Radiation-induced mucositis (RIM) pain confers substantial morbidity for head and neck cancer (HNC) patients undergoing radiotherapy alone (RT) or chemoradiotherapy (CRT), often reducing treatment compliance. However, no standard currently exists for the treatment of RIM, and high dose opioid therapy, with its associated side effects and increased risk for chronic opioid use, remains the cornerstone of HNC pain management. The goal of this randomized clinical trial is to compare multimodal analgesia using analgesic medications with different mechanisms of action, to the institutional standard of opioid analgesia alone, in order to ascertain the optimal analgesic regimen for the management of RIM pain in HNC patients.In this open-label, single-institution, non-inferiority, randomized clinical trial, sixty-two patients with mucosal head and neck malignancies treated with curative-intent radiation will be randomized in a 1:1 ratio, stratified by RT or CRT, between Arm 1: opioid analgesia alone as per the institutional standard, or Arm 2: multimodal analgesia using Pregabalin, Acetaminophen, and Naproxen, in addition to opioids, if required. The primary endpoint is the average 11-Numeric Rating Scale (11-NRS) score for pain during the last week of radiation treatment. Secondary endpoints include: average weekly opioid use, duration of opioid requirement, average daily 11-NRS score for pain, average weekly opioids dispensed, quality of life, hospitalizations for analgesic medication-induced complications, time to feeding tube insertion, weight loss, toxicity, treatment interruptions, and death within 3 months of completing RT treatment. Patients are eligible once analgesia is required for moderate 4/10 pain.This study will assess the efficacy and safety of multimodal analgesia and its impact on opioid requirements, clinical outcomes, and quality of life, as a potential new standard treatment for RIM pain in HNC patients undergoing definitive RT or CRT.ClinicalTrials.gov Identifier: NCT04221165. Date of registration: January 9, 2020. Appendix 2 reports the World Health Organization trial registration dataset.The online version contains supplementary material available at 10.1186/s12904-021-00735-0. Patients diagnosed with head and neck malignancies experience substantial morbidity, largely due to pain. Head and neck cancer (HNC) pain is multifaceted. It may be attributed to the malignancy or to its treatment with chemotherapy, radiation, and/or surgery . A signiRIM pain comprises both nociceptive and neuropathic pain. Nociceptive pain encompasses both somatic pain – described as a well-localized sharp, throbbing pain – and visceral pain, characterized by its poorly-localized, dull nature. The nociceptive component of RIM pain is likely explained by radiation-induced direct mucosal injury, inflammation, and fibrosis over time. Nociceptive pain responds primarily to opioids, but also to Acetaminophen and nonsteroidal anti-inflammatory drugs (NSAIDs). Conversely, neuropathic pain is characterized by a burning, tingling sensation as a result of neural injury. The neuropathic pain component of head and neck mucositis may be attributed to tumour infiltration or radiation-induced polyneuropathy . GabapenCurrently, opioid therapy remains the cornerstone of HNC pain management , 10–14. We believe that adequate treatment of the two components of RIM pain – nociceptive and neuropathic – requires a multimodal analgesic approach . MultimoGabapentinoids have been found to alleviate neuropathic pain in diabetic neuropathy, postherpetic neuralgia, trigeminal neuralgia, and post-operative pain , 18. FewNSAIDs may also play a role in decreasing the radiation-induced inflammatory response which contributes to mucositis pain , 10. SynThere is a paucity of evidence guiding the pharmacological management of RIM pain in HNC , 26, 27.Opioid Therapy vs. Multimodal Analgesia in Head and Neck Cancer (OPTIMAL-HN) randomized clinical trial are to:Determine whether multimodal analgesia using Pregabalin, Acetaminophen, and Naproxen, in addition to opioids, is non-inferior in terms of pain relief, to the institutional standard of opioid analgesia alone.Compare the safety, efficacy, quality of life outcomes, toxicity, duration of and quantity of opioid use for both analgesic regimens.The objectives of the Our hypothesis is that in HNC patients undergoing curative-intent RT or CRT, multimodal analgesia will be non-inferior to standard opioid analgesia alone for average pain scores during the last week of radiation treatment and will reduce the duration and quantity of opioid requirements.This study is an open-label, single-institution, randomized clinical trial designed to assess the non-inferiority of two different analgesic regimens for RIM pain. The required sample size is 62 patients. Patients will be randomized to either opioid analgesia alone Arm 1) or multimodal analgesia in the form of regular Pregabalin, Acetaminophen, and Naproxen in addition to opioids (Arm 2) in a 1:1 ratio, stratified by concurrent chemotherapy, once a threshold of moderate 4/10 pain is reached  for Pain during last week of treatment◦ Defined as the average weekly total opioid dose in oral morphine equivalent dosing (OMED) from date of randomization to 6 weeks after completion of radiation treatmentAverage Weekly Opioid Use◦ Defined as the time from the start of opioid treatment after date of randomization to the time of stopping opioid analgesia, in daysDuration of Opioid Requirement◦ Documented daily from date of randomization to 6 weeks after completion of radiation treatmentAverage Daily 11-NRS for Pain◦ Assessed with European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core module (QLQ-C30) , and HeaQuality of Life (QoL)◦ Defined as the average weekly total opioid dose dispensed by the pharmacy in OMED from date of randomization to 6 weeks after completion of radiation treatmentAverage Weekly Opioids Dispensed◦ Febrile neutropenia◦ Other serious infection requiring treatment with intravenous antibiotics◦ Gastrointestinal bleeding attributed to NSAID use◦ Myocardial infarction◦ Stroke■ an increase in serum creatinine by ≥26.5 μmol/L within 48 h, OR■ an increase in serum creatinine to ≥1.5 times the baseline value which is known or presumed to have occurred within the prior 7 days◦ Acute kidney injury defined by the KDIGO Guidelines  as:■ anAdmissions for any of the following, during radiation or within 3 months of radiation completion:◦ Defined as time to feeding tube insertion after randomization, in daysTime to feeding tube (e.g. gastrostomy-tube or nasogastric-tube) insertionWeight loss from randomization to end of radiation treatmentRates of pre-specified Common Toxicity Criteria for Adverse Events (CTC-AE) toxicitiesRadiation or chemotherapy treatment interruptionsDeath during or within 3 months after completion of radiation treatmentAge 18 years or olderWilling to provide consentHistologically confirmed mucosal head and neck malignancyUndergoing CRT or RT alone with a planned total radiation dose of 50 Gy or greaterEastern Cooperative Oncology Group (ECOG) performance status 0–2Life expectancy > 6 monthsOnset of 4/10 pain on the 11-NRS that is localized to the mucosa of the mouth or throat, before or during radiation treatment, that is not caused by a current oral candidiasis infection.Ability to take pills, either by mouth or crushed via nasogastric-tube or gastrostomy-tubeAbility to complete the study QoL questionnaires and pain diaryAbility to sign consent without requirement for a substitute decision makerSkin and salivary gland malignanciesHigh daily opioid use  for more than 7 days at time of enrollmentConcurrent second active malignancyPregnant or lactating womenPsychological disorder requiring pharmacologic treatmentRegular systemic steroid useRegular anticonvulsant, neuropathic or antidepressant useRenal ImpairmentDefined as creatinine clearance < 60 mL/min9.Liver DysfunctionDefined as total bilirubin > 34.2 μmol/L10.Documented true allergy or contraindications to Acetaminophen, NSAIDs, Pregabalin, pantoprazole or opioids11.History of upper gastrointestinal bleed12.Known bleeding disorder13.History of or current substance use disorderThe London Health Sciences Centre institutional standard for analgesic therapy in HNC patients undergoing RT or CRT is opioids, either with morphine or hydromorphone. Opioid analgesia for patients in Arm 1 will follow this institutional standard with initiation of opioids for moderate to severe pain, as per the World Health Organization (WHO) analgesic ladder. The use of Acetaminophen and NSAIDs in this arm will not be routinely recommended as that has not been the historic standard, due to concerns of masking a fever which could herald an infection.Moderate pain ):Low-dose morphine or hydromorphone may be prescribed at physician’s discretion.Severe pain :Regular strong opioids including morphine, oxycodone, hydromorphone, or fentanyl may be prescribed at physician’s discretion.Prescription of Methadone, Buprenorphine are discouraged since morphine dose equivalence is not well established for these opioids.Oxycodone/acetaminophen, codeine/acetaminophen or tramadol hydrochloride/ acetaminophen combination pills are also discouraged to limit the use of acetaminophen in this arm so as to prevent masking fevers.After initiation, the opioid dose may be titrated as necessary.An opioid rotation may be performed if either 1) opioid toxicity or 2) reduced analgesic efficacy despite dose escalation, are detected.Opioid toxicity may take the form of nausea, vomiting, constipation, sedation, respiratory depression, confusion, drowsiness, or hallucinations.A regular long-acting or regular short-acting opioid may be prescribed with breakthrough doses for transient pain exacerbations.The breakthrough dose should be calculated as 10% of the total 24-h opioid dose requirement.If more than 4–5 breakthrough doses are required daily for adequate pain relief, the baseline regular short-acting or long-acting opioid dose should be adjusted accordingly.The prescription of local analgesia in the form of creams or mouthwashes is left to the discretion of the treating physician since no clinically significant difference in pain relief has been observed between Doxepin Mouthwash or Diphenhydramine-Lidocaine-Antacid Mouthwash compared with placebo .Extended release opioid tablets may not be prescribed to feeding-tube dependent patients as crushing impedes their slow-release mechanism, thereby altering opioid absorption and efficacy.It is highly recommended to prescribe a concurrent laxative with opioids to reduce the morbidity of opioid-induced constipation. Patients will be provided with standard teaching materials on constipation management.Recommended opioid prescribing guidelines are as follows:PAiN Relief Regimen  in addition to opioids, if the latter become required. At the time of randomization, the following will be prescribed for analgesia using a standardized prescription template provided on the institutional electronic medical record:Pregabalin:▪ Step 1: 50 mg by mouth (PO) twice daily (BID) for 5 days▪ Step 2: 100 mg PO BID for 5 days▪ Step 3: 150 mg PO BID as a minimum maintenance dose if tolerated, until pain subsides▪ If the patient has not attained adequate pain relief, the dose may be escalated to 200 mg PO BID for 5 days, 250 mg PO BID for 5 days, and 300 mg PO BID.