The association between patient self‐reported pain severity and health‐related quality‐of‐life (HRQoL) is poorly understood.This real‐world study of symptomatic multiple myeloma (MM) patients sought to determine how pain severity from a single question asked during routine clinical consultation was associated with HRQoL.χ2 tests. Ninety‐six of the 330 patients (29.1%) reported moderate to severe pain. Increase in pain severity, from “no” to “severe” pain, was associated with significantly decreased overall HRQoL (mean score 70.2 to 33.3); significant decreases in levels of physical (82.7 to 35.1), social (81.1 to 44.4), emotional (78.1 to 48.3), and role functioning (79.5 to 38.9); and increased levels of WPAI usual activity impairment (35.4 to 71.4), and fatigue burden (26.0 to 68.9) .Point‐in‐time data on HRQoL of 330 patients with MM (median age 70 years) receiving anti‐myeloma therapy in Germany and Italy from November 2017 through February 2018 were analyzed. HRQoL was assessed using validated questionnaires . Physical pain severity was assessed during clinical consultation by a single question, asking patients to describe their pain as “no pain,” “mild,” “moderate,” or “severe.” Associations between patient‐reported pain severity and HRQoL scores were assessed by analysis of variance or Higher pain severity, based on a single self‐report question, was associated with poorer HRQoL in patients with MM, thereby supporting the clinical relevance of directly asking patients to self‐evaluate their pain severity. Patients with earlier manifest or new bone disease experience discomfort or pain and a decrease in HRQoL. With effective myeloma therapy, bone pain and other myeloma‐associated pain usually improves or resolves,Although pain management is an integral part of cancer care, pain is underreported, misunderstood, and often undertreated.Information on HRQoL is important to understand the patient's symptom burden and needs. While several valid and reliable tools exist for assessment of pain severity, these tools are established in clinical trials and outcome research but not commonly used in routine clinical care, where they may be impractical due to time constraints and other reasons.In this study, we examined whether patients' self‐reported pain severity based on a single question relates to the magnitude of changes in QoL items such as HRQoL, functional and emotional impairment, fatigue, and work productivity in a real‐world clinical setting. To our knowledge, no published study has examined the association between pain severity in patients with MM and specific other domains of HRQoL.2A point‐in‐time study was conducted using the Adelphi Multiple Myeloma Disease Specific Programme (DSP) patient‐level database. Details of the full DSP methodology have been described previously.2.1Consenting adults (≥18 years at time of survey) with symptomatic MM and who received either first‐line or second/subsequent‐line MM therapy voluntarily completed questionnaires independent of their treating physician at routine face‐to‐face consultations (referred to as time of survey) and were returned in a sealed envelope to ensure confidentiality. Each physician invited their next eight consecutively consulting patients to participate in the study to minimize selection bias.Patients were asked to rate their pain severity using a single question: “Please tick the box that best describes the level of pain that you are currently experiencing.” Each patient chose one response: “no pain,” “mild pain,” “moderate pain,” or “severe pain.” Responses to this question were aligned with responses from the validated EuroQol 5‐dimension 5‐level (EQ‐5D‐5L) questionnaire on pain/discomfortThe EORTC QLQ‐MY20 asked patients “During the past week, have you had the following symptoms or problems.” Patients were considered to have bone pain in the past 7 days before the survey if they answered “A Little,” “Quite a Bit” or “Very Much” to any combination of EORTC QLQ‐MY20 questions 31 to 33, and 35 on bone pain/aches (question 31) or site‐specific bone pain . Patients were considered to have bone pain/aches (non‐site specific) based on positive responses to question 31, and site‐specific bone pain  based on responses to questions 32, 33, and 35, respectively.Several dimensions of HRQoL  were assessed via the validated EORTC Core‐30 Questionnaire version 3 (EORTC QLQ‐C30).Detailed information on patient demographics, diagnosis, clinical status, concomitant conditions, current treatments  at the time of survey, and treatment history were available from medical records reported by treating physicians (hematologists or hematology‐oncologists) via electronic standardized forms. The stage of disease at the time of survey was classified using the Multiple Myeloma International Staging System (ISS).2.2Physicians consented to participate and provide patient medical information during screening. Patients provided informed consent prior completion of questionnaires, with all data aggregated and de‐identified before receipt. DSP data were collected according to procedures established at Adelphi Real World and are compliant with the European Pharmaceutical Market Research Association Code of Conduct, the Health Information Technology for Economic and Clinical Health Act2.3χ2 test for categorical variables and analysis of variance (ANOVA) for continuous variables. p‐values <.05 were considered statistically significant. Additionally, for some continuous outcomes, univariate linear regressions were conducted to show pairwise comparisons between no pain and each of the other three pain groups .Descriptive statistics are reported for demographics, clinical characteristics, and patient‐reported outcomes (PRO). Frequency and percentages are reported for categorical variables and mean and SD or median and interquartile range (IQR) for continuous variables. Comparisons between pain severity categories  were performed by Data were imputed for some PRO domains as instructed by the tool authors. Beyond that, incomplete or missing data were not imputed. Each individual estimate (such as mean or percent) were calculated based on available data and therefore patient numbers varied across analyses. The number of missing patients were included with patient demographic or clinical results as appropriate.Statistical analyses were performed using STATA statistical software version 15.1 .33.1n = 267; 80.9%) were from Germany. Approximately two‐thirds were female  and similar proportions were retired at the time of survey . Median age was 70 years (IQR: 62‐75 years)  , and about half (46.9%) of patients were receiving second‐line treatment or higher. A quarter of patients  had moderate‐to‐severe performance status  between MM diagnosis and the time of survey was 0.96  years. Nearly half (48.5%) of patients with MM had lived longer than 1 year with MM and 17.3% had lived with MM for more than 3 years (data not shown). The most common comorbidity was cardiovascular disease  reported bone pain (non‐site specific and site‐specific) at the time of survey. Over three‐quarters  of patients had self‐reported non‐site‐specific bone aches or pain. Vertebral (back) pain was reported by most patients . Other sites of bone pain were hip  and chest/rib   had a record of bone‐targeting agents (BTA). Of the 289 (87.6%) patients with self‐reported bone pain, 166 (57.4%) had received a BTA (data not shown); of the 73 (22.1%) patients not experiencing pain, 28 (38.4%) had received a BTA.Over half of the patients , 161 (48.8%), 81 (24.6%), and 15 (4.6%) patients, respectively (Table n = 73), about half were <65 years (50.7%), had an ECOG status of 0 (53.4%), and had no record of active comorbidities (46.6%) (Table Among those reporting “no pain” at the time of survey (%) Table . Around %) Table ; of thos%) Table .n = 80/81; 98.9%) or mild pain  also reported bone pain  recalled experiencing bone pain, with some specifying the site (Table Most of the patients (>95%) who reported experiencing pain  at the time of survey had suffered bone pain (either bone aches or pain or site‐specific bone pain) in the 7 days before the survey, with back pain being the most common Table . All patin Table . Among tte Table .3.4p < .001) . Means scores for WPAI usual activity impairment (35.4 to 71.4) and EORTC QLQ‐C30 fatigue burden (26.0 to 68.9) increased  as the level of patient self‐reported pain severity rose . As the level of patient self‐reported pain severity increased from no pain to severe pain, mean scores on overall HRQoL decreased from 70.2 to 33.3; this association was statistically significant  and the mean percentage of impairment experienced while at work  (data not shown).Overall work productivity loss was based on a subset of 42 patients in full‐ or part‐time employment who completed the WPAI questionnaire. As the level of patient self‐reported pain severity increased, we observed increases in both the mean percentage of work time missed  in all instances, with the exception of activity impairment due to a problem and social functioning in those with self‐reported mild pain. These results indicate that increasing self‐reported pain was associated with poorer overall health status and functioning, increased work and activity impairment, and fatigue.4This real‐world study examined how patients' self‐reported pain severity, from a single question asked during clinical consultation, is associated with HRQoL in symptomatic MM patients receiving anti‐myeloma therapy in routine practice. Higher pain severity self‐reported by patients with MM via the single question was associated with significantly poorer overall HRQoL, poorer physical, social, and emotional functioning, and greater functional impairment and fatigue burden.Although MM remains a largely incurable condition, the introduction of novel therapies has significantly improved clinical outcomes. For many patients, MM is a long‐term chronic condition characterized by a remitting and relapsing course.An accepted standard of care, recently reinforced by a guide from the European Society for Medical Oncology, is that healthcare professionals should routinely assess patient's cancer pain by asking them to rate their pain on a scale of 0 to 10, where 0 is no pain at all and 10 is the worst pain imaginable. Patients who find it difficult to give their pain intensity a number are asked to use linear analogue scales, which allows them to mark their individual pain severity between the extremes of no pain and very severe pain.Due to the lack of common sampling across studies and region, interpretation of the patient‐reported outcomes data from our study compared to other published studies is limited. A recent studyp < .001), suggesting that the characteristics would need to make a big difference to impact results. Despite these limitations, we observed statistically significant associations between patient‐reported pain severity and HRQoL. In addition, observations from a previous study is consistent with our findings. Ramsentaler et al. reported that clinically relevant anxiety and presence of pain were found to be more predictive of poor or declining HRQoL than demographic and disease clinical parameters, and that treatment history and age were not significantly associated with the HRQoL trajectory of MM patient.This point‐in‐time study was based on a sample of MM patients with different disease stages, with or without comorbidities who were treated in routine clinical settings. This lends greater representativeness to real‐world settings than findings based on samples from interventional studies. However, due to the heterogeneous nature of the population in this study, characteristics such as age, gender, specific comorbidities (such as cardiovascular or metabolic), and receipt of analgesics or BTA may act as confounders. Such factors were not assessed within this study due to data on bone complications and pain management not being available for all patients, which precluded the undertaking of multivariate analysis as this would not generate meaningful insights. Many of the analyses conducted in this study produced strongly significant results  than males. The median age of our patient population was 70 years, an age where the differences in the prevalence and life expectancy between males and females becomes relevant. Patients were voluntarily participating in the study, some surveys have shown a greater readiness of females to participate.As this was an analysis of secondary data, the base size of certain subgroups was small, such as those with “severe pain” and those in full‐ or part‐time employment. Data derived from small sample sizes should be interpreted with caution. Larger samples are needed to confirm our results in these subgroups with smaller bases. Approximately 40% of patients invited to participate in the survey by their consulting physicians took part in the survey. Because the survey respondents may differ from the wider MM population, results from this study may not be generalizable to all patients with MM. We saw marginally more female participants in this survey  Code of Conduct, the Health Information Technology for Economic and Clinical Health (HITECH) ActAppendix S1: Supporting information.Click here for additional data file.


