Patients and Methods. A prospective study was carried out in 2019 (NCT03819036) in adult patients. Data was collected on D0 on site and then on D1, D3, and D7 by phone, during daytime. The main objective and secondary objectives were, respectively, to assess the intensity of pain on D1; the intensity of pain on D3 and D7; the evolution of anxiety on D1, D3, and D7; and the patients' satisfaction. They were evaluated with a 0–10 numeric scale (NS) on D1, D3 and D7; mean scores were compared with nonparametric statistics .  The Dental Emergency Unit (DEU) of the Pitié Salpêtrière Hospital receives mainly painful emergencies. This study aimed at evaluating the suppression of pain and anxiety as well as the patient's satisfaction after a visit to the DEU. p < 0.0001) between D0 and D1, D3, D7. The mean NS anxiety scores were as follows: D0: 3.32 ± 0.15; D1: 3.69 ± 0.16; D3: 2.75 ± 0.16; D7: 1.98 ± 0.15. The decrease was significant between D0 and D7 (p < 0.0001). The perception of general heath improved between D1 and D7. The overall score of satisfaction was 8.64 ± 0.06.  814 patients were contacted and 581 patients included; 87 were lost to follow-up. 376 patients completed all the questionnaires. In the final sample , 86% had health insurance. The mean pain scores were as follows: D0: 6.36 ± 0.12; D1: 3.49 ± 0.13; D3: 2.23 ± 0.13; D7: 1.07 ± 0.11—indicating a significant decrease of 45%, 65%, and 93% on D1, D3, and D7, respectively, compared to D0 ( DEU enabled a significant reduction in pain and anxiety with high overall satisfaction. Orofacial pain (OFP) is a very prevalent condition, estimated between 5% and 57% in adults in the last 12 months, depending on country, age group, and sociocultural level . OFP is Even if some patients consult in the first place in medical services , OFP is There are however few studies devoted to the effectiveness of and satisfaction with emergency settings related to pain and anxiety , 54–57. The main objective of this study was to assess the reduction in pain 24 hours (D1) after the emergency visit (D0). The secondary objectives were to assess (1) the evolution of pain on D3 and D7; (2) the evolution of anxiety on D1, D3, and D7 after emergency visit; (3) the quality of reception of nursing and non-nursing staff; and (4) the perception of the quality of care.NCT03819036). STROBE recommendations were followed for the design of the study and the writing of the report. Good Clinical Practices for clinical trials were supervised by the Clinical Research Unit (URC) of the GHPS.A prospective monocentric observational cohort study was carried out from 01 April 2019 to 31 June 2019 at the Dental Emergency Unit (DEU) of the Pitié Salpêtrière Hospital (GHPS) in Paris. The study was approved by an IRB  and registered at clinicaltrials.org (The sample consisted of adult patients [>18 years old (y.o.)] presenting at the DEU of the GHPS for emergency care. The DEU is open 24 hours a day, 365 days a year, without phone call upstream regulating system. Care is provided by undergraduate students in their last year of study (6th year) under the responsibility of a senior . Upon arrival, patients take a ticket with a telephone number and time of arrival. They are called for care according to their order of arrival except for priorities . History taking, clinical examination and diagnosis are performed by students and controlled by a senior who validates the therapeutic decision, i.e., immediate care such as pulpotomy or avulsion, prescription, patient referral, one option not excluding the others. The treatment provided is the best suited to the situation of the patient and the service, as judged by the senior. For example, in case of AAA, the practitioner can either perform endodontic treatment or drainage in the service or prescribe antibiotic and analgesic treatment with referral to a GP. As the GHPS is an adult hospital, where children are only occasionally admitted, according to the state of emergency, the study was conducted in adult patients.Diagnostic criteria were defined according to international recommendations –63: pulpParticipation in the study was proposed to all consecutive patients presenting in the DEU. Those satisfying eligibility criteria and willing to participate after receiving information were included after giving written consent. Inclusion criteria were age ≥18 y.o., patient available for phone calls during the week following the visit, and good understanding of the French language. Subjects with impaired communication were not included in the study.The study lasted 25 weeks and consisted of 3 one-week phases, with 2-month intervals, in order to limit selection bias. The maximum observation time of the patient was 10 days. Data collection was performed by 2 