▪ Further dosage adjustments for tolerability and pain relief are to be titrated and optimized by the treating physician as needed. For example, the dose may be de-escalated to 25 mg or 50 mg PO BID if side effects occur.▪ Taken regularly during radiation treatment until pain subsidesMaximum dose: 600 mg/day2)Acetaminophen▪ 1000 mg PO thrice daily (TID) regularly  during radiation treatment and continued until pain subsidesPatients will be advised to take their temperature before each dose, only if they feel unwell or if they experience any infectious symptomsMaximum dose: 3000 mg/day3)Naproxen with concurrent Proton Pump Inhibitor (PPI)▪ 250 or 500 mg PO BID regularly, titrated for pain relief .Opioids are to be initiated when pain control on this regimen is inadequate despite appropriate dose titration. The opioid prescribing guidelines outlined above will be adhered to in both arms.Patients are encouraged to continue the PAiN relief regimen during opioid use to benefit from synergistic effects. However, if a patient is deriving no benefit from the PAiN relief regimen in the opinion of the treating physician, then they may continue on opioids alone.REDCap will be used to complete the patient enrollment form and provide patient randomization information instantaneously in clinic. This will allow the patient to receive the appropriate prescriptions for analgesia at the same visit in order to alleviate their pain promptly. A hired research radiation therapist will enroll, randomize and collect the relevant data for study participants using the REDCap system.Pain score data will be collected using the 11-NRS for pain. Patients will be asked to document average daily 11-NRS for pain in a pain diary which will be distributed at the time of enrollment and collected at the first follow-up visit, and 6 weeks after the completion of their RT treatment. Daily pain scores from the last 7 days of the radiation treatment course will be used to calculate the primary endpoint. This allows for capturing of pain scores when the patients have received most of the RT dose and when they are most symptomatic. Capturing data for several days takes pain variability into account and allows for a more accurate depiction of pain at the end of treatment. In order to ensure the preservation of pain score data, photocopies of the pain diary will be made for record-keeping purposes, every week, while the patient is receiving treatment.Patients will also be asked to purchase study analgesic medications from the London Regional Cancer Program (LRCP) pharmacy only, in order to facilitate capture of total opioids dispensed as a secondary endpoint.Patients will be instructed to bring in all study-related opioid medications on a weekly basis during their treatment, both empty and non-empty opioid bottles. The bottles indicate the name of the drug, the dose, as well as the total number of pills or volume dispensed for that specific bottle. This will all be noted for the empty opioid bottles and contents of empty opioid bottles will be considered consumed. Six weeks after the completion of RT, all remaining opioid bottles will be brought in by patients without exception, and the total opioid dose consumed based on empty bottles and remaining pills or opioid volume, will be recorded. The total opioid dose consumed by every patient from randomization until 6 weeks after the completion of radiotherapy will therefore be collected, tabulated, and converted into OMED, thereby allowing for the calculation of the secondary endpoint: average weekly opioid use. All excess unused opioids will immediately be returned to the patient once the data is collected. Patients will also be asked to indicate in the pain diary, the last day they required opioids for pain relief.For missing data, the principle of the last observation carried forward will be applied whereby data from the previous week’s pain scores and analgesic drug use patterns will be substituted as an estimate.Patient charts will be reviewed to document and capture hospitalizations, reasons for admission, and feeding tube insertions.Written informed consent will be obtained from all participants. A brief consent video will be shown to eligible patients, introducing them to the clinical trial and facilitating the informed consent process.Prominent signs will be placed in the LRCP patient review physician area indicating that if HNC patients have mucositis pain ≥4/10, to consider this trial, with contact information for study staff. Radiation therapists, nurses and nurse-practitioners caring for HNC patients are few with only a small rotation. They will be educated about the trial to facilitate candidate identification and accrual. During the consent process for radiation in the multi-disciplinary team clinic, the Clinical Specialist Radiation Therapist will mention the trial to patients to inform them of the option of the trial for pain management so they are aware they may be asked about it. If accrual stagnates despite this, the protocol will be amended to include signs in patients’ rooms in patient review stating: “Having pain because of head and neck radiation? Ask about the OPTIMAL trial.”To guard against accrual difficulties, the first six months of this protocol will be considered a feasibility phase. The study will proceed as designed during this phase, but monthly accrual totals will be emailed to the PIs. The accrual and randomization of the first 10 patients will be considered a feasibility phase. These first 10 patients must be enrolled within 6 months from the date of activation for the trial to be considered feasible to continue to full accrual. If this target is not met, the study investigators will meet with the Clinical Research Unit (CRU) leadership and make a joint decision as to whether the trial should be stopped, or if reasonable trial modifications could be instituted and another 6 months of accrual time be allowed to reach an accrual goal of 10 patients during that second period. Modifications which may be considered include: 1) a meeting before each patient review clinic with the nurses, nurse practitioners, and a clinical research coordinator to identify potentially eligible patients, and 2) a strategy meeting with head and neck radiation oncologists to further increase accrual. Patients participating in this clinical trial may also partake in other clinical trials if the trial protocol does not exclude patients enrolled in other trials.Adverse Event (AE) or reaction is defined as any unfavourable and unintended sign, symptom, abnormal laboratory finding, or disease temporally associated with the use of a medical treatment or procedure that may or may not be considered related to the treatment offered on trial.Serious Adverse Event (SAE) or reaction as includes any untoward medical occurrence that at any dose results in death, persistent or significant disability/incapacity, is life-threatening, or requires in-patient hospitalization or prolongation of existing hospitalization.Unexpected adverse reactions are of a nature and severity not consistent with the applicable prescribed medication in question, or occurs with more than expected frequency. Such reactions will be reported within 24 h.All AEs, including the pre-specified AEs listed in Table An adverse event or reaction is considered related to the research intervention  if there is a reasonable possibility that the reaction or event may have been caused by the research intervention.The relationship of an AE to the study treatment  will be described as unrelated, unlikely, possible, probable, and definitely related. Definitions of each have been previously published .The severity of AEs will be evaluated using the CTC-AE version 5.0 grading scale .Grade 1: Mild.Grade 2: Moderate.Grade 3: Severe.Grade 4: Life-threatening or disabling.Grade 5: Death.Note: The term “severe” is a measure of intensity of the symptoms, which may not necessarily be clinically concerning, as deemed by the treating physician.unexpected, related serious adverse drug reactions to the Central Office within 24 h of discovery, and to regulatory authority (ies).SAEs are to be reported using the SAE report form in REDCap. It is the responsibility of the Principal Investigator (PI) to report all SAEs to the REB as per local REB requirements. The PI should also comply with the applicable regulatory requirement(s) related to the reporting of Given that both arms of this trial represent treatment modalities that are in use as a standard at cancer centres worldwide, no DSMC will be used for this trial.Subjects may voluntarily discontinue participation in the study at any time. Subjects removed from the study due to an adverse event should be observed by the treating physician at their discretion. All end-of-study investigations should also be obtained, whenever possible, provided the patient consents to do so.Patients will be seen in follow-up 6 ± 2 weeks and 3 months after radiation treatment completion. Requirements for weight measurement, 11-NRS pain score, analgesic use, and CTC-AE documentation, as well as QoL questionnaires, and laboratory investigations are outlined in Table Laboratory investigations will be performed at the time of randomization, once during the last week of radiation treatment, once at the 6 to 8-week follow-up and once at the 3-month follow-up appointment. The requirement for further laboratory investigations will be left at the discretion of the treating physician and will be dictated by the patient’s clinical state. For baseline laboratory investigations, values available within 7 days of the day of randomization may be used if available.The study will employ a 1:1 randomization between Arm 1: Arm 2, stratified by use of concurrent chemotherapy . A permuted block design with one stratification factor for concurrent chemotherapy will be used with the size of the blocks known only to the statistician. Randomization will be performed on the day of enrollment using REDCap.The primary endpoint is defined as the average 11-NRS daily pain score during the last 7 days of the radiation treatment course. We assume a non-inferiority margin of 1 point on the 11-NRS for pain and a standard deviation of 1.5 in both arms. Using a two-sample T-test for non-inferiority, a one-sided alpha of 0.05, 80% power, and an estimated dropout rate of 6%, a total of 62 patients will be required to power this trial (31 patients in each arm).The study projects accrual over 24 months, with 3 months of additional follow-up. Accrual targets are as follows: 31 patients per year.n = 31). At this analysis, the PIs will be blinded to the identity of