Postoperative pain was compared by using Visual Analog Scale (VAS) scores and by tracking the use of painkillers during the day of surgery and the first two postoperative days; (3) Results: Women with chronic pain before the surgery reported higher VAS scores during the first postoperative days, while the use of analgesics was similar across the groups. There was no difference in the postoperative pain when comparing endometriosis patients to non-endometriosis patients; (4) Conclusions: Women with chronic pelvic pain demonstrated increased postoperative pain after laparoscopic hysterectomy, which was independent of the presence or severity of endometriosis. The increased VAS scores did not, however, translate into equally greater use of painkillers, possibly due to the standardised protocols of analgesia in the immediate postoperative period. These findings support the need for careful postsurgical pain management in patients with pain identified as an indication for hysterectomy, independent of the extent of the surgery or underlying diagnosis.(1) Background: The aim of this study was to evaluate the impact of endometriosis on postoperative pain following laparoscopic hysterectomy; (2) Methods: A total of 214 women who underwent a laparoscopic hysterectomy between January 2013 and October 2017 were divided into four subgroups as follows: (1) endometriosis with chronic pain before the surgery ( Endometriosis, defined as the presence of endometrial glands outside the uterine cavity, affects 10–15% of women of reproductive age . CPP is Hysterectomy is the most common surgical procedure performed in non-pregnant women ; approxiIt has been shown that women with endometriosis experience a decreased pain threshold and therefore a higher pain perception after noxious stimuli . HoweverThe aim of this study was to determine if, and to what extent, endometriosis or pre-existing pain affects the course of acute postoperative pain (pain occurring up to 7 days after the operation) experienced by women undergoing a total laparoscopic hysterectomy.This retrospective study included patients between 19 and 51 years of age with signed general consent who underwent a total laparoscopic hysterectomy between January 2013 and October 2017 due to a non-malignant cause in the Department of Gynaecology of the Bern University Hospital, Switzerland. Clinical data were obtained from the patients’ electronic medical records. Information regarding patients’ demographics and medical history were collected (Body Mass Index (BMI), number of previous abdominal surgeries, parity, use of hormones before the operation). Attention was paid to the indication for the surgery, focusing on the expression of pain before the operation. The patients were divided into 2 groups: for the first group, hysterectomy was indicated or partly indicated by pain, while the second group reported no pain symptoms before the operation. When one of the terms 1. chronic pelvic pain, 2. dysmenorrhea, 3. dyspareunia, 4. dysuria, or 5. dyschezia was found under preoperative diagnosis or clinical indication included in the operative report, the patient was assigned to the first group; otherwise, she was classified as non-pain patient and registered in the second group. Further indications for surgery that were recorded include abnormal vaginal bleeding, cervical dysplasia, growing fibroids, sex reassignment surgery , Lynch syndrome, Breast Cancer gene (BRCA) mutation, uterine prolapse, and uterine polyps. The following surgical parameters were evaluated: duration of the operation, estimated blood loss, uterine morcellation, and complications during or after the operation, using the Clavien–Dindo classification . In someThe primary outcome was postoperative pain during the first 3 days of the hospital stay (day of surgery as well as the first two postoperative days). Two different methods of pain evaluation were applied: the visual analogue scale (VAS) score, recorded at least 3 times a day, and the use of analgesics. For the latter, the pain point system scale (PPSS) was applied . The aveEach patient was assigned to one of the following four categories based on the indication for the hysterectomy and the presence of endometriosis or not: (1) endometriosis with preoperative pain (endo+/pain+); (2) preoperative pain without endometriosis (endo−/pain+); (3) endometriosis without preoperative pain (endo+/pain−); (4) no endometriosis and no preoperative pain (endo−/pain−).Ethics approval for this research was obtained from the Ethics Commission of the Canton of Bern, Switzerland (Reference Number: 2020-00937).t-test equivalent. Due to the increased likelihood of type II errors, adjustments for multiple testing were avoided [p values were considered statistically significant when <0.05.Statistical analysis was performed using IBM SPSS Statistics (version 25.0). For patient and clinical–pathological analyses, basic descriptive statistics were applied. To compare the characteristics within the groups, the chi-squared test and ANOVA were used. A non-parametric test was applied for variables not meeting the assumptions of the  avoided . All tesn = 56) of the patients underwent a simple laparoscopic hysterectomy; in 46.7% (n = 100) of the women, additional adnexal surgery was performed. For the rest of the collective, further interventions were recorded.After the inclusion criteria were applied, 214 women were included in the study. Patient characteristics are summarised in n = 57) of the women in the endometriosis group, a peritoneal or deep infiltrating endometriosis was reported. The rest displayed isolated adenomyosis uteri. Endometriosis was histologically confirmed in 47 cases. Severe peritoneal endometriosis (defined as endometriosis rAFS III and IV) was observed in 14 women and deep infiltrating endometriosis in 27 patients.The surgery-related data are summarised in t-tests for statistical significance between groups were conducted; patients with pain symptoms before the operation reported significantly higher VAS scores  during the first day , the mean VAS score during the third day , and the maximum VAS score during the third day  were also higher for patients with preoperative pain  used PCA for an average of 2 days.Endo−/pain+: 2 patients (4%) used PCA for an average of 2 days.Endo+/pain−: 3 patients (7.5%) used PCA for an average of 2.7 days.Endo−/pain−: 4 patients (6%) used PCA for an average of 2.25 days.p-value < 0.001). The presence of endometriosis did not play a significant role.The number of doctor’s bedside visits (as extracted from the electronic files) was statistically higher for patients reporting pain symptoms before the surgery . No other difference was found between the groups.Patients with endometriosis or preoperative pain tended to have a shorter hospital stay, compared with the group endo−/pain−  was handed to all patients before the surgery, as part of other prospective studies, only 35% of our study population answered the questionnaire. Furthermore, different high-volume endoscopic surgeons performed most laparoscopic hysterectomies included in this study, and thus, it is possible that our findings may not be directly applicable to other settings. Additionally, as acute postoperative pain is defined as the pain occurring during the first 7 days after the surgery, assessing only the first 3 days can lead to bias. Finally, although the groups were relatively homologous, they included predominantly Caucasian women living in a specific region of central Europe.Women with chronic pelvic pain demonstrate an amplified pain perception during the first days after laparoscopic hysterectomy; postsurgical pain does not correlate with the presence or extent of endometriosis. However, the increased pain does not translate into a corresponding administration of painkillers, possibly due to the standardised protocols of analgesia in the immediate postoperative period. In the era of personalised medicine, postoperative pain management should focus on the surgical approach and individual patient characteristics, such as pain before operation. Optimising the management of acute postoperative pain is crucial, as it is one of the main risk factors for developing chronic postoperative pain ,28,29.