investigators (GD and MA). On D0 in the DEU, after inclusion in the study and medical history taking, the patients filled the sociodemographic and medical questionnaire and had clinical evaluation, diagnosis, and emergency care/prescription/advice according to their medical condition; before leaving, they filled the satisfaction questionnaire. On D1, D3, and D7, the evaluation questionnaires were completed by the investigators through a telephone interview.Data were collected through questionnaires during the emergency visits and telephone calls. Sociodemographic data included social insurance status, habits of dental consultation, reason for consultation at the DEU, and how the patient attended the DEU. Medical data included medical history and actual treatments, diagnosis at the DEU, prescribed therapeutics, and further needed treatment. Efficacy measures included self-estimated pain and anxiety at the different time points of the study. Satisfaction measures included perception of the politeness of both medical and nonmedical staff, availability of nonmedical staff, care setting quality, cleanliness, waiting time, quality of medical information, and attitude toward recommending the DEU to friends.The main evaluation criterion was the self-evaluated pain score assessed on a simple [0–10] numerical scale (NS)  , collectN = 800.We aimed at assessing 1% of the population consulting at the DEU. As a pilot study carried out in the service  showed tThe investigators were specifically trained for the phone interview. Patients not answering phone calls at the follow-up period were contacted the next day, and the pain and anxiety scores were extrapolated by calculating the nearest point on the curve connecting the previous and the newly collected data. If the patients were again not answering, the data was considered as missing. The data were anonymized throughout the study.R2). Contingency analyses were performed with Chi2 test. Level of significance was set at 95%.A descriptive analysis of the sample was carried out. Pain and anxiety scores were grouped into 3 classes: absent or mild, from 0 to 4; moderate, from 5 to 7; and severe, from 8 to 10. Statistical analysis of the evolution of pain and anxiety scores on D0, D1, D3, and D7 was carried out with GraphPad Prism 5 software using ANOVA followed by Dunn's posttests. Correlations between the type of treatment and perceived pain as well as the type of treatment and perceived anxiety were searched with Pearson correlations  and those with no or minimum health insurance. 61% of the sample came directly to the DEU while 39% tried to have an appointment with a dentist before. Among the latter, 17% were addressed by the contacted dentist, 15% could not wait until the proposed appointment, and 7% evoked other reasons such as the cost of the care in a private practice. including financial reasons (1%). Patients came to the GHPS on the advice of relatives (27%), because they had already come (20%), after Internet search (14%), already informed by a dentist (12%), and 26% knew the DEU by other means.The sample included 59% men and 41% women, with an average age of 40 ± 16 years and a distribution of patients by age group as follows: <30: 30%; 30–39: 28%; 40–49: 16%; 50–59: 13%; 60–69: 7%; 70–79: 4%; ≥80: 2%. 14% of patients had no health insurance; 86% had it, including 69% social security , 10% CMU , and 6% AME . 74% declared no medical condition (MC) and 10% declared more than 2. Overall, the number of MC increased with age: patients with no MC represented 75% of the sample (mean age: 35.8 ± 0.6); patients with 1 MC represented 15% (mean age 49.8 ± 0.7); and patients with 2 MC or more represented 10% (mean age: 56.8 ± 0.9). 58% of the sample reported a visit to the dentist less than 1 year ago. However, 25% had none for more than 2 years, including 15% with more than 5 years. Overall, dental follow-up increased with the quality of health insurance; patients benefiting from dental follow-up of less than one year were indeed 35% without health insurance, 41% with AME, and approximately 60% with CMU and SS. Conversely, the decrease in social protection tended to space follow-up visits: 33% of patients without SS, 18% with AME, 16% with CMU, and 11% with SS had the last dental follow-up more than 5 years ago. There was a statistically significant difference in pain scores between subjects having a regular SS  including pain only (71.7%) or associated with either swelling (15.9%), mobility (1.9%), or trauma (1.2%). Among the 8% with no pain, 3.2% consulted for seeking advice.The medical diagnoses sorted by frequency were AAA , PAA , irreversible pulpitis (12.5%), cellulitis (9.2%), pericoronitis (5.8%), periodontal abscess (4.6%), trauma (3%), reversible pulpitis (2.1%), and septum syndrome (1.3%). The rest (2%) were pathologies of the oral mucosa, salivary pathologies, patient orientation errors, etc.p < 0.001). An already significant decrease is observed between D1 and D0.The distribution of pain scores on D1 and D0 and their evolution from D1 to D7 are illustrated in p < 0.001), except for traumas.Pain scores and distribution according to diagnoses are illustrated in N = 87) did not answer any call and were considered as non-responders (NR) and excluded from further analysis, while 85% (N = 494) answered at least one call. Mean pain scores on D0 were not significantly different for NR (6.9 ± 0.28) and responders (6.3 ± 0.09) (Mann & Whitney p=0.32). In the subgroup of responding patients, 376 (65%) responded to the 3 recalls, 53 (9%) to 2, and 65 (11%) to 1 with a D0 respective pain score of 6.1 ± 0.16, 7.0 ± 0.41, and 6.8 ± 0.36. There was a significant difference in pain scores on D1 for patients responding to 1, 2, or 3 calls; the more the patients responded, the more the pain decreased (15% of the sample (ecreased .p < 0.001). On D7, low scores of anxiety constituted 79% of the sample, moderate scores constituted 12%, and high scores constituted 9%.The overall level of anxiety on D0 was low since 57% of the scores were in the range 0–4, including 49% with no anxiety and 20% with moderate anxiety (scores: 5–7) . Severe p < 0.001) from 7.56 ± 0.09 on D1 to 7.95 ± 0.10 on D3 (p < 0.05) and 8.25 ± 0.10 on D7 .Overall, the perception of the patient's general health (GH) improved significantly with time. The average GH scores increased significantly .52% of the patients received a medical prescription alone while 8% received only advice without treatment or prescription. 21% of patients benefited from surgical treatment (extraction), and 18% benefited from endodontic treatment. Level of pain was slightly correlated with the type of therapeutic response; i.e., higher levels of pain resulted more often in surgical/endodontic treatment than lower ones (ChiN = 70) of the patients consulted again on, respectively, D1, D3, and D7. The mean reasons for reconsulting were persistent pain (30%) and worsening of the swelling (12.9%) while others came for extraction (24.3%) or control (32.9%). Observance of the instructions given on D0 was reported by 96% of the patients on D1 and 93% on D7, mainly because the patients stopped antibiotics with the subsiding of the pain. 60.2% of patients made an appointment for further care on D1 with a dentist, either in a private practice or at the GHPS, 68.5 on D3, and 70.3% on D7.In the sample, 9%, 12%, and 19% . Women reported significantly higher scores of pain than men , although mean pain scores were not significantly different: 6.49 ± 0.19 vs. 6.27 ± 0.17. There was a statistically significant difference between pain scores according to health insurance status with mean scores of 6.14 ± 0.15 vs. 6.85 ± 0.21 (p < 0.05) for, respectively, patients with SS and patients with minimum health coverage , although no statistically significant difference between subcategories could be found . The difference in pain scores between patients who consulted a dentist during the past year, 1-2 years ago, 2–5 years ago, and >5 years ago was not significant: 6.1 ± 0.17, 6.8 ± 0.26, 6.7 ± 0.39, and 6.5 ± 0.33, respectively.No correlation was found between pain and anxiety scores  between the overall score of satisfaction and the waiting time. The overall satisfaction was confirmed by the high percentage of patients intending to recommend the DEU to a friend/family member or consult again (98%).The average overall satisfaction score after visit to the DEU was 8.6 ± 0.06 . PerceptThe main results of this study are a high prevalence of pain and anxiety in the population consulting the DEU and a high efficiency of the DEU in reducing both of them, measured at 3 endpoints. Pain decreased on average by 83% and anxiety by 40% between D0 and D7. Furthermore, the perceived satisfaction was excellent since 97.8% of the sample gave an overall satisfaction score of ≥5 with a mean score of 8.6/10.There are relatively few cohort studies related to dental emergencies which overall tend to indicate that patients attending emergency departments are rather young and male with low socio-medico-economic status , 66–70, Pain was the main reason for consultation in 91% of the sample, being associated with swelling in 16% or trauma in 2%, which is in the upper range of emergency studies [39%–88%] , 76–78. Anxiety scores on D0 were low (3.3 ± 0.15), although not uniformly distributed since 30% reported scores of [5–10] and 20% reported scores of [8–10], which can be compared with other studies reporting similar findings with different evaluation tools , 81. TheIn the