrolled at the beginning of the study period. Between the two surgical techniques, extrapleural pneumonectomy demonstrated lower pain related score, measured through the VAS scale, with the most significant difference at 12 months after surgery. Conversely, pleurectomy/decortication demonstrated to have a smaller impact on forced vital capacity when compared to extrapleural pneumonectomy with the greatest difference 24 months postoperatively.These results are consistent with previous reports demonstrating both the transitory improvement of symptoms in patients undergoing pleurectomy/decortication and the persistent reduction in pulmonary function following extrapleural pneumonectomy. In patients undergoing pleurectomy/decortication, an initial improvement in chest pain followed by a rapid re-exacerbation within the first 6 months post-operatively was already described . Indeed,As secondary outcomes, symptoms, and the quality of life evaluation results at fixed time points for both pleurectomy/decortication and extrapleural pneumonectomy have been independently compared with the preoperative values. Thus, the durability of the favorable and detrimental effects of surgery during the follow-up period have been compared and pictorially shown in Most of the symptoms and quality of life evaluation tools demonstrated an initial improvement at 3 months after surgery when compared to the preoperative values, regardless of the surgical strategy. This seems to be in contrast with previous reports demonstrating a reduction in both symptoms and the quality of life in the early post-operative time ,33,34. PDespite no differences being found between the two types of surgery in the measured quality of life determinants, the differences in the durability of the effects of surgery on the quality of life may be relevant in the management of these patients. Overall, extrapleural pneumonectomy was demonstrated to improve bodily pain as measured in the SF-36 up to 12-months after surgery, while the same domain returned to the baseline preoperatory values within 6 months after pleurectomy/decortication. These results confirm the efficacy of extrapleural pneumonectomy in local control of the disease in terms of chest pain reduction, and are supported by a prolonged improvement in symptoms evaluated by the SGRQ. Pain management in patients affected by mesothelioma can be controversial and leads to uncontrolled pain despite multimodal treatment . As demoTherefore, in patients with a high symptom-burden that are candidates for cytoreductive surgery, the effects of the surgical approach on symptoms and pain control durability may have a role in the management algorithm.Pleurectomy/decortication failed to significantly enhance physical and social functioning and achieved a brief improvement of role-functioning physical only at 3 months after surgery. Differently, extrapleural pneumonectomy was proved to achieve a prolonged improvement in both physical functioning and role-physical functioning up to 6 months after surgery, as well as a 3 month improvement in social functioning. Therefore, patients undergoing extrapleural pneumonectomy achieved both prolonged control of pain and of pain impact on their lives, as well as an overall improvement of their everyday and social functioning, with a lower disease-related impact on their lives. As expected, at 24 months after surgery, both groups showed a drop in the mental component summary. Despite the efficacy of each surgical strategy in symptom control and the quality of life improvement, the trend towards the pre-operative high symptom-burden characterizes all the measured parameters. The relation between symptom-burden and mental status impairment has been previously stated in patients with advanced cancer and further enlighten the role of a mental support along with the oncological pathway .When analyzed, no differences could be found in the chemo/radiotherapy compliance rate. Therefore, the surgical strategy did not affect the continuation of the multimodal approach. On the contrary, we noted an elevated compliance to chemotherapy after any kind of surgery. This is possibly due to the amelioration of perceived general health status. Indeed, patients enrolled in this study presented a high preoperative symptom-burden that was partially relieved by the surgical treatment. Therefore, the surgical-induced symptoms relief may have enhanced treatment compliance in this population.Notably, we also found that patients undergoing diaphragmatic or pericardial reconstruction did not show any difference in the quality of life compared to the others, thus implying that demolitive surgery on advanced stages, where adequately treated, did not alter the perceived heath status.Finally, the surgical approach was demonstrated not to have an impact on prognosis as well as symptoms and quality of life determinants. The prognostic role of symptoms and the quality of life