Opioid-free anesthesia (OFA) is associated with significantly reduced cumulative postoperative morphine consumption in comparison with opioid-based anesthesia (OBA). Whether OFA is feasible and may improve outcomes in pancreatic surgery remains unclear.n = 42) or an OFA (n = 35). OFA included a combination of continuous infusions of dexmedetomidine, lidocaine, and esketamine. In OBA, patients also received a single bolus of intrathecal morphine. All patients received intraoperative propofol, sevoflurane, dexamethasone, diclofenac, neuromuscular blockade. Postoperative pain management was achieved by continuous wound infiltration and patient-controlled morphine. The primary outcome was postoperative pain . Opioid consumption within 48 h after extubation, length of stay, adverse events within 90 days, and 30-day mortality were included as secondary outcomes. Episodes of bradycardia and hypotension requiring rescue medication were considered as safety outcomes.Perioperative data from 77 consecutive patients who underwent pancreatic resection were included and retrospectively reviewed. Patients received either an OBA with intraoperative remifentanil  and opioid consumption  were both less in the OFA group. Length of stay was shorter by 4 days with OFA . OFA (P = 0.03), with postoperative pancreatic fistula (P = 0.0002) and delayed gastric emptying (P < 0.0001) were identified as only independent factors for length of stay. The comprehensive complication index (CCI) was the lowest with OFA . There were no differences in demographics, operative time, blood loss, bradycardia, vasopressors administration or time to extubation among groups.Compared to OBA, NRS (3 [2–4] In this series, OFA during pancreatic resection is feasible and independently associated with a better outcome, in particular pain outcomes. The lower rate of postoperative complications may justify future randomized trials to test the hypothesis that OFA may improve outcomes and shorten length of stay. Pancreas cancer is currently the seventh leading cause of cancer death worldwide. A major concern is that the incidence of pancreatic cancer is increasing in the Western world. It is anticipated to become the second leading cause of cancer-related mortality by 2030 . The onlRecent reviews have emphasized the importance of the perioperative period on oncologic outcome after cancer surgery . Indeed,Data from patients who underwent pancreatectomy for tumors with curative intent at the Department of Abdominal Surgery and Transplantation, CUB Érasme, Free University of Brussels (ULB), from December 2019 to February 2021 were reviewed from a prospectively maintained database. Indeed, by law, data from all patients undergoing surgical resection for a suspected pancreatic or periampullary tumor must be communicated to a national advisory body funded by the federal government: the Belgian Healthcare Knowledge Center (KCE) . The KCEThis single-institution retrospective cohort study was handled in accordance with the Declaration of Helsinki. This manuscript adheres to the applicable STROBE guideline.2, body temperature, and capnography.All procedures were performed under general anesthesia with advanced vital sign monitoring, such as electrocardiogram, central venous pressures and invasive arterial blood connected to an advanced monitoring platform , SpOBefore induction, all patients received antibiotic prophylaxis, and intravenous (IV) loads of magnesium (30 to 40 mg/kg), dexamethasone (10 mg) and diclofenac (75 mg) according to the presence of a contraindication . Patientment}μg) .The standardized IV induction included propofol (1.5 to 3 mg/kg), lidocaine (1.5 mg/kg bolus with a maximum of 100 mg) and rocuronium before tracheal intubation (0.6 to 1.2 mg/kg). In the OBA group a target-controlled infusion (TCI) of remifentanil (3–5 ng/ml) was used, while in the OFA group, patients received IV esketamine (0.25 mg/kg bolus) along with a continuous infusion of dexmetedomidine (0.5 μg/kg/h) started 10 min before induction.2In all patients, depth of anesthesia was individually adjusted to achieve and maintain a Bispectral Index between 40 and 60  with sevoflurane in an oxygen–air mixture to obtain a SpOy weight .2 94% or above on room air. Adequate urine output (0.5–1 mL/kg per hour) had to be maintained. NRS pain score had to be ≤ 4 before discharge based on a 0 to 10 pain scale with opioids administered no less than 15 min prior to discharge. Nausea and vomiting had to be under control.All patients were monitored in post-anesthesia care unit (PACU) for at least one night. They received a weight-adapted thrombosis prophylaxis with low molecular-weight heparin combined with compression stockings, and an IV pancreatic secretion inhibitor . Patients were transferred to the ward if they were appropriately responsive or unchanged from preoperative status. Respiration had to be easy and unobstructed within 12 to 25 breaths/min. Heart rate and blood pressure had to be within acceptable range (60 to 100 beats/min and a MAP > 65 mmHg) with a SpOPostoperative pain treatment was identical in both groups and performed by a combination of continuous wound infiltration  with ropThe main objective of this study was to determine the benefit, if any, of the administration of OFA on postoperative pain control evaluated by numerical rating scale (NRS) and cumulated opioids consumption within 48 h after extubation. These two parameters were evaluated at several time points after extubation . Complications are also important indicators of immediate postoperative outcomes. Therefore, all adverse events within 90 days after surgery were recorded and evaluated by the surgical team according to the Clavien-Dindo classification (CDC), a widely used index for the classification of surgical complications and the comprehensive complication index (CCI) . The CDCPharmacy data allowed for electronic abstraction of each opioid dose charted in the medication record. All routes of opioids (tramadol included) were summarized, including intermittent intravenous, oral, and IV-PCA totals. After collection of individual patient opioid doses, amounts were converted to IV morphine milligram equivalents (MME) using accepted conversion factors , 21. ForSince a recent study reported that OFA with dexmedetomidine might increase serious adverse events, mainly bradycardia with the possibility of asystole requiring cardiopulmonary resuscitation (CPR) , safety P value of < 0.05 was considered significant for all statistical tests. Finally, Using the Gpower computer program  with 71.4%  while cumulative morphine consumption was only significant from 24 h and beyond . Three patients did not need any morphine administration after surgery in the OFA group and none in the OBA group.The cumulative postoperative morphine consumption and analgesia measures are given in Fig. Descriptive statistics comparing patients according to the anesthesia regimen and the overall cohort are shown in Table P = 0.03). Compared to OBA, hospitalization was reduced by 4 days in case of OFA . Multivariable analysis identified OFA (P = 0.03), the absence of POPF (P = 0.0002) or a POPF requiring a change in the postoperative management (P < 0.0001) [P < 0.0001) as significant independent factors for length of stay  , and DGEP = 0.000 or a POPP = 0.14) and the maximal dose administered was 0.75 mg. As for atropine, need for hemodynamic support to achieve a MAP P = 0.73, Chi-square test) with a median dose of 0.043 gP = 0.73) (Table Bradycardia requiring atropine administration was more frequent in the OBA group than in the OFA group (11.9% vs 5.7%). However, this difference was not statistically significant  while a NRS pain scores ≤ 4 in the OFA group was the standard. However, there is large variation in how patients translate their pain to an NRS score. Therefore, without a pain assessment beyond the NRS, there is a risk of both undertreatment and overtreatment of the patient postoperative pain . Since tThe time required until patients consistently report minimal postoperative pain is also key feature of pain control. It must be noted that NRS scores increased in the OBA group at 24 h but not in the OFA group. This might be explained by the anti-hyperalgesic techniques included in the OFA regimen, and/or by an opioid-induced hyperalgesia induced by OBA. These non-mutually exclusive hypotheses are supported by the fact that movement-related pain is substantially more intense than pain at rest and seems to be more closely associated with pain-related functional impairment . The 24 P < 0.001) [Compared to OBA, with a discharge on median day 10, we report a shorter postoperative stay. This indicate that OFA might be more than a feasible option but also a viable one. In our cohort, independent variables associated with extended length of stay included, as expected, the presence of index complications mainly POPF  grade C . This st grade C , was the< 0.001) . Althoug< 0.001) . A recen< 0.001) . In our < 0.001) , 39.Recently, OFA with dexmetedomidine was associated with more adverse events such as bradycardia, asystole, hypoxemia delayed extubation, and prolonged PACU stay, despite a lower overall opioid consumption and less postoperative nausea and vomiting . Most ofAccording to some authors, the intentional adoption of perioperative lidocaine infusion over an extended time frame could increase the likelihood for local anesthetic systemic toxicity leading to a virtual certainty for clinically significant, even fatal events . AlthougLimitations of these work are linked to the retrospective, single-institution cohort design with a relatively limited number of patients. Our sample size was one of convenience, chosen from the time of first OFA implementation. However, to limit selection bias, we analyzed consecutive patients. Also, based on the post hoc power calculation, it is unlikely that our findings can be attributed to the limited sample size. However, even if an inclusion bias is controlled, the non-blind assessment by nurses may have influenced results and other confounders cannot be formally excluded, including the anesthesiologist in charge, the day of the week, among others. Determining the incidence of any opioid related side effects in PACU and/or on the ward would also have added value to this study. However, the retrospective nature of the analysis prevented us to obtain these information’s. More in case of suspected side effects based on some prescriptions such as antiemetic, the causal relationship could not be affirmed. Despite these limitations, we believe that our findings add information about feasibility, safety, and viability of OFA in major abdominal surgery. It shows that, in experienced hands, the technique is deemed appropriate, and potentially better than the others, even if demonstrating a direct effect of OFA will require a randomized-controlled trial.The implementation of an OFA protocol was associated with a better pain control as measured by pain rating at 24 and 48 h and cumulative opioid dose, a reduced comprehensive complication index compared to OBA, and a 4-day reduction in length of stay after pancreatic resection without an increase in morbidity or readmissions. No adverse hemodynamic effect was suspected in the OFA group.