present study, the overall perception of the DEU was excellent, reflecting specific satisfaction with quality of care and attitudes of both medical and nonmedical staff. The worse item was waiting time which exceeded 4 h in 7.8% of the sample. Few studies precisely assessed waiting time in DEU, which is part of patient satisfaction , especiaCare provided in the DEU is the most adapted to condition of the patient according to the resources of the service. In the present sample, 52% of the patients received a prescription, 21% had extraction, 18% got endodontic treatment (pulpotomy/pulpectomy) or cleaning/disinfection of infected root canals, and 8% received solely advice. The specific nature of the treatment is of little importance for the patient, who is more concerned with the relief of pain and attitude of caregiver which includes empathy, listening, explanations, and advice, especially in a context of emergency , 80.The results of this study are very similar to the pilot study of  with a fA potential selection bias is related to language. The patients who do not speak French enough to understand the protocol and questionnaires have been excluded. They might belong to a lower socioeconomic status and health coverage. This study evaluated the DUE only during working days and daytime. Out-of-hours periods have been evaluated in an ancillary study . The samThis study focused on daytime emergencies and did not evaluate out-of-hours periods. Therefore, an ancillary study was planned (NCT04352881) but interrupted by the COVID-19 pandemics. During COVID-19 time, an additional study (NCT04354272) performed with the same methodology was launched in order to compare pain anxiety and efficacy of the DEU during the two periods. These two ancillary studies will complete the present data when published.Measuring the quality of care is a complex issue including many domains and dimensions . This st


Patients with chronic idiopathic axonal polyneuropathy (CIAP) can have neuropathic pain that significantly impacts quality of life. Oral neuropathic pain medication often has insufficient pain relief and side effects. Topical phenytoin cream could circumvent these limitations.The primary objectives of this trial are to evaluate (1) efficacy in pain reduction and (2) safety of phenytoin cream in patients with painful CIAP. The main secondary objective is to explore the usefulness of a double-blind placebo-controlled response test (DOBRET) to identify responders to sustained pain relief with phenytoin cream.This 6-week, enriched enrollment randomized double-blind, placebo-controlled triple cross-over trial compares phenytoin 20%, 10% and placebo cream in 48 participants with painful CIAP. Enriched enrollment is based on a positive DOBRET in 48 participants who experience within 30 minutes ≥2 points pain reduction on the 11-point numerical rating scale (NRS) in the phenytoin 10% cream applied area and ≥1 point difference in pain reduction on the NRS between phenytoin 10% and placebo cream applied area, in favour of the former. To explore whether DOBRET has predictive value for sustained pain relief, 24 DOBRET-negative participants will be included.An open-label extension phase is offered with phenytoin 20% cream for up to one year, to study long-term safety.The main inclusion criteria are a diagnosis of CIAP and symmetrical neuropathic pain with a mean weekly pain score of ≥4 and <10 on the NRS.The primary outcome is the mean difference between phenytoin 20% versus placebo cream in 7-day average pain intensity, as measured by the NRS, over week 2 in DOBRET positive participants.Key secondary outcomes include the mean difference in pain intensity between phenytoin 10% and phenytoin 20% cream, and between phenytoin 10% and placebo cream. Furthermore, differences between the 3 interventions will be evaluated on the Neuropathic Pain Symptom Inventory, EuroQol EQ5-5D-5L, and evaluation of adverse events.This study will provide evidence on the efficacy and safety of phenytoin cream in patients with painful CIAP and will give insight into the usefulness of DOBRET as a way of personalized medicine to identify responders to sustained pain relief with phenytoin cream.NCT04647877. Registered on 1 December 2020.ClinicalTrials.gov  The order of the items has been modified to group similar items  is a slowly progressive distal symmetric sensory or sensorimotor polyneuropathy without a known cause . SensoryThus, new treatment strategies are needed to improve neuropathic pain management with less side effects. Topical analgesics are an interesting therapeutic option, because they might influence only the nerve endings in the epidermis without reaching the bloodstream, thus resulting in fewer or no systemic side effects , 13. TopThe