each treatment arm and provided with the average daily 11-NRS for pain during the last 7 days of treatment and the standard deviation, for each arm. If the standard deviation differs substantially from the assumed standard deviation in the sample size calculation, the sample size may be increased or decreased at the discretion of the PIs, in order to maintain statistical power for non-inferiority between arms. No statistical comparisons will take place at the interim analysis.In order to assess the sample size calculation assumptions, one interim analysis will take place after half of the patients have been accrued and have completed their 6-week follow-up visit .Time to feeding tube (e.g. gastrostomy-tube or nasogastric-tube) insertion will be defined as time to feeding tube insertion after randomization, in days. Weight loss from randomization to end of radiation treatment, radiation or chemotherapy treatment interruptions, and death during or within 3 months after completion of radiation treatment will be collected.Differences between treatment arms for continuous endpoints (e.g. duration of opioid requirement) will be compared using the two-sample T-test for non-inferiority. Differences between treatment arms for categorical or binary end points including CTC-AE rates of grade 2 or higher and admissions will be compared using the Chi-square test or Fisher’s Exact test as appropriate. Differences between treatment arms for time-to-event end points (e.g. time to gastrostomy-tube insertion) will be compared using Kaplan-Meier estimates and the stratified log-rank test (adjusting for stratification by concurrent chemotherapy). Linear mixed effects models will be used to test for non-inferiority between treatment arms for the average daily 11-NRS for pain (from the start of randomization to 6 weeks after completion of radiation treatment). Any tests which meet non-inferiority criteria will be tested for superiority .Subgroup analyses will be performed to assess the primary and secondary endpoints based on the stratification factor (chemotherapy), disease site, and smoking status.The PIs have obtained ethical approval and clinical trial authorization from the Western University Health Science Research Ethics Board (Project ID: 115201).Any modifications to the trial protocol must be approved and enacted by the PI . Protocol amendments will be communicated to all participating centres, investigators, IRBs, and trial registries by the PIs.The consent video as well as the written informed consent form that will be provided to potential study subjects was approved by the IRB/REB and adhere to ICH GCP and the ethical principles that have their origin in the Declaration of Helsinki. Informed consent from each subject prior to beginning any study procedures and treatment(s) will be obtained by the treating physician and confirmed by the hired radiation therapist. Patients enrolled will be informed of all aspects of the study, including the potential risks and benefits involved. They will be given ample time and opportunity to ask questions prior to deciding about participating in the study and be informed that participation in the study is voluntary and that they are completely free to refuse to enter the study or to withdraw from it at any time, for any reason.The informed consent must be signed and dated by the patient and by the person who conducted the informed consent discussion. A copy of the signed and dated written informed consent form will be given to the patient. The process of obtaining informed consent will be documented in the patient source documents.All data will be stored on REDCap, which is a secure web application for building and managing online databases commonly used in the clinical trials research community . OngoingTrial results will remain embargoed until conference presentation of an abstract or until information release is authorized.Upon completion of this project, the results will be presented at national and international conferences and subsequently published in a peer-reviewed journal. Authorship of the trial abstract and ultimately the full manuscript will be decided by the PIs at the time of submission. Professional writers will not be used for either abstract or manuscript preparation.Final decisions on authorship will be made by the PIs and will be commensurate with the amount of individual contribution, including study design, patient accrual, data analysis and interpretation and manuscript drafting.Any communication or publication of trial results will be led by the PIs and is expected to occur within 1 year of the primary analysis.The clinical trial will pay for the cost of medications for a total of $250 per patient. It is possible that the medications may cost more or less than this, depending on the amount of medication the participant may need, or if they have third-party coverage. Participants will only receive $250 regardless of the cost of their medications. This will be paid by cheque, which will be mailed to their home address once the patient is enrolled, randomized, and has been provided with a prescription for analgesic medications. The participants’ address will be obtained from their medical record. It will not be collected.Deidentified patient data from this trial will not be shared publicly, however, the full manuscript detailing the clinical trial results will be published along with the primary analysis of the outcomes.Patients with HNC who are undergoing definitive RT with or without chemotherapy suffer significantly from RIM pain , 3. Two OPTIMAL-HN is the first randomized clinical trial to assess the efficacy of multimodal analgesia for the management of RIM pain in HNC patients. The multimodal analgesia arm was inspired by the post-operative multimodal analgesia paradigm applied across most surgical specialties in modern practice to reduce post-operative opioid requirements whilst optimizing pain relief . The mulThe results of OPTIMAL-HN may help establish multimodal analgesia as a new treatment paradigm in the management of RIM pain in HNC patients receiving RT. This paradigm is based on utilizing analgesic medications from different classes and various mechanisms of action with the objective of targeting both the nociceptive and neuropathic components of RIM pain.Additional file 1. Pain Diary.


Stereotactic radiosurgery (SRS) is an effective treatment for trigeminal neuralgia (TN). Nevertheless, a proportion of patients will experience recurrence and treatment-related sensory disturbances. In order to evaluate the predictors of efficacy and safety of image-guided non-isocentric radiosurgery, we analyzed the impact of trigeminal nerve volume and the nerve dose/volume relationship, together with relevant clinical characteristics.Two-hundred and ninety-six procedures were performed on 262 patients at three centers. In 17 patients the TN was secondary to multiple sclerosis (MS). Trigeminal pain and sensory disturbances were classified according to the Barrow Neurological Institute (BNI) scale. Pain-free-intervals were investigated using Kaplan Meier analyses. Univariate and multivariate Cox regression analyses were performed to identify predictors.3, and median prescription dose 60 Gy. Pain control rate (BNI I-III) at 6, 12, 24, 36, 48, and 60 months were 96.8, 90.9, 84.2, 81.4, 74.2, and 71.2%, respectively. Overall, 18% of patients developed sensory disturbances. Patients with volume ≥ 30 mm3 were more likely to maintain pain relief (p = 0.031), and low integral dose (< 1.4 mJ) tended to be associated with more pain recurrence than intermediate (1.4–2.7 mJ) or high integral dose . MS, integral dose, and mean dose were the factors associated with pain recurrence, while re-irradiation and MS were predictors for sensory disturbance in the multivariate analysis.The median follow-up period was 38 months, median maximal dose 72.4 Gy, median target nerve volume 25 mmThe dose to nerve volume ratio is predictive of pain recurrence in TN, and re-irradiation has a major impact on the development of sensory disturbances after non-isocentric SRS. Interestingly, the integral dose may differ significantly in treatments using apparently similar dose and volume constraints. Trigeminal neuralgia (TN) is the most common cranio-facial pain syndrome. Medical therapy, usually based on carbamazepine, is the first treatment option, but effective pain control often requires doses associated with severe side effects. Surgical treatment option is considered when drug therapy deems ineffective in controlling pain and/or causes severe side effects ; thus, sThe aim of our study was to evaluate predictors of efficacy and safety of image-guided robotic radiosurgery in a large multicentric patient cohort.The patient data were retrospectively analyzed; thus, consent forms were deemed unnecessary. Data were pooled from two Italian  and one German  centers. The retrospective analysis was approved by the Ethics Committee Campus Charité Mitte (EA1/233/18) and by Comitato Etico Interaziendale Messina (80/19).Patients with TN, as defined by the International Headache Society (2003), who were treated using non-isocentric, image-guided robotic radiosurgery for medically resistant pain between 2010 and 2016 (center A), 2013–2018 (center B), and 2011–2018 (center C) were included in this study.mean, Dmax), target nerve volume, prescription dose (PD), and integral dose  were the parameters investigated.We gathered data regarding the presence of multiple sclerosis (MS), re-irradiation, decision making for SRS, clinical outcome, and therapy-associated morbidity with a focus on sensory dysfunctions. Mean and maximal treatment dose (D3)  as described before . The tre3) Fig. . The tarTreatment planning, determination of target and dose, and treatment delivery are described in detail in Additional file Clinical follow-up was carried out 3–6 months after CK-SRS and then once yearly. The latest follow-up was included in this study. The focus of the follow-up was to verify the pain relief and new onset of facial numbness; accordingly, the endpoints analyzed were: i) pain relief, ii) occurrence of sensory disturbance, and iii) rate of pain recurrence.Pain and hypoesthesia evaluation were scored using the Barrow Neurological Institute (BNI) scales for pain I-V and for hypoesthesia I-IV, respectively . We dichOverall, the entire pain-free interval was examined using Kaplan Meier analysis. Pain-free intervals for 6, 12, 24, 36, 48, and 60 months were calculated. Group comparison was carried out using the log-rank test. In order to assess risk factors potentially associated with pain relapse or occurrence of numbness, univariate and multivariate Cox regression analyses were performed using clinically selected variables. The selection process of variables for the multiple regression model included two steps as described before .The treatment parameters were reported as mean (standard deviation [SD]) and median. SPSS version 25.0.  