The purpose of this narrative review was to assess the effect and safety of dexmedetomidine given intraoperatively during anaesthesia compared to placebo and demonstrate the effect on acute postoperative pain in adult patients undergoing craniotomy. Literature published from 1996 until 2021 were analysed through a search of PubMed, Medline and Embase. Randomised controlled trials investigating intraoperative administration of Dexmedetomidine with evaluation of postoperative pain were included. Medical Subject Headings terms and free-text words were used to identify articles related to the intraoperative use of Dexmedetomidine and postcraniotomy pain. Thirteen distinct randomized controlled trials with 882 recruited patients undergoing craniotomy were identified as eligible for final inclusion. Intraoperative administration of dexmedetomidine is associated with decreased postoperative pain and opioid consumption, and it assures haemodynamic stability. Dexmedetomidine is an efficacious adjunct in craniotomy in adults, showing benefits in reduction of postoperative pain and analgesic consumption. Dexmedetomidine also offers haemodynamic stability. However, widespread methodological heterogeneity of the papers prohibits a valid meta-analysis.Craniotomy involves procedures with high incidences of postoperative pain. Dexmedetomidine, a highly selective a Studies have reported that 40–84% of neurosurgical patients experience moderate to severe pain during the first postoperative days, despite liberal use of intraoperative opioids ,2. Pain 2-adrenoreceptor agonist, has unique characteristics in providing sedation and analgesia [2c- and a2a-receptors located on neurons in the dorsal horn [2c-receptor subtype in the spinal cord also seems to accentuate the analgesic actions of opioids by inhibiting the afferent transmission of nociceptive signals [Dexmedetomidine (DEX), a highly selective analgesia . Due to nalgesia ,13. Morenalgesia . The anasal horn . Activat signals ,15. Take signals . In thisWe conducted a literature search to identify relevant randomised controlled trials (RCTs) in PubMed, Medline and Embase between 1996 until October 2021. Medical Subject Headings (MeSH) terms and free-text words were used to identify articles related to the intraoperative use of DEX and postcraniotomy pain. The complete search string can be found in the Clinical RCT study design.Patient groups >18 years of age.Patients underwent elective craniotomy under general anaesthesia and were extubated immediately after surgery.Intraoperative intravenous administration of DEX compared to any control group.One or several of the following outcomes reported: postoperative pain intensity, opioid/analgesic consumption at the postoperative care unit, postoperative pain-scores and/or number of patients experiencing pain at the postoperative pain unit.Descriptions of protocols for anaesthesia, analgesia and rescue analgesics.Availability of full text in English.To be eligible for this review, publications had to meet the following inclusion criteria: There were no limitations as to the dosing or duration of the DEX regimens, whether administered as continuous infusion or as bolus pre- and/or intraoperatively. If a study used two different doses of DEX and no dose-response relationship was detected, we decided to combine both groups as a single treatment group. The final search was performed on 13th October 2021. References of related reviews and meta-analysis were screened for additional papers. The authors (N.S. and I.J.) searched and retrieved abstracts, screened them for relevance, retrieved full-text manuscript, and extracted data. Any controversy concerning study selection or data extraction was resolved by discussion and consensus with a third reviewer (E.S. or T.S.) if agreement was not achieved. The outcomes of interest were procedural success and postoperative pain intensity rated on a Verbal- or Numeric Rating Scale (VRS/NRS) or a Visual Analogue Scale (VAS) during postoperative care, including the number of patients with moderate or severe pain . If pain intensity in the post-anaesthesia care unit (PACU) and the post-surgical ward was measured at several points in time, the highest pain score within the defined time period was registered. Procedural success was defined as completion of the specific neurosurgical operation without serious intra- or postoperative complications that caused patients to withdraw or be excluded from the study. Other outcomes of interest involved cumulative morphine/analgesic consumption, patients with DEX-related side effects  and procedure-related outcomes . Relevant data from the included trials were extracted, tabulated and entered on Excel sheets . The following outcomes were collated for analysis: The American Society of Anaesthesiologists Physical Status score, physical status and age, exclusion criteria, administration of DEX before induction, interventions , administration of DEX after induction and all outcomes of interest; pain intensity during the stay in PACU, frequency of patients experiencing pain and PACU analgesic consumption.A total of 185 articles were identified from the literature search. After deduplication, title and abstract screening and identification of eligible trials for inclusion, a detailed full-text review was retrieved. Thirteen distinct RCTs with a total of 882 recruited patients undergoing craniotomy  were selected for final analysis. See Patients in the included studies were comparable as to age, sex, BMI, ASA-PS grade, comorbidity and planned neurosurgical procedure, further summarized in All study participants received anaesthesia intraoperatively according to a standard anaesthesia protocol, including infusion of the study drug or placebo. Some of the included trials had antiemetics, corticosteroids or analgesics as a part of the standard protocol as prophylaxis against PONV or pain, given before or at the time of endocranium closure. A majority of these trials had prophylactic measures for both PONV and postoperative pain. In three trials, ondansetron was given to all patients as PONV prophylaxis together with other substances as a part of a standard protocol; in one trial together with tramadol ; and in Two studies used VRS postoperatively for evaluating pain every 0, 2, 6, 12, 18, 24 and 48 h, or at 1, 5, 15 and 30 min in the PACU as soon as the patients were responsive to verbal stimuli. Postoperative analgesia was considered insufficient if the VRS score exceeded 8 or remained >4 for 15 min, and additional analgesic was administered as boluses ,20. Two A majority of the included trials documented significantly less PACU opioid and analgesic consumption in the DEX groups as compared to the control groups ,17,20. GAll 13 included trials reported pain intensity in the PACU but in widely different manners. One trial reported PACU pain intensity as a number of patients experiencing significant pain. This specific trial used VRS to assess pain and concluded that 30 patients in the DEX group  and six patients in the control group  experienced no pain . A totalSide effects between the treatment and control groups were evaluated to estimate the safety of DEX administration during craniotomy. The consolidated results indicated that hypertension occurred more often in the control groups and that a lower incidence of cardiovascular variabilities was associated with the groups receiving DEX ,21,24. IIn this review limited to and focused on craniotomies only, we found that the use of intraoperative DEX during craniotomy was associated with reduced postoperative pain and opioid consumption, constituting a safe alternative to opioid combinations. DEX-treated patients displayed fewer immediate haemodynamic responses that needed treatment. Liu et al. published a recent review on the effects of DEX on several neurosurgical procedures, including trans-sphenoidal procedures. They found a reduction in intra- and postoperative opioid consumption . We havePostoperative pain is one of the major causes of agitation and discomfort after neurosurgery . AdminisDEX has also proven useful in other areas of surgery. A study by Arain et al. evaluating postoperative outcomes after major inpatient surgery showed a consistent reduction of opioid requirements by 30–50% in the group receiving DEX . Xin et However, in one study where DEX was compared to remifentanil as anaesthetic adjuvants, it was noted that DEX may not offer sufficiently desired effects during all stages of a craniotomy, and therefore it may not fully replace opioids. Administering a low-dose remifentanil infusion in addition to DEX may potentially achieve successful pain control . This cop release [2c- and a2a-receptors located on neurons in the dorsal horn, by inhibiting the pro-nociceptive transmitters, primarily substance p and glutamate, and by hyperpolarization of spinal interneurons [2c-receptor subtype seems to accentuate the analgesic actions of opioids in attenuating the transmission of nociceptive signals to brain centres [DEX has been shown to reduce opioid requirements ,12,28. I release . This isrneurons . The mos centres . HoweverWhile remifentanil is rapidly metabolized and facilitates quick awakening, higher doses of fentanyl may cause delayed