on survival in malignant pleural mesothelioma has been previously stated . NeverthThis study has several limitations. Particularly, a relatively small sample size was enrolled in a large timespan. This is mainly and luckily due to the rarity of the disease in our geographic area. Secondarily, undetected, and unmeasured bias may have operated in the selection criteria between procedures. As we stated, patients enrolled at the beginning of the study were more likely to undergo extrapleural pneumonectomy as it was the surgical treatment of choice at the time. During the study period, surgical treatment choice moved towards extended pleurectomy/decortication. However, no differences could be found between the two populations in terms of disease stage, performance status, or in the other preoperative measured characteristics.Another limitation could be represented by the type of questionnaires used. In fact, we privileged the investigation of the general quality of life instead of an instrument more specific for neoplastic disease. SF-36 and SGRQ were administered to patients with any thoracic condition, considering them more appropriate to detect quality of life changes, especially in patients undergoing such an extensive pulmonary resection. Moreover, the chemotherapy regimen adopted during the study was mostly based on classic chemotherapeutic agents.Finally, it was impossible to evaluate the impact of the recurrence on the quality of life due to the retrospective nature of this study and it was impossible to retrieve data about chemo/radiotherapy drop out during treatment.In this study, we demonstrated that patients affected with high symptom-burden malignant pleural mesothelioma may benefit from surgery. In our experience, pleurectomy/decortication achieved some temporary advantages in symptom control and the quality of life, especially in the first months after surgery. We also noticed a more effective and long-lasting pain control after extrapleural pneumonectomy. Unexpectedly, this procedure was also able to achieve a more durable relief of dyspnea and to improve dynamic resistance to strain despite the immediate and obvious reduction of forced vital capacity. We can conclude that although cytoreductive surgery proved not very effective in prolonging overall survival in malignant pleural mesothelioma, it can have some effects on symptom control and the quality of life in patients with high symptom-burden. Hence, despite poor survival results and challenging efforts for both patients and surgeons, it remains a worthy and valid option in patients with a so limited chance of care.


Neck pain and headache intensities decreased by almost half (p < 0.001). The median number of monthly headache days decreased from 20 days to 6 days (p < 0.000). The quality-of-life level decreased significantly from severe to substantial level (p < 0.001). According to our results, ONA treatment was effective in reducing neck-related problems in CM patients. Long-term follow-up results may provide researchers with more comprehensive results in terms of the treatment of chronic migraine–neck-related problems.Neck disability and pain are frequently encountered problems in patients with chronic migraine (CM). The long-term stimuli of neurons in the trigeminocervical junction may explain this situation. OnabotulinumtoxinA (ONA) treatment is one of the proven treatments for CM; however, there is no study data on the efficacy of ONA treatment on neck disability and pain in CM patients. Therefore, we aimed to investigate the effect of ONA treatment on disability, neck pain and headache intensity in CM patients. One hundred thirty-four patients who met the inclusion criteria were included in the study. ONA treatment was administered at a dose of 195 U to 39 sites in total as per Follow-the-Pain PREEMPT protocol. The disability was evaluated with the Neck Disability Index and the Migraine Disability Assessment; pain intensity was evaluated with the Visual Analogue Scale; the monthly number of headache days were recorded; quality of life was evaluated with the Headache Impact Test. All assessments were recorded at baseline and 3 months after treatment. After the treatment, neck–migraine disabilities decreased from severe to mild for neck and moderate for migraine ( Migraine is a type of headache that reduces the quality of life and causes disability . Neck pap = 0.008; I2 = 10.0%) [According to the diagnostic criteria of The International Classification of Headache Disorders-3 (ICHD-3), Episodic Migraine (EM) is defined as having a headache for less than 15 days per month, and Chronic Migraine (CM) is defined as the presence of migraine headaches more than 15 days per month for more than three months, and 8 days per month and more [= 10.0%) ,10,11. INeck pain can radiate from the base of the neck to the temporal, frontal and periorbital regions during migraine attacks. Pain may remain permanently in