was used for statistical analyses.p-values, described as significant if < 0.05, are meant as indicators and should not be interpreted as confirmatory.As this was an exploratory study where a series of group comparisons, regression analyses, and tests of normal distribution for continuous variables were performed, the two-sided Patient characteristics are listed in Table n = 17) of the patients. The median age at therapy was 64 years (range 22–91 years).There was overall a minor female predominance (1.4:1.0). MS was diagnosed in 6.5% .mean, Dmax, and ID data for the three different institutions are summarized in Table max, and ID.The treatment plans and target nerve volume, PD, DFor this analysis, we focused on the response to the first SRS treatment and excluded the retreated patients. Actuarial pain control rates could be acquired in 88.2% of the cases (231 patients). In 54.1% of the patients, full pain control (BNI I) could be achieved (Table We identified 34 SRS re-irradiations in our cohort. None of the retreated patients had MS. The majority of the patients (70%) suffered from new onset numbness after re-irradiation. Actuarial pain control rates (BNI class I-III) for re-irradiation at 6, 12, 24, 36, 48, and 60 months were 91.2, 88.1, 88.1, 88.1, 79.8, and 79.8%, respectively ; Dmean: HR = 1.038, CI = 0.999–1.079). The probability of maintaining pain relief was then compared according to the categorized treatment parameters (Table <30 vs. ≥30 mm3), ID , Dmean (< 63 vs. ≥ 63 Gy), Dmax (< 72 vs. ≥ 72 Gy), and PD (< 58 vs. ≥ 58 Gy). Here, only the volume and ID comparisons resulted in significant differences. Patients with volume above 30 mm3 were less likely to experience pain recurrence .Re-irradiation using CyberKnife-SRS and presence of MS were independent predictors for the development of bothersome post-treatment numbness in the univariate and multivariate analysis. We also detected a minor but still significant association of isodose in the univariate analysis Table . As with3 and an ID > 1.4 mJ offer better outlooks of sustained pain control. MS as a cause of TN was an independent prognosticator of treatment failure and shorter pain free interval. Furthermore, re-irradiation and presence of MS were independent predictors of the occurrence of numbness.This study was aimed at identifying irradiation parameters that may predict efficacy and safety of image-guided non-isocentric radiosurgery for treatment of TN. For this purpose, we analyzed the impact of target nerve volume, target dose, and the dose/volume relationship, together with relevant clinical characteristics, in a large multicenter German-Italian cohort of patients with a follow-up interval of up to 10 years. As expected, smaller target volume and lower ID were associated with worse pain outcome. In particular, we suggest that a target volume around 30 mmn = 138 pts.), who reported 76% pain relief after 3 years compared to 81.4% in the present cohort [The results of this series in terms of pain relief are consistent with those previously reported and suggest that image-guided robotic radiosurgery represents an effective treatment of TN , 10, 17.t cohort . Furthert cohort .Tuleasca et al. summarized various treatment regimens regarding dose and target delineation of SRS in the treatment of TN . RomanelIn 2008 Villavicencio et al.  publishe3), and a lower PD (< 58 vs. > 58 Gy) as predictors for treatment failure in univariate analysis, while none of these factors remained significant in multivariate analysis [3 were more likely to suffer pain relapse. In addition, this was also observed for patients with low ID (< 1.4 mJ). The ID is the product of the mean dose and the target nerve volume and therefore represents an ideal parameter for non-isocentric treatments in which not only the dose, but also the target volume can be modulated to fit individual anatomy and clinical objectives. Mousavi et al. [Romanelli et al. have recently found a shorter treated nerve length (< 6 vs. 6 mm), a smaller treated nerve volume (< 30 vs. > 30 mmanalysis . Those ri et al.  investigi et al. , we catei et al. , 31.Finally, we identified re-irradiation as the major independent predictor for sensory disturbance, with almost a six times higher risk after CKS as already described by Romanelli et al.  In our uOur follow-up length is longer than that of most studies focusing on the efficacy of SRS in TN published so far –17, but mean, and nerve volume are apparently relevant, as they may differ significantly in treatments using apparently similar dose and volume constraints. Our study supports the concept of personalized radiosurgery for the best treatment outcome and warrants future prospective studies.This study represents the largest multicenter frameless CKS series conducted to analyze possible treatment parameters as predictors of outcome in addition to the description of efficacy and safety profile of the technique. Our study confirmed that single treatment parameters are not enough to predict treatment efficacy of SRS in TN. The ID, DAdditional file 1.


Achieving optimal analgesia with few side effects is the goal of pain management after cesarean delivery. Intrathecal (IT) morphine is the current standard but ultrasound-guided quadratus lumborum block (QLB) may offer superior pain control with fewer side effects. This study compared the pain-free period after cesarean delivery among parturients who received spinal block with IT morphine, with IT morphine and bilateral QLB, or only bilateral QLB.Parturients having elective cesarean delivery under spinal block were randomized and allocated into IT morphine 0.2 mg with sham QLB (Group IT), IT morphine 0.2 mg and bilateral QLB with 0.25% bupivacaine 25 ml in each side (Group IT+QLB), or bilateral QLB with 0.25% bupivacaine 25 ml in each side (Group QLB). A PCA pump was connected after completion of the QLB or sham block. The first time to PCA morphine requirement was recorded and compared.p < 0.001)]. The median  amount of morphine required during 24 h was 5.5 (0–25) in Group IT vs. 5.0 (0–36) in IT+QLB vs. 17.5 (1–40) mg in Group QLB (p < 0.001). In the final analysis the median pain-free period was 2.50 (1.23–3.77) hours (95%CI) in Group IT (n = 27) vs. 8.02 (5.96–10.07) in IT+QLB (n = 28). (p = 0.027).Eighty parturients were included. Analysis of Group QLB was terminated early because at the second interim analysis, median pain-free period was significantly shorter in Group QLB [hours (95%CI): 2.50 (1.04–3.96) in Group IT vs. 7.75 (5.67–9.83) in IT+QLB vs. 1.75 (0.75–2.75) in QLB (US-QLB used in conjunction with IT morphine yielded a statistically significant longer median pain-free period compared with standard IT morphine alone. However, QLB alone provided inferior pain control compared with standard IT morphine. When combined with IT morphine, QLB could provide additional analgesic benefit as a part of multimodal analgesic regimen, especially during the early postoperative period.ClinicalTrials.gov no. NCT03199170 Date registered on June 22, 2017. Prospectively registered. Achieving optimal analgesia with the fewest possible side effects is the goal of postoperative pain management after cesarean delivery. Effective pain relief improves maternal ambulation and reduces the risk of thromboembolism, accelerates and facilitates breastfeeding, improves mother-child interaction, and decreases the risk of chronic pain and depression –4. IntraAs a result of recent advances in ultrasound (US)-guided regional anesthesia, the popularity of abdominal wall block has dramatically increased during the last decade. US-guided transversus abdominis plane block (TAPB) has been shown to be an effective component of multimodal analgesia in parturients who are unable to receive neuraxial opioids or whose pain is not adequately controlled. However, there is no significant analgesic or opioid-sparing benefit of routine TAPB after cesarean delivery in patients who receive intrathecal morphine .US-guided quadratus lumborum block (QLB) reflects the continued evolution of US-guided TAPB. The upward spreading of local anesthetic into the thoracic paravertebral space –13 to meAccordingly, we aimed to evaluate whether US-guided posterior QLB (QLB type 2) at the lumbar interfascial triangle , 18 coulClinicalTrials.gov (reg. no. NCT03199170).This study was conducted during March 2017 to October 2018. The Siriraj Institutional Review Board (SiRB) of the Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok, Thailand approved the study (COA no. 817/2559[EC1]). The study report has been prepared in accordance with the Consolidated Standards of Reporting Trials (CONSORT) guidelines. Prior written informed consent was obtained. Parturients were eligible if they were having an elective cesarean delivery with a low transverse incision under spinal block. Inclusion criteria were American Society of Anesthesiologists physical status I or II and a normal singleton pregnancy with a gestation of at least 37 weeks. Patients with a history of chronic pain, allergy to the study drugs , local infection at one or both flank areas (the puncture sites for QLB), requiring additional analgesic drugs and/or general anesthesia to complete operation or having an inability to comprehend or use the numerical rating scale (NRS) for pain assessment and/or the patient-controlled analgesia (PCA) pump were excluded. This trial was registered with A computer-generated block of six randomization scheme was used to allocate parturients into each of three groups: IT morphine 0.2 mg with sham QLB (Group IT), IT morphine 0.2 mg and bilateral QLB with 0.25% bupivacaine 25 ml and adrenaline 1:250,000 in each side (Group IT+QLB), or bilateral QLB with 0.25% bupivacaine 25 ml and adrenaline 1:250,000 in each side (Group QLB). Randomization assignments were placed in envelopes and sealed. On the day of the operation, the sealed opaque envelope containing that patient’s group allocation was opened before the patient was taken into the operating theater. Surgeons, patients, and the research nurse who evaluated patients postoperatively were all blinded to the group assignment. The anesthesiologist caring for the woman and the anesthesiologist performing the QLB were not blinded.All patients were instructed how to use the Numeric Rating Scale (NRS)  for pain assessment during the preoperative visit. Pain with movement was assessed during ambulation. Patients received 150 mg ranitidine by mouth in the evening before surgery, and again in the morning of surgery. With the patient in the lateral decubitus or sitting position, spinal block was performed at the levels of L3–4 and L4–5 intervertebral spaces using 0.5% hyperbaric bupivacaine 2–2.2 ml depending on the judgment of the anesthesiologist responsible for that patient. After the baby was delivered, ondansetron 8 mg was given intravenously. Before ultrasound scanning and performing QLB blocks, pinprick sensation test was used to check the patient’s pain level. All QLB and sham blocks were performed in the postoperative care unit immediately after