awakening and respiratory depression . In one 2-agonist, causes a dose-dependent reduction in the sympathetic output from the brain, which may explain the haemodynamic findings in patients receiving this anaesthetic [DEX has been associated with bradycardia and hypotension. This may predispose patients to cerebral ischemia ,22. DEX,esthetic . Howeveresthetic . The samesthetic . A possiesthetic  or a relesthetic . This shEvidence on the cost-effectiveness of intraoperative DEX on postoperative pain is lacking. A few studies have evaluated the cost-effectiveness of DEX on sedation in ICU patients finding benefits due to shorter ventilation days and shorter extubation times ,36. HoweThe current review has a number of limitations. Trials did not include measuring a target plasma level concentration of DEX. Instead, a constant dosage regimen was selected which might have led to individual variations in patients due to inherent differences in drug metabolization. Furthermore, in several trials, patients received prophylactic drugs against postoperative pain and-/or PONV at the end of the surgical procedures. This might have affected levels of postoperative pain and analgesic consumption, making it difficult to assess the sole effects of DEX on postoperative pain per se. All studies had various intraoperative treatment protocols, including different administration methods and postoperative analgesia protocols. Variable times and methods of measuring pain among the trials, including different combinations of opioids with variable duration of actions, made the outcome measures of the included trials highly variable and challenging to compare. The main focus of this review was the effect of intraoperative DEX on postoperative pain. Relevant articles discussing pain only as a secondary outcome may therefore have been overlooked or not found by the search string.There is no universal definition of the term “pain” and “experience of pain”. How to interpret pain is therefore a subjective matter, in addition to the subjectivity of pain assessment techniques. In this review pain was assessed by evaluating the postoperative pain scores, opioid/analgesic consumption and by looking at the number of patients experiencing pain between the study groups. However, due to heterogeneity of the included trials, especially in definitions and interpretations of pain, it was not possible to quantify the reviewed results from the different publications in a statistical manner . One RCTWe found that intraoperative infusion of DEX during craniotomy is associated with decreased postoperative pain and analgesic consumption, with improved pain scores. In addition, DEX did not compromise hemodynamics among patients undergoing elective craniotomy. However, there were significant heterogeneities in treatment protocols. Future research and clinical implementation of DEX as an anaesthetic adjuvant is needed, emphasising better standardization of intra- and postoperative anaesthesia protocols.


The percentage of patients with pain freedom at 2 h was 7.2% higher in verum (25.5%) compared to sham . Resolution of most bothersome migraine-associated symptom was 14.1% higher in verum (56.4%) compared to sham . With regards to secondary outcomes, pain relief at 2 h was 14.3% higher in verum (69.5%) than sham , absence of all migraine-associated symptoms at 2 h was 8.4% higher in verum (42.5%) than sham , sustained pain freedom and pain relief at 24 h was 7.0% and 11.5% higher in verum (22.8 and 45.9%) than sham . No serious adverse events were reported. Treatment with 2-h e-TNS is a safe and effective, non-invasive, and non-pharmacological alternative for the acute treatment of migraine attacks in an at-home setting.Migraine is one of the most common and debilitating neurological disorders worldwide. External Trigeminal Nerve Stimulation (e-TNS) is a non-pharmacological, non-invasive therapeutic alternative for patients with migraine. The TEAM study was a prospective, multicenter, randomized, double-blind, sham-controlled, Phase 3 trial for 2-h, continuous, e-TNS treatment of a single moderate or severe migraine attack at home. A total of 538 adults meeting the International Classification of Headache Disorders 3rd edition criteria for 2–8 migraine headache days per month were recruited and randomized in a 1:1 ratio to 2-h active or sham stimulation. Migraine pain levels and most bothersome migraine-associated symptoms (MBS) were recorded at baseline, 2 h, and 24 h using a paper diary. The primary endpoints for the study were pain freedom at 2 h and freedom from the MBS at 2 h. The secondary endpoints were pain relief at 2 h, absence of most bothersome migraine-associated symptoms (MBSs) at 2 h, acute medication use within 24 h after treatment, sustained pain freedom at 24 h, and sustained pain relief at 24 h. Adverse event data was also collected and compared between groups. Five hundred thirty-eight patients were randomized to either the verum (Trial registration Clinicaltrials.gov Identifier: NCT03465904. Registered 14/03/2018. https://www.clinicaltrials.gov/ct2/show/record/NCT03465904. Acute pharmacological treatments for migraine may result in intolerable side effects, may be contraindicated in patients with cardiovascular and/or cerebrovascular disease, or may lack efficacy for pain freedom7. Consequently, this leaves up to 40% of episodic migraine patients with unmet migraine treatment needs8. Another concern in the acute treatment of migraine is acute medication overuse. The frequent intake of acute migraine medications may lead to an increased risk of adverse events, migraine chronification, and medication overuse headache (MOH)12.Currently, the first line acute treatments available for migraine include triptans, non-steroidal anti-inflammatory medications (NSAIDS), lasmiditan, and gepants (ubrogepant and rimegepant)14. External Trigeminal nerve stimulation (e-TNS) is a non-pharmacological, non-invasive therapeutic alternative for patients with migraine who do not respond to pharmacologic acute migraine therapies, have intolerances/contraindications to acute migraine therapies, or prefer to avoid pharmaceutical therapies. A few proposed mechanisms exist for the role of e-TNS treatment for migraine. The role of the trigeminovascular system in migraine has been well established. The supraorbital nerve which is stimulated directly by e-TNS, is a branch of the first division of the trigeminal nerve. FDG-PET studies have shown that e-TNS may modulate the function of pain-controlling brain regions15.Studies have shown that a majority of patients use non-pharmacological approaches for migraine treatment19. E-TNS treatment in the ACME trial took place in a hospital setting, with a limited sample size and after a migraine duration of 4 h prior to intervention. Additionally, the findings of the ACME trial indicated a trend of longer treatment durations favoring improved migraine relief. However, to the best of our knowledge, no data are available from a clinical trial using similar protocol design and endpoints in a real-world, at-home setting. A single-center open-label trial of a patient's self-administering 2-h e-TNS treatments for acute treatment of a migraine attack suggested favorable outcomes in 2-h pain freedom, most bothersome migraine-associated symptom, and sustained pain freedom at 24-h20.Several trials, including the sham-controlled Acute Migraine therapy with External Trigeminal Neurostimulation (ACME) clinical trial, demonstrated efficacy and safety of e-TNS in the acute treatment of migraine attacksThe objective of the Trial of e-TNS for the Acute treatment of Migraine (TEAM) study is to evaluate the efficacy and safety of self-administered, 2-h (two consecutive 1-h) e-TNS treatments for migraine attacks, with and without aura, in an at-home setting.The study protocol and informed consent form were reviewed and approved by the ADVARRA (formerly IntegReview) Investigational Review Board, protocol #51401, on February 15, 2018 and approved at all sites. The study was also registered with Clinicaltrials.gov Identifier: NCT03465904, 14/03/2018. Written informed consent was obtained from all participants. The full protocol design is included with 24.This study was a prospective, multi-center, randomized, double-blind, sham-controlled study conducted across ten centers in the United States . This trial used the traditional protocol design and endpoints for many acute migraine medications, following FDA guidance and International Headache Society guidelines12, (2) migraine diagnosis before 50 years of age, and (3) 2 to 8 monthly migraine frequency with moderate to severe intensity. The inclusion and exclusion criteria are listed in Table Men and women adults (aged 18–65 years) were eligible for enrollment if (1) they had a diagnosis of episodic migraine with or without aura, for at least 1 year, according to the diagnostic criteria listed an International Classification of Headache Disorders, Third edition (ICHD-3)After enrollment and prior to randomization, patients were trained to use the migraine diary, the application and operation of the e-TNS device, and then were tested with a 20-min nociceptive assessment. Patients were eligible for randomization if they met all inclusion criteria, none of the exclusion criteria, and demonstrated capability to self-apply, operate, and tolerate the device stimulation.