newly developed phenytoin cream could fulfil the need of a novel neuropathic pain treatment –21. PhenA randomized clinical trial evaluating topical clonidine in diabetic neuropathic pain patients found a more profound pain reduction when patients experienced more burning sensation after application of topical capsaicin, suggesting that treatment success might be dependent on the preservation of signal transduction of sensory nerves from the skin to the brain . An alteThe primary objectives are to evaluate (1) efficacy in pain reduction and (2) safety of phenytoin cream in participants with painful CIAP. Safety is evaluated by asking for local and systemic side effects, and by measuring phenytoin plasma levels. Possible reported systemic side effects will be correlated with phenytoin plasma levels. The secondary main objective is to explore the usefulness of DOBRET as a way of personalized medicine to identify responders to sustained pain relief with phenytoin cream.This is a 6-week single-centre, enriched enrollment randomized double-blind, placebo-controlled triple cross-over trial to evaluate the efficacy and safety of phenytoin cream (20% and 10%) versus placebo in 48 participants with painful CIAP. The enriched enrollment is based on a positive double-blind placebo-controlled response test (DOBRET) in 48 participants who experience within 30 minutes at least 2 points pain reduction on the 11-point numerical rating scale (NRS) on the phenytoin 10% cream applied area and at least 1 point difference in pain reduction on the NRS between phenytoin 10% and placebo cream applied area, in favour of the former. To explore to which extent and which responder definition for the DOBRET has a predictive value for sustained pain relief, an additional 24 DOBRET negative participants will be included.Participants will be randomly allocated to one of the 6 possible intervention sequences. Participants and investigators will be blinded. The duration of each treatment period is 2 weeks. Participants will cross-over two times to each of the other treatments. The study does not have wash-out periods between treatments, because the mean duration of the analgesic effect after an application is expected to be less than 9 h . A flow This monocentric trial will be executed in the University Medical Center Utrecht (UMCU), the Netherlands.Patients will be recruited from the UMCU neurology outpatient clinic. When patients from outside of the UMCU want to participate, a consultation for the confirmatory diagnosis will be carried out. Inclusion criteria are age ≥ 40 years; confirmed CIAP diagnosis ; presencUpon confirmation of willingness to participate, the eligible patient will be sent the patient information regarding the study and the informed consent form. One week later the research physician will phone the patient to answer any questions and will ask if the patient is willing to participate. Upon the patient’s agreement, the research physician will obtain the patients’ written informed consent at the first study visit.In the patient information letter, the trial outline is presented. During the trial, at the second visit blood withdrawal will be performed to determine phenytoin plasma concentrations in patients who applied 10% and 20% cream, in order to evaluate the safety of topical phenytoin. Possible reported systemic side effects will be correlated with phenytoin plasma levels. Plasma phenytoin analyses will be performed after data analyses to maintain blinding. The written consent form contains statements that the participant has read the information letter, could ask questions, had enough time of reflection on the trial, gives permission of collection and use of participant data, and can withdraw from the trial at any time.In this cross-over, double-blind trial the comparator will be placebo cream applied 2 to 4 times daily according to the duration of effect. The active and placebo cream have the same white appearance and neutral smell. All participants will receive this treatment during a 2-week treatment period. Placebo cream is chosen to identify the magnitude of pain reduction attributable to the active interventions. Furthermore, a placebo cream is also used in the DOBRET to explore the predictive value of this test .All participants will receive placebo, phenytoin 10% and phenytoin 20% cream, each during a period of 2 weeks. The participant will be instructed to apply the cream 2 to 4 times a day with a maximum of 1.5 g per application, measured in Finger Tip Units (FTU).One FTU is defined as the amount of cream expressed from a tube with a 5 mm diameter nozzle, applied from the distal skin crease to the tip of the index finger, which amounts to approximately 0.5 g see Fig. . The numParticipants are allowed