cesarean delivery, before the patients experienced any postoperative pain or pain during the QLB procedure. One anesthesiologist (PP) with more than 5 years of experience in performing US-guided regional anesthesia who not involve with the data collection performed all blocks. Postoperatively, all parturients received regular acetaminophen  and ibuprofen . For breakthrough pain, intravenous morphine via a patient-controlled analgesia (PCA) pump was used with the setting of bolus morphine 1 mg, a lockout of 5 min, and a 4-h-maximum dose of 30 mg.A FUJIFILM SonoSite Edge ultrasound unit  with a 2–5 MHz curved transducer was used to identify all relevant muscles and fascial layers. Patients were positioned in the supine position, and both iliac crests were slightly elevated by pillows placed underneath the patient’s hips. The US transducer was placed in the transverse plane on the flank of the patient cranially to the iliac crest at the level of the L3 or L4 transverse process. The muscle layers of the abdominal wall were identified. The transducer was then moved posteriorly to visualize the aponeurosis of the transversus abdominis muscle. The pararenal fat and the quadratus lumborum muscle were imaged medial to the aponeurosis. A 20-gauge 80 mm Stimuplex® Ultra 360 needle  was advanced in-plane under US guidance in an anteroposterior direction through the muscle layers of the abdominal wall. The needle tip was advanced and aimed to the lumbar interfascial triangle on the posterolateral aspect of the quadratus lumborum muscle as described by Blanco R . One to A PCA pump was connected to each parturient after completion of the QLB or sham block for 48 h (study period). All parturients were instructed to press the hand-held button to activate the PCA when they experienced pain-related discomfort an NRS score of 4 out of 10. Parturients were asked to record their level of pain at 4, 6, 12, 24, and 48 h after QLB or sham block. A research nurse that was blinded to group assignment assessed and confirmed each parturient’s report the next day. The puncture sites were also examined, and the patient was assessed for block-related complications. The time to first PCA use, daily PCA demand, delivery counts, and cumulative dose were extracted from the internal memory of the pump.The severity and management of all complications were recorded and analyzed. Sedation was rated as 0 (none), 1 , 2 , 3 , or S . Respiratory depression was defined as a respiratory rate lower than 8 breaths/min, and was rated as absent or present. Nausea, vomiting, and pruritus were rated as 0 (none), 1 , 2 (moderate with resolution via medication), or 3 (severe and persistent despite medication). Muscle weakness of the lower extremities and sign of local anesthetic systemic toxicity, both of which have been reported as side effects from QLB in previous reports, were also asked and examined. Straight leg raising test to evaluate quadriceps was used.Since QLB is a relatively new technique for post-cesarean analgesia at our center, interim analysis was performed after 10 and 20 women were recruited into each study arm. The aim is to compare analgesia with the current standard analgesic technique and to ensure patient safety. The statistician involved in the analysis remained blinded to the group allocation until the final analysis was complete.The primary hypothesis was that the pain-free period would be longer when QLB was combined with IT morphine compared to standard IT morphine alone. The reference data we used to calculate our sample size was reported by Triyasunant, et al. That study found the median pain-free period  after cesarean delivery under IT morphine 0.2 mg alone to be 2 h (120 min) . We consp-value of less than 0.05 was considered statistically significant. Statistical analyses were performed using SPSS Statistics version 18 . The interim analyses were performed after 10 and 20 women were recruited into each arm by a blinded statistician using Kaplan-Meier curve to evaluate the pain-free period, and using one-way ANOVA to compare the amount of morphine consumption during 24-h period after cesarean delivery.Continuous data are reported as mean ± standard deviation for normally distributed data, and as median and interquartile range for non-normally distributed data. Categorical data are reported as frequency and percentage. Comparisons between groups were performed using the independent t-test, Chi-square test, Mann-Whitney U test, one-way analysis of variance (ANOVA), and the Kruskal-Wallis test. A Kaplan-Meier curve for time to first PCA was constructed and tested among the three groups using log-rank test to give equal weight to all differences. At the final analysis comparing two Kaplan-Meier curves notable differences in the early time point were apparent and therefore results from the Gehan-Breslow and the Tarone-Ware tests using different weights were also presented. Gehan-Breslow test was chosen because it gives more weight to earlier failures (require PCA morphine), while log-rank test gives equal weight to all failures and Tarone-Ware test falls in between. A Eighty-five parturients were invited to participate in this study. Five parturients were excluded because of planning for midline incision due to their diagnosis. The remaining 80 parturients were randomized into three arms using block of six randomization until the second interim analysis, at which point the QLB group was terminated. The interim analyses were performed after 10 and 20 women were recruited to each arm. Analysis of Group QLB was terminated early because Kaplan-Meier survival analysis showed the elapsed time between completion of the block and the first administration of morphine by PCA (pain-free period) to be significantly shorter in Group QLB at the second interim analysis. A CONSORT flow diagram describing the study protocol is shown in Fig. p = 0.002). Log-rank test for pairwise analysis revealed the differences in Group IT vs. IT+QLB (p = 0.318), IT vs. QLB (p = 0.166), and IT+QLB vs. QLB (p < 0.001). The mean amount of morphine required during 24 h was 10.70 ± 9.04 mg in Group IT vs. 7.40 ± 10.35 IT+QLB vs. 17.00 ± 5.94 QLB (p = 0.057).The first interim analysis revealed the pain-free period to be 2.50 (1.34–3.66) [hours (95%CI)] in Group IT vs. 7.75 (5.68–9.82) in IT+QLB vs. 1.75 (0.33–3.17) in QLB . Log-rank test for pairwise analysis revealed the differences in IT vs. IT+QLB (p = 0.486), IT vs. QLB (p = 0.019), and IT+QLB vs. QLB (p < 0.001). The NRS pain scores both at rest and at movement 4, 6, 12, 24, and 48 h postoperatively between groups were shown in Fig. p = 0.001). Cumulative morphine use (mg) and demands between groups at 2nd interim analysis are shown in Table Demographic and clinical data at the second interim analysis (after 20 parturients were recruited into each of the 3 arms) are shown in Table p = 0.027 vs. Tarone-Ware p = 0.076 vs. log-rank p = 0.238). The NRS at 4, 6, 12, 24, and 48 h between groups are shown in Fig. After Group QLB was terminated, Group IT and IT+QLB were continued in order to analyze whether QLB could be effective for improving postoperative analgesia by extending the pain-free period. Randomization was resumed until there were 30 patients allocated to each of the two remaining study groups. Three patients in Group IT and two patients in IT+QLB were excluded from the analysis due to conversion to general anesthesia. Demographic, surgical, morphine requirement, and side effect data are shown in Table No patients in Group QLB experienced pruritus compared with other two groups (55% in Group IT and 16.7% in IT+QLB) at the 2nd interim analysis  to the current analgesic regimen (IT morphine) after cesarean delivery by comparing the pain-free period after cesarean delivery. The results showed the improvement in the pain-free period during the early postoperative period when QLB was combined with IT morphine. However, posterior QLB alone had a significantly shorter pain-free period compared with IT morphine alone, and patients required significantly more morphine during the first 24 h.17 reported that initial pain scores associated with non-morphine groups were significantly higher than those of IT morphine groups. Group QLB was terminated at the 2nd interim analysis when inferior analgesia results were observed. In our study, the Kaplan-Meier curve showed a median pain-free period or median time to first request for IV-PCA morphine of 2.5 h in the Group IT morphine. Similarly, a previous study at our center reported a median time to first request for IV-PCA morphine of 2.1 h when adding IT morphine 0.2 mg  in Group IT morphine and 8.02 (5.96–10.07) in IT+QLB  because it is the most superficial location, the safest approach for introducing the needle, and the supine position allows uncomplicated access to the patient. Recently from cadaveric and contrast studies, it is worthwhile to note that some of these studies could not demonstrate paravertebral spreading or even transient spreading , 23, 24.The target location of QLB in these three studies  was similar  and all compared QLB with standard IT morphine. Slightly different needle tip targets may explain these contradictory findings. Contrary to traditional peripheral nerve or plexus blocks with defined neural endpoints, the exact targets of interfascial plane blocks have not been well studied . MoreoveThis study has some limitations. First, it was impossible to establish the sensory blockade of QLB after spinal block was performed. Unfortunately, it is neither practical nor ethical to perform QLB prior to delivery in order to test the level of sensation. Nonetheless, these data could still be analyzed using the intention-to-treat principle. This will reflect the actual clinical scenarios where both success and failure can happen even in experienced hands. Second, it has been very hard to inform parturients to differentiate between somatic and visceral pain. Therefore, it still cannot conclude whether QLB could provide visceral pain coverage or not. Lastly, this study included only elective cesarean delivery with a low transverse incision (Pfannenstiel incision). Thus, the results could not generalize for all type cesarean delivery such as ones with midline incision.US-guided posterior QLB (QLB type 2) at the lumbar interfascial triangle) used in conjunction with IT morphine yielded a statistically significant longer median pain-free period compared with standard IT morphine alone. However, QLB alone provided an inferior postoperative pain control after cesarean delivery compared with standard IT morphine. QLB can provide an additional analgesic benefit when combined with IT morphine especially at early postoperative period.Cost effectiveness studies comparing IT morphine with QLB and standard IT morphine could further inform the criteria for using QLB. Moreover, investigating the analgesic efficacy of QLB in special groups such as chronic opioid users or those who experience severe breakthrough pain may provide additional insights.