® Technology, Seraing, Belgium) for a 2-h, continuous session. The device is a constant current generator for a maximum skin impedance of 2.2 kΩ that delivers rectangular biphasic symmetrical pulses with a zero electrical mean25. Verum and sham devices used identical rectangular biphasic symmetrical pulses of 250 μs, with a width that induced paresthesia. The sham device provided low frequency pulses of 3 Hz, while the verum device produced high frequency pulses of 100 Hz. During stimulation, the intensity increases linearly to reach a maximum of 16 mA after 14 min. After 14 min, the stimulation intensity remains constant for the remainder of the treatment (106 min). The total dose of current delivered during a 2-h session is 2.728 coulombs26.Neurostimulation was applied with an e-TNS device (CEFALY2) placed on the forehead and designed to cover and excite  the supratrochlear and supraorbital nerves bilaterally.The electrical pulses are transmitted transcutaneously via a supraorbital bipolar self-adhesive electrode  in which participants were unable to differentiate between sham and verum stimulation. The study participants and care providers were blinded to intervention assignments. If a subject had not treated a migraine attack within 2 months following the screening visit, the study material  was required to be returned to the study site.The overall study design flow is illustrated in Fig. Each patient received a migraine diary and device to record and treat one qualifying migraine within a 2-month period. A qualifying migraine attack had to meet the following criteria: (1) a migraine with moderate or severe headache intensity, and (2) with at least one migraine-associated symptom, being photophobia, phonophobia, nausea, and/or vomiting. The patients were instructed to self-administer the e-TNS treatment, according to the training and instruction, within 4 h of migraine onset or within 4 h of awakening with a migraine headache. Migraines occurring within 48 h of a prior migraine did not qualify for e-TNS treatment. Patients were also advised not to start e-TNS treatment for a migraine spontaneously resolving. In addition, patients were advised to not take any acute migraine medications prior to or during e-TNS therapy. Patients were permitted to use acute migraine therapy after a 2-h e-TNS treatment was completed if needed.During the acute migraine phase, patients reported the following data in their headache diary: (1) pre-treatment (baseline) migraine pain severity ; (2) presence of migraine associated-symptoms ; (3) which migraine-associated symptom was their most bothersome symptom (MBS); and (4) any adverse effects. Patients were advised to record these data prior to the start of the e-TNS session. The same data were recorded at 2 h (following e-TNS treatment), and at 24 h (post-treatment). Patients were also asked to record intake of any acute anti-migraine medication between 2 and 24-h after the start of e-TNS treatment. Patients recorded all adverse event (AE) dates, nature, treatment (if any), and progress in a provided AE collection form. Patients were instructed to notify the investigator immediately for any serious or severe AE experienced with the stimulation.At the conclusion of the 2-month period, subjects were required to return their headache diary and e-TNS device. The e-TNS device for each subject was interrogated for proper device functioning, and duration of stimulation delivered. Subjects who failed to return the migraine diary or had the absence of a qualifying migraine were excluded from the analysis.The primary outcome measures included pain freedom at 2 h and resolution of most bothersome migraine-associated symptom at 2 h from the beginning of e-TNS therapy for one qualifying migraine attack. The secondary outcomes measures included (1) pain relief at 2 h defined as a reduction of a moderate or severe migraine headache at baseline to a mild or no headache, (2) resolution of any migraine-associated symptom at 2 h after beginning of e-TNS treatment, (3) sustained pain freedom, defined as pain freedom at 2 h and pain freedom at 24 h without the use of anti-migraine medication during those 24 h, (4) sustained pain relief at 24 defined as mild or no headache at 2 h and mild or no headache at 24 h after beginning the eTNS session without the use of anti-migraine medication during those 24 h, and (5) use of a rescue medication between 2–24 h after beginning of e-TNS session.Identical statistical analyses were performed for the intent-to-treat (ITT) and the per protocol (PP) populations. The ITT population consisted of all randomized patients, who received any duration of sham or verum treatment and returned completed study materials. The PP population consisted of patients who strictly met inclusion criteria and completed at least 60 min of treatment. Patient exclusion from the PP analysis is displayed in Table p < 0.05.Our power analysis indicated that a minimum of 239 patients per group was needed to provide 90% power to detect a 13.4% difference in the primary outcome, pain freedom at 2 h. Accounting for an estimated attrition rate of 20%, we aimed to enroll 299 patients per group. Data were assessed for normality and to confirm that test assumptions were met. Means and standard deviations (SD) summarized continuous, normally distributed data; continuous, non-normally distributed data are summarized with medians and interquartile ranges (IQR). Categorical data are presented as frequencies and percentages. All analyses were performed using SPSS, version 26.0 with two-sided levels of statistical significance established at A Chi-square test of independent proportions was used to compare primary and secondary efficacy outcomes between groups. A Fisher’s exact test was used (due to cell counts < 5) to compare the proportion of each type of adverse event between groups. In addition, a multivariate logistic regression analysis using a hierarchical approach was performed for each efficacy outcome as the dependent variable and treatment group as the primary independent variable, while controlling for potential confounders in the model including age, duration of treatment (minutes), and having an adverse effect (yes/no).The study protocol and informed consent form were reviewed and approved by the IntegReview Investigational Review Board on February 15, 2018 protocol #51401, and approved at all sites. The study was conducted in accordance with Good Clinical Practice guidelines, the principles of the Declaration of Helsinki, and all applicable regulatory requirements. All participants of the study provided written informed consent prior to initiation of any study procedures.n = 259, sham n = 279) which were included in the intention-to-treat (ITT) analysis. Figure Between April 10, 2018 and January 11, 2019, 626 subjects were screened for eligibility, and 607 were randomized . Twenty-three (23) patients had absence of a qualifying migraine, 20 were lost to follow-up, 14 patients withdrew from the study, and 12 did not return their diary and study materials, resulting in a total of 538 patients (verum ps > 0.05).There were no statistically significant differences in any patient characteristics between groups including age, gender, headache pain severity, headache symptoms at baseline, migraine with and without aura, and duration of treatment . The percentage of patients experiencing resolution of most bothersome migraine-associated symptom at 2-h after beginning of e-TNS was similarly higher in the verum (56.4%) compared to sham group (42.3%), for a therapeutic gain of 14.1% (p < 0.01).For succinctness, ITT analysis results are described in text and presented in results tables, while PP analysis results are only presented in results tables. With regards to primary outcome measures Table , the perp < 0.01). Absence of any migraine-associated symptoms at 2 h was also higher in verum (42.5%) compared to sham (34.1%), with a therapeutic gain of 8.4% (p < 0.05). Sustained pain freedom  and sustained pain relief at 24 h  were higher in verum compared to sham, with therapeutic gains of 7% and 11.5%, respectively. There was no statistically significant difference between groups for use of rescue medication between 2 and 24 h post treatment. The categories of anti-migraine rescue medications reported by patients are summarized in Supplemental Table With regards to secondary outcomes Table , pain rep < 0.05), having an adverse event was a predictor for using rescue medication (p < 0.05), and age was a significant predictor of sustained pain freedom (p < 0.05) and sustained pain relief (p < 0.01) at 24 h.Multivariate logistic regression analysis indicated that treatment group was a significant predictor of all primary and secondary outcomes, while controlling for potential confounders, with the exception of rescue medication use between 2- and 24-h post-treatment. These results are consistent with the results from the primary and secondary bivariate analysis. The multivariate regression analysis also indicated that in the overall sample, duration of treatment (minutes) was a predictor of pain relief