to drop out at any time without giving a reason. Other criteria are serious adverse event (SAE), unacceptable adverse event (AE), and/or protocol violation, including use of prohibited pain medication.Participants can choose to fill in the pain diary and questionnaires electronically or on paper. Participants fill in every day the pain diary to score daily pain intensity on the NRS, number of daily cream applications and possibly used escape medication. Questionnaires are filled in only at the last day of each 14-day intervention period. When the pain diary is not filled in, the electronic questionnaire system Castor will send reminders the next day in the morning and the day after. Every 2 weeks the participant will visit the outpatient clinic to receive the study medication. The research physician checks at every visit the pain diary and questionnaires for completion.In case the questionnaires are not filled in on the 14th day, the research physician will ask the participant to fill in the questionnaire at the visit on the 15th day.When the pain diary is incomplete at the first visit, the research physician will stipulate the importance of filling in the pain diary and will monitor in Castor thereafter every day. In case the pain diary is not filled in, the patient will be phoned to ask the pain intensity on the NRS of the previous day, which will be noted, and will resolve the problem of poor adherence. When after the first 2 weeks less than 2 daily cream applications have been entered in the pain diary, the participant will be reinstructed during the second visit. The research physician will then monitor in Castor every day, and patients will be contacted in case of poor adherence. When poor adherence on paper diary and questionnaires is noticed in the first visit, daily phone calls will be performed in the second and third intervention periods. The outcomes will be registered in Castor and compared with the paper version. In case the participant experiences adverse events, one of the research physicians can be contacted for advice. Participants can contact the neurology department 24 h a day.Participants can continue their neuropathic pain medication when the dosage has been stable for at least one month. Acetaminophen and non-steroid anti-inflammatory drugs are allowed as escape medication for acute pain other than the neuropathic pain due to CIAP. Oral phenytoin, opiates and other topical analgesics are not allowed. Use of escape medication will be recorded in the on a daily base.Participants can be reimbursed for transportation expenses. After the double-blind phase, participants can participate in a 1-year open-label extension phase. Hereafter, the general physician can prescribe phenytoin cream made by a compounding pharmacy. The UMCU has a liability insurance which is in accordance with article 7 of the Dutch law on medical research. This insurance provides cover for damage to research participants through injury or death caused by the trial. The insurance applies to the damage that becomes apparent during the trial or within 4 years after the end of the trial.The primary outcome is the mean difference between phenytoin 20% cream versus placebo cream in the 7-day average pain intensity, as measured by the NRS, over week 2 in DOBRET-positive participants.All secondary outcomes are evaluated for phenytoin 20% versus 10% versus placebo cream in DOBRET positive, negative and all participants.NRSNeuropathic Pain Symptom Inventory (NPSI), evaluating on the NRS neuropathic pain characteristics NRS for the 3 worst pain characteristics≥30% and ≥50% improvement on the NRS compared to placebo within one participant, reflecting at least moderate and at least substantial improvement Patient-reported percentage of pain reduction at the end of the second week of each interventionOnset of the analgesic effect after applicationDuration of the analgesic effect after one applicationDaily number of cream applicationsUse of escape pain medicationPain intensity measured on thesubscales of the Brief Pain Inventory (sBPI), evaluating on the NRS pain interference regarding general activity, mood, walking ability, normal work, relations with other people, sleep, and enjoyment of life EQ5-5D-5L, measuring the health status on the visual analogue scale, and on a 5-point scale pain/discomfort, anxiety/depression, mobility, self-care and usual activities Quality of life measured on thePatient Global Impression of Change Scale (PGIC), measured on a 7-point scale Tolerability is defined as time-to-discontinuation of an assigned treatment since randomization.Safety is based on the safety assessments including physical examinations, clinical laboratory evaluations, vital signs and frequency of AEs or SAEs. (S)AEs will be