IntroductionIncreasing the duration of regional anesthesia in orthopedic surgery is of vital importance, as it prolongs postoperative analgesia, allowing faster rehabilitation of patients. Dexamethasone has been found to extend the block duration in animal and human studies. The aim of this study is the assessment of the effect of the addition of dexamethasone to ropivacaine on the onset and duration of axillary brachial plexus block, along with the intensity of postoperative pain.MethodsForty patients undergoing below-elbow surgery under ultrasound-guided axillary brachial plexus block were randomly allocated to receive either 30 mL ropivacaine 0.75% with 2 mL of saline  or 30 mL ropivacaine 0.75% with 2 mL of dexamethasone (4 mg) . Sensory and motor blockade were assessed, with the use of the pinprick test and the modified Bromage scale, at five, 10, 15, and 20 min after the block. The duration of analgesia, intensity of postoperative pain, postoperative opioid consumption, overall satisfaction, and perioperative complications were compared between the two groups.ResultsWe found no difference at the mean onset time of the sensory and motor block between the two groups. The mean duration of postoperative analgesia was three hours higher in the dexamethasone group . Pain intensity was lower in the dexamethasone group, at six and 12 hours after surgery . Postoperative opioid consumption, patient overall satisfaction, and perioperative complications were not significantly different between groups.ConclusionsDexamethasone prolongs the duration of ropivacaine in an axillary brachial plexus block and decreases postoperative pain in patients subjected to below-elbow surgery. As upper limb operations are associated with severe postoperative pain, it is important to apply techniques with a more powerful analgesic effect, without the use of intravenous (IV) analgesics and opioids that have significant side effects. An axillary brachial plexus block has gained more popularity for the limitation of postoperative pain for forearm and wrist surgeries is a reliable and safe option, well-tolerated by patients, with a low complication rate . HoweverIncreasing the duration of regional anesthesia in orthopedic surgery is of vital importance, as it prolongs postoperative analgesia, allowing faster rehabilitation of patients . RopivacSeveral studies have shown the analgesic effect of local and systemic corticosteroids when added to bupivacaine . DexametThe aim of this study is the assessment of the effect of the addition of dexamethasone to ropivacaine on the onset and duration of the axillary brachial plexus block, along with the intensity of postoperative pain.This was a prospective, randomized, double-blind, placebo-controlled study on patients undergoing ultrasound-guided axillary brachial plexus blockade for below-elbow surgery. After institutional review board approval of the study, all individuals were fully informed of its purpose and signed the relevant consent form. The Consolidated Standards of Reporting Trials (CONSORT) recommendations for reporting the randomized, placebo-controlled clinical trials were followed Figure .Inclusion criteria were patients aged between 18 and 70 years old, subjected to hand, wrist, forearm, and elbow surgery under axillary brachial plexus blockade. Patients with American Society of Anesthesiologists (ASA) score > III, neurological deficits, allergy in local anesthetics, INR > 1.4, a contradiction in dexamethasone use, diabetes mellitus, or chronic opioid use were excluded from the study.Patients who met the inclusion criteria in the study were randomized into two groups: group A  and group B . On arrival to the operating room, heart rate (HR), systolic and diastolic arterial blood pressure (SAP/DAP), and peripheral oxygen saturation (SpO2%) were monitored. Ten minutes before the axillary blockade, all patients received 40 mg omeprazole intravenously, 4 mg ondansetron, and a midazolam solution of 0.01 - 0.1 mg/kg for mild sedation.The patient was placed in a supine position, with the arm in 90° abduction and the elbow in 90° flexion, with the shoulder in external rotation and the whole arm next to the patient's head. An ultrasound device  was used to perform the blockade. Initially, the ultrasound probe was placed perpendicular to the axis of the axillary artery, between the biceps and triceps muscles. Once 10 ml of local anesthetic was administered dorsally to the axillary artery, the needle was redirected to the median and ulnar nerve, where another 12-15 ml was administered. Finally, the needle was withdrawn back into the biceps and was redirected to the musculocutaneous nerve. As soon as the needle was adjacent to the nerve, 5-7 ml of local anesthetic was administered.Group A (control group) received 30 ml (0.75%) of ropivacaine mixed with 2 ml (0.9%) of normal saline (placebo) while group B received 30 ml (0.75%) of ropivacaine mixed with 2 ml (4 mg) dexamethasone. The administered local anesthetic solutions were always prepared by the same anesthesiologist who was the only one who knew their contents while the blockade was performed by a second anesthesiologist unaware of their contents. The type of solution administered was also unknown to the patient.The pinprick test was used to assess sensory blockade in the area of distribution of the musculocutaneous nerve (forearm), radial nerve , median nerve , and ulnar nerve . The motor blockade was evaluated with the use of the Modified Bromage Scale (MBS) in the radial nerve (thumb abduction), ulnar nerve (thumb adduction), median nerve (thumb opposition), and musculocutaneous nerve (elbow flexion and forearm pronation). The degree of sensory and motor blockade of the axillary block was monitored and recorded by the anesthesiologist performing the blockade 0, 5, 10, 15, and 20 minutes after its execution. Time = 0 was considered as the moment of completion of the technique. Patients who showed a degree of sensory blockade < 1 in 20 minutes after the blockade, were excluded from the study. The onset time of sensory blockade was defined as the time period between the end of injection and loss of pain around the injury site. The onset time of the motor blockade was defined as the time period between the end of injection and complete motor paralysis. Neither the patient nor the anesthesiologist who assessed the sensory and motor blockades was aware of the used anesthetic solution.The patient was then transported to the operating room where standard monitoring was maintained  and oxygen was delivered through a simple oxygen mask at a rate of 5 L/min. If at the start of the operation, the patient complained of pain  > 4) or discomfort in the operated limb, 50 μg of fentanyl was administered intravenously. If pain persisted and surgery could not be continued, the blockade was considered as failed and general anesthesia was added. The patient was then excluded from the study. In addition, any side effects were recorded up to the induction of general anesthesia . Postoperatively, the patient was taken to the resuscitation unit. Instructions for initial postoperative analgesia consisted of 1 gr of intravenous paracetamol at the time when the patient first complaint of pain (VAS > 4). If the pain persisted, intravenous tramadol was administered. All patients were kept in the hospital overnight.The following data were recorded and compared between the two groups: 1. Demographic characteristics of the patients ); 2. Surgical data ; 3. Block performance time, defined as the time period from the first contact of the ultrasound probe with the patient until the end of local anesthetic injection; 4. Time of onset of sensory and motor block; 5. The Ramsay Sedation Scale of the patient at the beginning of the blockade and when the patient entered the post-anesthesia care unit; 6. The side effects that the patient experienced throughout the blockade, the operation, and when he entered the post-anesthesia room; 7. HR, SAP, DAP, and SpO2 were measured at 0, 5, 10, 15, 30, and 60 minutes after the blockade; 8. Pain intensity was measured with the VAS, graded from 0 (no pain) to 10 (worst experienced pain), at 6, 12, 24, and 48 hours after the start of the blockade both at rest and during passive movement of the joint by the anesthesiologist; 9. The duration of analgesia, defined as the period from drug injection to the first occasion when the patient first complains of pain (VAS ≥ 4); 10. The total number of opioid consumptions requested by the patient in the first 48 hours postoperatively; 11. The degree of patient satisfaction with the quality of postoperative analgesia with the help of the Likert scale.Statistical analysisBased on a priori power analysis, it was estimated that at least 16 patients per group were needed to detect a 35% change in the duration and strength of analgesia to achieve a statistical power of 80% at significance 0.05. The baseline characteristics for categorical variables were expressed in number and percentage. The continuous variables were expressed as mean ± standard deviation (SD). Data were evaluated with the Kolmogorov-Smirnov and Shapiro Wilk normality tests. The student’s unpaired t-test was used to compare continuous values with normal distribution. If the distribution of the continuous values was not normal, the Mann-Whitney test was used. Fischer’s exact test was used to compare categorical values. Statistical analyses were performed using PASW 18.0  with a level of significance set at p < 0.05.Forty patients were included in the study and randomly assigned to the treatment groups. The patient characteristics of the study population are summarized in Table Group A (control group) included 20 patients , with a mean age of 42.1 ± 13.7 years (range 16 - 69 years). Group B (dexamethasone group) included 20 patients , with a mean age of 37.6 ± 15.3 years (range 18 - 66 years). As shown in Table  As shown in Table Table Table To the best of our knowledge, this is the first prospective, randomized, double-blind, placebo-controlled study that has shown that the addition of 4 mg of dexamethasone to ropivacaine provides a longer duration of analgesia as compared to ropivacaine alone using an ultrasound-guided axillary block in patients with below-elbow surgery. Furthermore, dexamethasone reduces postoperative pain intensity until 12 hours after the operation.Several studies in the literature have indicated that the addition of 8 mg dexamethasone to local anesthetic solutions prolongs peripheral nerve block analgesia -12. It hDexamethasone has been extensively tested in the axillary block with different doses and topical anesthetics. A paper published in 2005 that evaluated the addition of dexamethasone to lidocaine for an axillary brachial plexus blockade arrived at similar conclusions to our study on the mean onset time of sensory and motor block but no data regarding the pain intensity and postoperative use of analgesics were presented . A studyThe addition of a single dose of 8 mg of the intravenous administration of dexamethasone to ropivacaine has been found to delay the onset of postoperative pain after an axillary brachial plexus blockade . HoweverThe effect of dexamethasone in increasing the duration of peripheral nerve blocks can be explained by several theories while the mechanism of the steroid-induced analgesia is not elucidated. On topical application, steroids may produce a degree of vasoconstriction that may decrease the absorption of local anesthetics ,21. ThisThe administration of dexamethasone in a nerve sheath is not an absolute indication of this drug, raising some safety concerns . In animThe optimal dose of perineural dexamethasone remains unclear. In the present study, the dose of the administered dexamethasone was 4 mg. The most common dose for a brachial plexus blockade is 8 mg. For brachial plexus blocks, 4 mg of perineural dexamethasone has provided a longer sensory and motor block and analgesia than intravenous administration . On the In the present study, we chose to use ultrasound-guided blockade for better precision of nerve localization. Ultrasound guidance of peripheral nerve blocks may minimize discomfort by avoiding nerve stimulation and may reduce the number of needle passes . MoreoveIt is interesting to note that topical administration of dexamethasone has no effect on late postoperative pain after 24 hours. This finding is in line with a recent meta-analysis by De Oliveira et al. . This maOur study does present some limitations. First, the conclusions of the study are specific to the ropivacaine solution that was used. More trials are required for other local anesthetic solutions. Second, the dose of dexamethasone we used was the same (4 mg) and not adjusted to the weight of the patient. Moreover, we did not engage another group with intravenous administration of the same dose of dexamethasone, so we cannot exclude the possibility that prolongation of analgesia occurred because of the systemic effects of dexamethasone.The present study has proven that, in an ultrasound-guided axillary brachial plexus block, the topical addition of dexamethasone to ropivacaine significantly prolongs analgesia and decreases the intensity of postoperative pain in comparison to the group given ropivacaine alone. Unexpectedly, there was no difference in postoperative opioid administration for patients receiving dexamethasone. Moreover, the mean time for the onset of sensory and motor blocks along with the hemodynamic changes was similar to those observed for the ropivacaine group. The increase of postoperative analgesia can offer substantial benefits for outpatient upper limb surgery. Taking into consideration the beneficial effect produced by the addition of dexamethasone to ropivacaine, we suggest that the combination of topical dexamethasone/ropivacaine may be used in ultrasound-guided axillary brachial plexus blockade.