at two hours (p < 0.01). Table p < 0.01). All other adverse events did not reach statistical significance between groups .The percentage of patients that reported an adverse event was higher in verum (8.5%) compared to sham  and sham (62.4% and 84.6% respectively) groups.The prospective, multicenter TEAM trial provides the first Phase 3 evidence demonstrating efficacy and safety of patient-administered, 2-h e-TNS treatment for acute treatment of migraine with and without aura in the out-of-hospital setting. We will discuss the outcomes and safety findings, address practical implications of these findings, and then examine limitations of this study.17. In the TEAM study, 2-h e-TNS treatment in acute migraine demonstrated significantly higher rates of migraine pain freedom at 2 h, and resolution of migraine associated MBS compared to sham. In addition, 2-h e-TNS for acute treatment of migraine attacks resulted in an increased rate of pain relief at 2 h, resolution of all migraine-associated symptoms, and sustained pain freedom and sustained pain relief at 24 h when compared to the sham group. These findings substantiate prior hypotheses that duration of e-TNS treatment is a significant parameter in achieving optimal pain relief16.Prior studies of e-TNS for acute treatment of migraine attacks suggested longer duration of therapy may result in improved pain freedom and sustained migraine relief17 found similar results for the proportion of patients experiencing MBS resolution (56.4% vs. 60.4%), sustained 24-h pain freedom (23.2% vs. 25%), sustained pain relief at 2-h (69.5% vs. 70.8%), and absence of all migraine-associated symptoms (42.5 vs. 48.8%). These findings indicate consistent evidence supporting efficacy of 2-h e-TNS in the management of acute migraine with and without aura.The percentage of patients experiencing pain freedom after 2-h of e-TNS was lower in the TEAM study than previously reported in a non-sham controlled, open-label Rochester trial . However, the TEAM study and the precedent open-label trial27. Prior e-TNS studies demonstrating efficacy used similar sham stimulation parameters20. A future randomized, self-control longitudinal study, which allows subjects to treat more than one migraine attack over a 3–4-month period, would be helpful in assessing the consistency of the response of acute e-TNS treatment in migraine attacks27.There were no significant differences in the use of acute migraine medication use at 2 and 24-h between verum and sham groups. This finding was also consistent with the ACME trial. Though e-TNS is shown to be an effective and safe, non-invasive, and non-pharmacological alternative to acute migraine pharmaceuticals, the concordance of these findings may support the use of e-TNS as an augmentative or complementary therapy in the at-home setting. Further study is needed to elucidate the applied role of e-TNS in a stratified-approach to acute treatment of migraine. Although the stimulation frequency between the sham and verum differed in this study, it remains unclear to what extent the sham stimulation provided a partial therapeutic effect as opposed to a true placebo effect31. In the TEAM study, the e-TNS start time from migraine onset was not obtained. Further studies are needed to clarify the effectiveness of e-TNS therapy early versus late in the migraine attack trajectory.As an aggregate, patients with migraine with aura appeared to have a more robust response to e-TNS stimulation in both sham and verum groups. There were no consistent differences in response between verum and sham groups. The mechanism of these findings is unclear. Patients with migraine aura may have early indicators of migraine onset allowing them to identify and treat migraine earlier. Several studies of acute migraine medications demonstrate early migraine detection and treatment is associated with greater likelihood of migraine treatment succes33. Unlike prior studies, the proportion of patients reporting this device-related adverse effect was higher in the verum compared to the sham group. Although the actual number that experienced this adverse event was small (3.9%), this finding may indicate that 2-h e-TNS treatment is associated with a higher incidence of forehead paresthesia.There were no serious adverse events and all non-device and device-related adverse events were minor and fully reversible without intervention after cessation of treatment. The most common adverse side effect of forehead paresthesia and discomfort was consistent with findings of prior studies33. In the TEAM study, ten patients were excluded from randomization due to intolerance of the nociceptive test. Furthermore, multivariate analysis indicates that patients reporting adverse events were 1.33 times more likely to use acute migraine medication between 2–24 h compared to patients without adverse events. These findings highlight the importance of patient tolerability of the stimulation parameters in the compliance and success of migraine and migraine-associated symptom response.The presence of adverse events and tolerance of e-TNS therapy is important in the outcome of migraine relief. In a prior survey of 2313 patients using e-TNS, the rate of adverse events was higher in patient’s unsatisfied with therapy. In this survey, 2% of respondents stopped e-TNS therapy due to adverse events, and approximately 9% of patients with suboptimal compliance reported adverse events34. This feature may help mitigate potential intolerance to stimulation of higher intensities, particularly with initial therapy. Therefore, it is crucial that patients are educated about the function and operation of this feature to optimize compliance and tolerability of the therapy27.In clinical practice, the e-TNS device has a “stabilization feature” (not utilized in this study) which allows patient to plateau or stabilize the stimulation intensity within the first 14 min if paresthesia becomes too intense16.The practicality of a 2-h treatment duration may raise concern in terms of patient compliance. Overall, the compliance rates were higher for 60-min treatment duration compared to 2-h treatment. This finding may suggest a balance between optimal treatment time with neuromodulation therapy and desired pain relief from treatment. The rates of compliance and median duration of treatment in the TEAM study were similar to the prior open-label study, and this suggests that 2-h e-TNS treatments are feasible and practical alternatives to medicinal therapies in the real-world settingPatients had one opportunity to correctly identify a qualifying migraine and apply and administer e-TNS treatment in an out of hospital setting. In attempts to limit potential selection bias, patients were required to distinguish between migraine and tension type headache as part of the study inclusion criteria. While an in-hospital setting may have improved accurate migraine attack identification, the current study was conducted outside of a hospital setting so that efficacy of e-TNS could be assessed in an environment where the device is commonly used .31. This observation highlights the importance of thorough device familiarization and instruction and underlies the importance of available, out-of-hospital patient education resources for proper e-TNS application and operation35. In addition to the device familiarization phase, future, self-application, neuromodulation clinical trials should provide patients thorough instructions for re-familiarization including online video tutorials and other training materials for the patient to review at home27.Ninety-four patients (17.5%) were unable to provide at least 60 min of therapy during a migraine. Self-administered treatments for a single migraine attack increased risk of incorrect device application, operation, and treatment disruption despite the 20-min training session. This is further complicated by possible interictal cognitive issues in patients with active migraineThe baseline number of headache years, average headache severity, usual preventative and acute anti-migraine treatments were not recorded and therefore their potential effect on the treatment outcomes could not be assessed. Although the at-home setting was permissive to early self-administered treatment, the specific timing of e-TNS intervention relative to migraine onset was not accurately assessed in this study. Migraine intervention timing may be a critical variable in symptom response, and further study is needed to elucidate this finding. Finally, longitudinal studies are needed to assess the consistency of the response of acute e-TNS treatment in migraine attacks.This was the first randomized, sham-controlled trial examining a 2-h e-TNS treatment for acute treatment of a migraine attack in an at-home scenario using a protocol design and outcomes for medications according to the Food and Drug Administration (FDA) and International Headache Society (IHS) guidance. The results suggests that 2-h e-TNS is an effective and safe, non-pharmacological, non-invasive treatment for acute treatment of a migraine attack with and without aura. E-TNS may be a clinically impactful alternative or complementary therapy in the stratified approach to acute management of migraine.Supplementary Table 1.