the occipital region, cervical vertebral area and trapezius/deltoid region. Scientific discussion has generally focused on the hypothesis that this complaint arises from the activation of the trigeminocervical system in migraine ,13. The ONA is one of the treatments with proven effectiveness in the treatment of CM ,26,27,28The disability and pain experienced can affect daily work, family and social life, causing patients to try to find solutions to their problems . The litThe mean age of the patients was 53.38 ± 12.36 years. Of the sample, 89.55% were women. The median migraine diagnosis year was 20. The median neck pain duration was 132 months. The demographic and clinic information are given in p = 0.000; −28 points as median, p = 0.000, respectively). While the patients had severe neck disability before ONA treatment, the level of neck disability was mild after the treatment. The MIDAS level decreased from severe to moderate with ONA treatment (The Neck Disability Index (NDI) and Migraine Disability Assessment (MIDAS) scores significantly decreased after four weeks of ONA treatment . The median reduction in neck pain intensity was 4 cm, while the median reduction in migraine headache intensity was 5 cm  (The median number of monthly headache days decreased from 20 days to 6 days (= 0.000) .p = 0.000). While the quality of life level was severely affected at 68 points before treatment, it decreased to a substantial effect with 58 points after treatment  [p = 0.0002), with a mean decrease of 21.89 ± 5.78 from the beginning to the 3rd month of ONA treatment [p < 0.001) [The NDI and MIDAS assess disability in daily activities for neck pain and migraine headaches ,41. The  0.0541) . Blumenfreatment . Demiryu< 0.001) . Migrain< 0.001) . Therefo< 0.001) ,49 increp < 0.001), and the decrease in neck pain intensity was almost 50% (p < 0.001). Naderinabi et al. showed that after 3 months of ONA treatment, the intensity of pain decreased significantly from 8.9 cm to 5 cm on average (p < 0.001) [p < 0.01) [p < 0.001) [In our results, we found that with ONA treatment, at the end of 3 months, the median of headache intensity decreased by 50% from 10 to 5 ( < 0.01) . Demiryu< 0.001) . Patient< 0.001) ,13,14,15< 0.001) . Althougn = 248/2879). Since this rate increased in the 6th and 9th months, it was stated that the 3rd-month data were predictive for long-term results [p < 0.001). In a systematic review of 2022 that synthesized the literature studies, it was emphasized that ONA treatment in migraine headache is an effective option in reducing the number of days with monthly headache, frequency of attacks and the intensity of pain and disability [p < 0.001) [p < 0.001) [The decrease of more than 30% in the number of days with headache after the first month with ONA treatment indicates that ONA treatment can be successful . The dec results . In the sability . The revsability ,54. Demi< 0.001) . Dodick < 0.001) ,56. Therp < 0.001). In our study, we showed similar results with the literature studies, and we found that ONA treatment had positive effects on the quality of life at the 3rd month [p < 0.001) [The intensity of pain and the disability experienced during attacks can cause bed rest and a reduction in work–home–social activities. Therefore, the quality of life of patients with CM is affected ,58. In ord month ,60. Resu< 0.001) . Beckman< 0.001) . It seemp < 0.02) and visits to health professionals, such as family doctors or migraine professionals (p < 0.001) [The CM has an economic burden associated with migraine . In a st< 0.001) . In real< 0.001) . In anot< 0.001) . In a sy< 0.001) .n = 18/633—a mild result of ONA) due to injection in the neck region after ONA treatment [Some side effects may be reported by patients after ONA administration . Neck pareatment . Howeverreatment . In a streatment . Due to reatment . It is areatment . Howeverreatment ,68,69. TThere are several limitations in our study. First of all, the lack of long-term follow-up of the study is one of the limitations. While the literature studies have reported positive results on headache intensity, disability and quality of life for the long-term effect of ONA treatment, such as 6 and 12 months, there are no data on long-term results related to neck problems. Secondly, the psychological status of chronic migraine patients was not evaluated. Since the psychological state can play a role in pain intensity, disability and quality of life, it can affect neck disability and pain intensity. Finally, retrospective studies have some disadvantages. When symptoms related to the disease are very severe, patients may not be able to pay attention at certain points. Due to the imperfect human memory, they may not be able to remember details and may skip some details. Therefore, they may not be able to clearly answer the questions asked. The natural limitations of retrospective studies are that the accuracy of the answers