This prospective observational study aimed to evaluate discomfort after extraction of deciduous teeth under local anesthesia. The primary objective was to describe the prevalence of post‐extraction pain (PEP), post‐extraction bleeding (PEB), post‐extraction biting injury (PEBI), and analgesic usage in children. The secondary objective was to define whether it is possible to determine a profile of patients or a type of extraction procedure predictive to PEP, administration of analgesics, PEB, or PEBI.One hundred and twenty‐five children, aged 3–13 years, with indications of at least one deciduous tooth extraction, were included. Immediately after extraction, information concerning the patient and the extraction were collected. Eighteen to 32 hr after extraction, parents were called by phone to request reports concerning the onset and intensity of PEP assessed using the Wong‐Baker Faces (WBF) scale, the administration of paracetamol (acetaminophen) to their children, and the appearance of PEB and/or PEBI.p < .05).Of the children, 37.3% reported PEP (WBF ≥2), but 23.3% of these children did not receive any analgesic drugs to help relieve pain. Pain appeared before 3 hr after extraction in 69% of the children. Higher incidences of PEP and usage of analgesics were found both in the group of children with unfavorable socioeconomic level compared to favorable level and in the group with pre‐operative pain compared to no pre‐operative pain (About a third of the children reported pain after extraction, but the instructions for pain relief were not followed by all parents. The socioeconomic level of the young patient and the pain felt during the extraction were important predictors of discomfort. Therefore, our study could help the dentist to provide information on predicted post‐operative discomfort and to allow suitable care depending on the patient's profile or procedure. In fact, neglecting experiences perceived as unpleasant by the child, such as local anesthetic administration, tooth extraction, and post‐operative discomfort, can lead to the development of anxiety and interfere with the acceptance of dental treatment during future visits  is a common analgesic with high usage and availability , indicated for tooth extractions for reason of tooth decay, orthodontic treatment, obstacle, infection, or traumatism, were included in this study. The exclusion criteria were patient under analgesic the day of the appointment or taking non‐steroidal anti‐inflammatory agents for 8 days before the extraction; contraindication to paracetamol/acetaminophen; incomplete mental health; extractions of permanent teeth; and/or extraction under sedation (including nitrous oxide/oxygen) and general anesthesia. Children were also excluded from the study if the parents could not be reached by phone within 32 hr after extraction or if the parents did not speak French.Subjects' rights have been protected by the local ethic committee of Nantes , which approved this study . All parents signed informed consent forms, and each child consented verbally according to their age.2.2After application of xylocaine gel for topical anesthesia of oral mucosa, anesthesia by local infiltration of 4% articaine with adrenaline (epinephrine)  was administered for all the recruited children. Extraction of the deciduous tooth was then performed consistently by all the operators  following standard protocol with routine behavioral guidance techniques. Immediately after extraction, parents were instructed with a written guide for home care of their children; the pain relief instruction was to give one adequate dose of pediatric paracetamol , and, if necessary, others doses every 4–6 hr, not to exceed four doses in 24 hr, only when children felt pain with a score greater than or equal to 2 on the Wong Baker Face (WBF) scale. On this scale, which contains six faces, the children were asked to point to the face that displayed the amount of pain they were experiencing . To prevent injury to the mouth while the area remained anesthetized, the recommendation was to supervise the children and to cook mixed foods. To protect the clot that was formed and to prevent bleeding, children should not suck on the extraction site and should avoid excessive exercise for several hours. Written recommendations in the case of appearance of these discomforts were given.Finally, parents were asked to fill out a form containing the precise time and WBF score of PEP, PEBI, and PEB, and the administration (dose and time) of analgesic drugs. Eighteen to 32 hr after extraction, a clinical research technician unaware of the extraction performed telephoned to the parents to request reports concerning PEP, administration of analgesic, PEBI and/or PEB.A structured form was designed to obtain information on the patients' ages, sexes, and socioeconomic levels differentiated by their health insurance status , as well as cooperation of the child before and during anesthesia or extraction, influence of the accompanying person, number of previous extractions, and dental hygiene. Moreover, details about the type of extraction, the indication of extraction , the type of tooth (incisor‐canine or molar), the level of root resorption, number of doses of local anesthetic, and presence of pre‐existing or pre‐operative pain were reported by the operator on a faces pain scale, revised (FPS‐R).The data were collected to ascertain the number and relative proportion of children who felt pain. Then, data were analyzed to determine the possible association between the type of patient or the nature of intervention and the report of discomfort.2.3The prevalence of post‐operative pain after extraction of primary teeth is reported to be around 40% in the literature .3.1The incidence of pain (WBF ≥ 2) following deciduous tooth extraction was 37.3%. Among the 44 patients who had being suffering, the proportion of patients reporting mild or moderate pain reached 60.4% (39.5% WBF = 2 and 20.9 WBF = 4) Table . For halIn the present study, post‐extraction biting injury (PEBI) was rare: only six of the 120 children (5%) reported this discomfort , accompanying person, as well as tooth position, degree of difficulty (length and number of roots), tooth history, pre‐existing pain or dento‐alveolar abscess (antibiotic before extraction), and number of teeth extracted during a single appointment (one tooth or more than one tooth) were not significantly associated with report of discomfort Tables  and 3.p = .03). In addition, children with pre‐operative pain, as assessed by the student who performed the extraction using the FPS‐R scale, were significantly more likely to have PEP than those without pre‐operative pain  with higher usage of paracetamol in the group with pre‐operative pain and when the tooth extracted had 2/3 of root length. In addition, a significantly higher percentage of parents from the socioeconomically disadvantaged group administered analgesics compared to parents with a favorable socioeconomic level . Our data are in the same range of the occurrences of PEP previously reported: 38% . These percentages of patients without analgesic administration despite PEP were lower than previously reported . These results could be explained by the clear advice given to prevent these discomforts. Previous studies found that local anesthetics, especially the inferior alveolar blockers, provoked biting in children (Calis et al., 5This study was a thorough evaluation based upon the patients' characteristics and the tooth and surgery factors that may be used in predicting unpleasant responses by children after deciduous tooth extraction. The dental surgeon, and subsequently the patients, should benefit from advanced knowledge of any variables that may ultimately influence the patients' responses to painful stimuli. The practitioner may consider the pain reported by the young patient during extraction and his/her socioeconomic level in determining the potential for PEP. However, because effective pain control is essential in pediatric dentistry, and in view of the fact that pain after treatment is an etiological factor leading to dental fear, further studies should be performed to produce guidelines and recommendations.Brigitte Alliot‐Licht: Conceived the idea, designed the study, analyzed the data, drafted the manuscript. Claire Baillargeau: Designed the study, collected the data and analyzed the data. Hugo Charles and Aline Ordureau: Designed the study, collected the data and analyzed the data. Sylvie Dajean‐Trutaud, Tony Prud'homme, Isabelle Hyon and Assem Soueidan: Collected the data and critically revised the manuscript. Emmanuelle Renard: Conceived the ideas, collected the data and critically revised the manuscript. All authors gave their final approval of the text and agree to be accountable for all aspects of the work.Appendix S1: Supporting informationClick here for additional data file.Appendix S2: Supporting informationClick here for additional data file.