Spinal degenerative joint disease (DJD) is associated with lower back pain (LBP) arising from the degeneration of intervertebral discs (IVD), facet joints, intertransversarii muscles, and interspinous ligaments among other anatomical structures. To circumvent the socioeconomic burdens and often-problematic surgical options imposed by DJD therapy, cell-based biologic modalities like bone marrow aspirate concentrate (BMAC) have been investigated in pre-clinical and clinical settings, mostly for IVD degeneration (IDD), with encouraging outcomes. In this study, we evaluated the differences in therapeutic benefits of BMAC between IVD- and facet joint-originating chronic LBP. Eighteen patients diagnosed with chronic LBP met the selection criteria. Following discography and provocation testing, 13 patients tested positive and were assigned into IDD-associated LBP (1st arm), while the remaining 5 tested negative and were assigned into facetogenic LBP (2nd arm). Autologous BMAC was injected intradiscally in the 1st arm, while the 2nd arm received posterior spinal chain injections. No procedure-related serious events ensued. Clinical improvement was evaluated over 12 months based on pain and functionality questionnaires , opioid use, and changes in disc parameters assessed by magnetic resonance imaging (MRI). Ameliorated VAS and BPI scores differed significantly between both arms in favor of IDD patients who also took significantly less opioids. Average RAND-36 scores showed no significant difference between groups albeit a trend suggesting improvement was observed in IDD patients. MRI scans conducted on IDD patients demonstrated marked elevation in disc height and spinal canal space size without worsening disc quality. Overall, this is the first study investigating the potency of BMAC as an IDD treatment in Canada and the first globally for addressing facetogenic pain using cellular therapy. Lower back pain is a commonly confounding and costly health problem –4. In CaThe standard of care for chronic LBP includes exercise, heat/cold therapy, pharmacological treatments, and/or surgery. However, anatomical LBP associated with DJD remains difficult to treat since current therapeutic regimens do not address disc regeneration, but are rather limited to symptomatic relief and/or improving spinal range of motion (ROM) to preserve patient functionality . BiologiWe herein report the first Canadian retrospective, non-randomized, comparative case series with the goal to evaluate differences in pain and functionality outcomes in DJD-associated LBP between IDD and facetogenic pain patients in response to a single lumbar autologous BMAC injection. Outcomes were assessed by measuring: (i) longitudinal changes in pain and functionality using the clinically validated pain scoring systems, the visual analog scale pain score (VAS) , the BacEighteen patients with anatomical LBP and meeting the selection criteria  presentevia a right paramedian approach, and ultimately positioned slightly lateral to the superior articulating process (SAP) at a midpoint between the endplates. When the needle was correctly positioned, the stylet was removed to allow the insertion of a 22-gauge 7-inch spinal needle through. The needle was passed lateral to the SAP and medial to the exiting nerve root. During its passage through the annulus, resistance and back pain were noted. When pain in the extremities was reported, the needle was redirected due to potential nerve root contact. Upon disc penetration, antero-posterior and lateral disc images were obtained, both of which visualized the needle tip in the center of the disc space. The procedure was repeated at all concerned levels. Afterwards, pain was localized through the injection of a pressurizing contrast  and subsequently assessed with a disc pressure-measuring manometer connected to the needle. The amount of pain provoked in the disc tested and while the patient was blinded was delineated as such: P0 (no pain on injection), P1 , P2 (discordant pain), and P3 (concordant pain). Discs were considered positive if P1 or P3 was recorded and concorded with the MRI. Negative levels (P2) were used as control. Simultaneously, disc quality was interpreted further by discogram findings under fluoroscopic guidance. Positive imaging findings were not considered significant if teamed with P0 levels. The patterns of imaging findings based on discography and their corresponding significance are described in Unless non-conforming to the pre-discography inclusion criteria included in −CD44+CD90+CD105+) among others  . In the The first evaluation post-procedure occurred after 2 weeks at the Canadian Center for Regenerative Therapy . Subsequently, all patients were instructed to follow up 1, 3, 6, 9, and 12 months following injection. At each visit, range of motion (ROM) and tenderness to palpation at the joint line level were assessed. Pain and patient functionality were re-assessed as well using the clinically validated scoring systems . Radiological follow-up entailed a second MRI between 8–12 months post-procedure. MRI scans were performed at different centers, and images reflecting the best anatomical integrity were chosen to assess changes in disc quality compared with the pre-procedure MRI in terms of disc height; spinal canal space size; and disc quality according to Pfirrmann grading. Specifically, disc height and spinal canal space size were measured by 2 blinded investigators, and disc quality was graded using the clinically accepted 5-level Pfirrmann scale for disc degeneration with level 5 being the utmost degenerate .t-test for normally and Chi-Square-test for non-normally distributed data were performed to analyze score outcome differences between baseline findings of both treatment arms. The repeated-measures general linear model (GLM) with Sidak test for pairwise comparisons was performed to investigate the influence of the treatment on the evolution of VAS, BPI, and RAND-36 scores within a group. The repeated-measures GLM with Sidak test for pairwise comparisons was used to compare change in VAS, BPI, and RAND-36 scores between treatment groups over time. As such, time was considered a within-subject variable and treatment a between-subject factor. The primary variable of interest between both groups was the effect of treatment and the difference of estimated marginal means. Based on the variable type and normality or non-normality of distribution, Paired t-test or Chi-Squared test was performed to analyze opioid use and MRI outcomes between pre- and post-procedure. Pearson correlation (2-tailed) was performed to detect correlations between score improvement and total BMAC volume injected in both groups. The GLM with scores as dependent variable and treatment group as fixed factor was adopted to detect significant co-variate effects  and interaction effects on score improvement of both groups. P < 0.05 was considered statistically significant.Statistical analyses were conducted using SPSS 20.0 . Results are depicted as mean ± standard deviation (SD) unless otherwise specified. The Shapiro-Wilk test was used to verify the normal data distribution. Independent samples Of the 18 patients recruited for this study, 13 tested positive for disc provocation and were assigned into the first treatment arm . The remaining 5 patients tested negative and were assigned to the second treatment arm . Although no serious complications or adverse events were recorded, the increased pain reported in some patients 48 h following the procedure resolved within 5–7 days. Overall, no significant differences were detected between both groups with respect to demographics and baseline self-reported test scores obtained prior to discography .p < 8 × 10−6), such that disc provocation-positive patients self-reported on average a pain score of 2.23 (±1.3) at the final follow-up , while disc provocation-negative patients scored 6.8 (±0.44)  (p = 0.2), while disc provocation-negative patients reported 58.8 (±10.99) (2% improvement) (p = 0.6), while disc provocation-negative patients reported 47.6 (±21.47) . Although RAND-36-based changes were not significantly different between both cohorts, an improvement trend was observed in the disc provocation-positive group  . Patientp = 0.8) . Averageovement) . Besidesovement) . Averageve group .p = 0.005) from 76.9% before intervention to 15.4% after a month post-procedure. Among disc provocation-negative patients, the frequency of Percocet use decreased from 60% to 40% albeit without statistical significance (Percocet (oxycodone/acetaminophen) is an opioid analgesic indicated for the relief of moderate to moderately severe pain . Among Iificance .p = 0.001) by 11.45% from 7.44 mm (±2.18 mm) at baseline to 8.26 mm (±2.38 mm) post-treatment (p = 0.001) by 4.66% on average from 16.06 mm (±2.7 mm) at baseline to 16.85 mm (±3.09 mm) post-treatment  in VAS scores with most patients reporting a non-significant 7–94% improvement (31% on average) in BPI scores between baseline and 12 months post-injection. The patients who showed no overall pain amelioration in both tests were either the eldest (patient 4) or had the highest number of positive discs and/or worst disc quality (patients 5 and 13). Between both treatment groups, average VAS and BPI scores differed significantly in favor of IDD patients. Similarly, IDD patients experienced a statistically significant 61.5% drop in opioid use.In terms of functionality, RAND-36 scores improved, albeit non-significantly, by an average of 60% in 10 of 13 IDD patients with 8 of 13 patients reporting better scores in all three tests. With respect to facetogenic pain patients, RAND-36 scores improved non-significantly by 23% on average and in 3 of 5 patients. Between the remaining 2 patients whose RAND-36 scores did not improve (patients 1 and 5), one did not show pain amelioration in VAS and BPI and had the highest baseline (patient 1). In addition, 1 out of 5 patients reported better scores in all three tests (patient 2).Most IDD patients underwent MRI 8–12 months post-injection to anatomically corroborate their ameliorated pain and functionality. On average, IVDs and spinal canal spaces witnessed, respectively, a significant 11.45% increase in height  and a marked 4.66% increase in size . In terms of disc quality, only 6.25% of injected discs worsened, compared to 93.75% that improved or exhibited no changes. Noteworthy, despite choosing the MRI scans with the most integrity for comparison and the blinding of IVD measurements, there exists a possibility of data interference imposed by the involvement of different imaging centers and associated issues of MRI standardization .The therapeutic benefits of BMAC  can be lR = −0.586; p = 0.035; p = 0.02; p = 0.034; Previously, the concentration of intradiscally injected MSCs was shown to positively correlate with overall patient beneficence , 47. ConAlthough our results highlight improved outcomes in most treated spinal DJD patients, the study weaknesses are its: (i) small sample size, (ii) differences in group sizes, (iii) uncontrolled nature of the study, (iv) unstandardized concentration and application of the biologic, and (v) MRI standardization issues. A larger randomized controlled trial with a more robust standard operating procedure is therefore needed to authenticate the efficacy of the investigated biologic in the selective treatment of IDD-associated chronic LBP. Whether higher BMAC volumes and/or multiple injections can improve clinical outcomes and augment statistical power is also an open avenue for future investigations.Lumbar autologous BMAC injections safely and effectively reduced pain and opioid intake, ameliorated mobility, and induced parallel anatomical disc changes in spinal DJD-associated chronic LBP to a greater extent in IDD compared to facetogenic pain subgroups. These data further exhibit the clinical utility of BMAC, which may prove to be a substitute for IDD surgery following wider-scale studies.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.Ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. The patients/participants provided their written informed consent to participate in this study.AE-K analyzed the data and wrote the first draft of the manuscript. CL managed the logistics of the study and participated in the treatment procedures. MR conceived the study, analyzed data, and edited the manuscript. RS conceived and conducted the studies, analyzed the data and edited the manuscript. All authors contributed to the revision of the manuscript.This work was supported by the Merck Frosst Start-up funds (Grant #RH000569) provided by Université de Montréal and by a grant from Merck-Sharp and Dohme Corp. (Grant #SFMERE58) to MR. MR holds a Fonds de la Recherche en Santé du Québec Junior I and II Awards. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.