sought during retrospective analysis is uncertain depending on symptom severity and memory, and that different results cannot be analyzed in different time periods because the study is not prospective .The results of our study showed that headache and disability of patients with chronic migraine can be accompanied by neck disability and neck pain. Since the trigeminocervical junction plays a role in sensitization, it is important to question neck problems in patients with chronic migraine. In addition to the pain and disability in migraine attacks, neck disability and problems related to neck pain may affect the quality of life of individuals and cause deterioration in the daily functional activities of patients. According to the 3-month results of ONA treatment, neck pain, headache and disability experienced by patients with CM decreased and their quality of life increased. However, we think that conducting long-term treatment follow-up studies on neck disability and pain in patients with CM will provide more comprehensive results regarding the management of chronic migraine–neck-related treatment.Ethical approval for this retrospective open-label real-world study was obtained from Sapienza University (52 SA_2020). The study was conducted at Sapienza University Sant’Andrea Hospital Headache Centre with patients diagnosed with chronic migraine by an internist with headache expertise according to the International Classification of Headache Disorders criteria. All patients gave informed consent for the application of ONA treatment. The evaluations of 156 consecutive chronic migraine patients who received one session of ONA treatment in the Headache Clinic between June and October 2022 were analyzed retrospectively with an interview with the patient at the time of the visit for the injection session. Analyzes were performed between September and November 2022. Inclusion criteria were between the ages of 18 and 65 and diagnosed with chronic migraine. Exclusion criteria were diagnosis of any accompanying headache other than chronic migraine, diagnosis of any pathology in the cervical spine, any systemic disease and an acute infection–fracture–inflammatory condition. In total, 134 patients met the inclusion criteria.ONA administration of all patients was performed by an internist with headache expertise. The application included a total of 39 regions as corrugator, procerus, frontalis, temporalis, occipitalis, upper cervical paraspinal muscle group and trapezius. ONA administration was completed by injecting a total of 195 U, 5 Units to each region as per the PREEMPT protocol Follow-the-Pain procedure ,49,71,72Age, Body Mass Index, migraine-diagnosed years and neck pain duration (months) were recorded for all patients. The primary outcome measures were the Neck Disability Index (NDI), the Migraine Disability Assessment (MIDAS), headache and neck pain intensity and the number of monthly headache days. The secondary outcome measure was the Headache Impact Test (HIT-6). The primary and secondary outcomes were evaluated at baseline and three months after ONA treatment.The NDI consists of 10 questions, each scored from 0 to 5, including neck pain, headache, lifting, reading, sleeping, driving, working, self-care, concentration and recreation  ,41.The MIDAS assesses the last 3 months of disability and consists of a 5-item self-administered test, including disability-related in work/school, housework, family and social or leisure activities. The total number of days missed in these activities is the total score and classes the disability as minimal disability (0–5 points), mild disability (6–10 points), moderate disability (11–20 points) or severe disability (≥21 points) ,43,44. IThe headache and neck pain intensity was assessed with a Visual Analogue Scale (VAS). The patients selected their pain level on a horizontal line between 0 and 10 cm  .The number of monthly headache days obtained from the monthly headache diaries of the patients were recorded.The HIT-6 is a quality-of-life questionnaire for headaches that assesses vitality, pain, psychological distress, sociability, role and cognitive functioning. Each item is scored on a 5-point Likert scale . A score between 36 and 78 points is determined by summing the scores on the six items  ,75,76.The sample size was calculated using G*Power 3 software . The samn) and percentage (%) were presented for categorical variables. The Paired samples t-test was used if parametric test assumptions were confirmed, otherwise the Wilcoxon signed-rank test was used to evaluate the difference before and after ONA treatment. Statistical significance was accepted as p < 0.05.The data analysis was performed using SPSS version 23.0 . The Shapiro–Wilk test of normality analyzed whether the numerical data were normally distributed. The results were given as mean and standard deviation (SD) or median and minimum–maximum for continuous variables; number (