Although commercially available analgesic indices based on biosignal processing have been used to quantify nociception during general anesthesia, their performance is low in conscious patients. Therefore, there is a need to develop a new analgesic index with improved performance to quantify postoperative pain in conscious patients.This study aimed to develop a new analgesic index using photoplethysmogram (PPG) spectrograms and a convolutional neural network (CNN) to objectively assess pain in conscious patients.PPGs were obtained from a group of surgical patients for 6 minutes both in the absence (preoperatively) and in the presence (postoperatively) of pain. Then, the PPG data of the latter 5 minutes were used for analysis. Based on the PPGs and a CNN, we developed a spectrogram–CNN index for pain assessment. The area under the curve (AUC) of the receiver-operating characteristic curve was measured to evaluate the performance of the 2 indices.P<.01. The AUC and balanced accuracy were 0.76 and 71.4%, respectively. The spectrogram–CNN index cutoff value for detecting pain was 48, with a sensitivity of 68.3% and specificity of 73.8%.PPGs from 100 patients were used to develop the spectrogram–CNN index. When there was pain, the mean (95% CI) spectrogram–CNN index value increased significantly—baseline: 28.5 (24.2-30.7) versus recovery area: 65.7 (60.5-68.3); Although there were limitations to the study design, we confirmed that the spectrogram–CNN index can efficiently detect postoperative pain in conscious patients. Further studies are required to assess the spectrogram–CNN index’s feasibility and prevent overfitting to various populations, including patients under general anesthesia.Clinical Research Information Service KCT0002080; https://cris.nih.go.kr/cris/search/search_result_st01.jsp?seq=6638 Efficient management of postoperative pain affecting the prognosis of patients is becoming increasingly important . To propA photoplethysmogram (PPG) is a biosignal that can be obtained continuously and noninvasively using a pulse oximeter. Because a PPG conveys much information about a patient’s condition, many attempts have been made to quantify pain by analyzing PPG signals ,5-7. TheDeep learning architectures, such as a convolution neural network (CNN), can be a good solution to elucidate the hidden features in a PPG because they can identify optimal abstracted features that are beyond human comprehension without any manual procedure . FurtherThis study aimed to develop a new analgesic index using PPG spectrograms and a CNN to objectively assess pain in conscious patients. In addition, the performance of our newly developed index was compared with that of the SPI.The study protocol was approved by the Institutional Review Board of Asan Medical Centre  and registered on an international clinical trials registry platform (registration number KCT0002080). Written informed consent was obtained from all patients. All procedures were conducted in accordance with relevant guidelines and regulations. In total, 120 patients  between the ages of 20 and 80, who were scheduled to undergo elective surgery, were included in this observational study. Exclusion criteria were as follows: clinically significant impairment of the cardiovascular, hepatic, or renal function; history of cardiac arrhythmia; use of medication that might affect autonomic function; the presence of presurgical acute or chronic pain ; clinically significant laboratory findings; and evidence of pregnancy.Ces) of propofol were titrated to maintain the bispectral index (Covidien) at less than 60 during the induction and maintenance of anesthesia. The target Ces of remifentanil were adjusted to maintain stable hemodynamics . All patients received a bolus dose of oxycodone (0.1 mg/kg) 30 minutes prior to the end of surgery.All patients fasted from midnight on the day of surgery without premedication. In the operating theater, patients were monitored for their heart activity using electrocardiography, end-tidal carbon dioxide partial pressure, and noninvasive blood pressure measurement. Neuromuscular transmission was monitored using an M-NMT module at the adductor pollicis muscle . A reusable SPI sensor was placed on the index finger of each patient (on the arm not used for blood pressure measurement). Patients were allowed to acclimatize for at least 5 minutes in the supine position in a quiet operating theater, after which baseline data (without pain) were collected for 6 minutes, of which the latter 5 minutes were used for analysis. General anesthesia was performed by administering propofol and remifentanil by a target effect-site concentration–controlled infusion using the Schnider and Minto models ,12. TargIntravenous patient-controlled analgesia with oxycodone began after the administration of the bolus dose of oxycodone. Neuromuscular blockade was reversed with neostigmine and glycopyrrolate at the end of surgery. Tracheal extubation was performed when the train-of-four ratio was greater than 0.9 and bispectral index value was greater than 80. Patients were then transported to the postanesthesia care unit (PACU). When the patients arrived in the PACU, their state of consciousness was assessed with a modified Aldrete score . ElectroA spectrogram–CNN model was developed and validated through fivefold cross-validation. The developed model outputs the spectrogram–CNN index as a pain score using a PPG spectrogram as input and CNN as a pain scorer. During model development, patients and test sets were separated to prevent intrasubject interference to avoid data overlaps between the development and test sets of each fold. For model training, 90% of the development set was used as a training set and 10% as a validation set. Finally, for each fold, 20, 73, and 7 patients’ data were used as a test set, training set, and validation set, respectively. Pain and nonpain data labels were created based on the VAS, where VAS>0 was defined as pain and VAS=0 was defined as nonpain with labels “1” and “0,” respectively. Detailed descriptions of the spectrograms and CNN used in this study are given below.z-scores were obtained by subtracting the mean of the measured values from each measured value and dividing by the standard deviation. The spectrogram generation process is illustrated in Spectrogram creation is a method used for time–frequency analysis of time series signals. A spectrogram reconstructs 2D images while maintaining the information contained in 1D time series data . SpectroSpectrogram images were generated by short-time Fourier transforms of 10-second PPGs every 10 seconds without overlap A. At theCNNs are useful for image analysis because they have the advantage of maintaining the spatial information of 2D or higher inputs. CNNs enable data-driven learning, are highly representative, and effectively combine the spatial information of multidimensional inputs ; superviP values <.05 were considered to be statistically significant.Receiver-operating characteristic (ROC) curves were computed to compare the sensitivity and specificity of the spectrogram–CNN index and SPI for detecting pain. Cutoff values used for calculation of sensitivity and specificity were computed as “best fit” (highest combined sensitivity and specificity) . The difIn total, 120 patients were enrolled, of whom 20 dropped out because of failure of PPG data storage (n=8), failure of SPI data storage (n=2), abnormal SPI data that could not be included in the analysis (n=9), and failure to measure VAS after surgery (n=1). Thus, 100 patients were included in the final analysis. The characteristics of these patients are summarized in P<.01 in paired t test; baseline SPI: 42.5 (SD 16.7) versus PACU SPI: 53.5 (SD 17.8), P<.01 in paired t test). The area under the curve (AUC) of the ROC and cutoff values for detecting pain in terms of spectrogram–CNN index and SPI are listed in P<.01). Moreover, as shown in Individual changes in the spectrogram–CNN index and SPI without and with pain are presented in P=.78, Kruskal–Wallis one-way ANOVA on ranks) nor SPI  could statistically distinguish between mild, moderate, and severe pain. The frequency distributions of the spectrogram–CNN index and SPI values observed without and with pain during the data collection period are shown in P<.05) in patients with and without pain, suggesting that the spectrogram–CNN index can distinguish pain more clearly than the SPI.Neither spectrogram–CNN index (mild: 69.5 [53.2-87.7], moderate: 71.8 [40.5-89.3], severe: 74.6 [62.9-84.7], The spectrogram–CNN index proposed in this study outperformed the commercialized SPI pain index in the postoperative pain assessment of conscious patients. One of the main reasons for its outperformance is the spectrogram input containing the PPG’s intact waveform information, making it possible to use hidden pain-related factors that could not be provided only by the peaks. Because existing pain assessment methods, such as the SPI, use only certain features of a PPG that show significant changes in surgical stimuli, numerous pain-related information reflected in the PPG may be overlooked. To overcome these limitations, research has been conducted on new pain-related features derived from sophisticated PPG waveform analysis in addition to the heart rate interval and PPG amplitude reflected in the SPI -7. HowevAnother key technique proposed in this study is the discrimination of postoperative pain using machine learning. Although machine learning–based pain assessment has already been studied -31, it iIn this study, patient data used for model development and validation were separated, and fivefold cross-validation was performed to eliminate interindividual interference and to generalize the model. Therefore, the proposed spectrogram–CNN index is expected to show similar performance in other groups of patients of similar age who did not participate in model development. However, there may be a few new variables to consider. In The spectrogram–CNN index may not have been able to distinguish pain intensity because the number of observations was relatively small. A previous study showed that SPI distinguishes postoperative pain intensity ; howeverThe database used in this study was shared by 2 research groups. Another group, independent of this study, has already published their results. Their pain classifier, based on a deep belief network using various PPG features, discriminated well between the presence and absence of pain . CompareThere are some limitations to this study. First, the SPI was selected as a comparative index to evaluate the performance of the spectrogram–CNN index, but its suitability is somewhat debated. The SPI is neither developed nor recommended for use in conscious patients. However, when a new analgesic index is developed, it is essential to evaluate its performance, and this is commonly done by comparing it with an existing index using the same data. Although the SPI is not recommended for use in conscious patients, some studies on conscious patients suggest that SPI can discriminate between the presence and absence of pain ,38. BetwIn conclusion, although there were several limitations to the study design, we confirmed that the newly developed spectrogram–CNN index can effectively detect postoperative pain in conscious patients. Further validation studies are required to assess its feasibility and prevent overfitting to various populations, including patients under general anesthesia.