categorized according to the Common Terminology Criteria for Adverse Events and will be rated for severity and association with the study drug.Detection of phenytoin in plasmaTo evaluate the safety and tolerability of phenytoin 10% and 20% creamPredictive value of DOBRET in sustained pain reduction due to phenytoin creamTo evaluate the correlation between the PCS and the pain-reducing effect of topical phenytoinThe change between baseline and week 2 for each intervention is assessed for:Participant timeline is shown in Table We hypothesized a mean difference of 2 points on the NRS between placebo and the 20% cream (π1), and a mean difference of 1 point between 20% and 10% cream (π2). Based on preliminary data , we assuOn behalf of treating physicians, a standardized letter will be sent to patients who visited the neurology outpatient clinic of the UMCU from 2016 onwards and who were diagnosed with CIAP. When patients are interested to participate, they can contact the research physician, who will recruit the patients. The patients will be fully informed about the study, verbally and in writing, with special emphasis pertaining to the explanation of blood withdrawal for study purposes. The patients will be given at least one week to decide about their participation. Also, letters are sent to neurology departments of surrounding hospitals asking colleagues to refer eligible patients. On several websites such as the Princess Beatrix Muscle Foundation, the trial is described and interested patients can contact the outpatient clinic.The pharmacist who prepares the study medication externally, according to Good Manufacturing Practice (GMP pharmacist) will randomly assign a label A, B or C to the tubes each containing 90 g of phenytoin 10%, 20% or placebo cream. For the DOBRET the GMP pharmacist will randomly assign a label A or B to the test tubes with phenytoin 10% cream and placebo cream. The final labelling on each study medication set of tubes will thus be S1A, S1B and S1C (first box), S2A, S2B and S2C (second box), and so on. The final labelling on each DOBRET tube set will thus be D1A and D1B (first box), D2A and D2B (second box), and so on. The study medication and DOBRET randomization list will be given by the GMP pharmacist to the UMCU pharmacist and only accessible by the UMCU pharmacist.A blinded research physician will perform DOBRET, were after the results will be sent to the UMCU pharmacist, who will stratify participants according to the result of the DOBRET: 48 participants into the DOBRET positive arm, and 24 participants into the DOBRET negative arm. The tubes and cream are identical in appearance, to ensure the blinding of the participants and the treating physicians.The GMP pharmacist is not involved in any other aspect of the study and will randomize the study medication in blocks of 6 with a randomization list generated with the Excel software programme. This will result in a balanced distribution of the labels A, B and C to the tubes with phenytoin 10%, 20% and placebo cream. The research physician will enrol the patients after performing DOBRET. The UMCU pharmacist will evaluate the outcome of the DOBRET, will stratify to DOBRET positive and DOBRET negative participants, and will randomly assign the participant to a study medication sequence  using a predefined randomization list.Participants, investigators, site personnel, and the study statistician are masked to treatment allocation. All randomized participants who received at least one dose of the study drug will be included in the analysis.Only the UMCU pharmacist can unblind the creams in case of emergency. Unblinding can be performed 24 h a day.Demographic data and baseline assessments will be collected through an electronic or paper questionnaire. Medical history and past and current analgesic use with its effects will be asked at baseline visit or extracted from the UMCU electronic medical records. At baseline, at the 14th day of each treatment period, 3, 6 and 12 months of the open-label extension self-administered questionnaires will be collected  tube to measure free phenytoin (10%) and bound phenytoin (90%) in plasma. The specimen label will contain the participant study number. Blood samples will be stored at the UMCU laboratory, until the study is completed. The batch of blood samples from patients who were randomized during the first treatment period in the groups phenytoin 10% and 20% cream will be analysed to determine phenytoin plasma concentration. Unblinding of laboratory staff for treatment allocation will be done by the UMCU pharmacist. All samples will be destroyed after testing.Descriptive statistics will be used for baseline characteristics/demographics , use of study creams .The primary endpoint measured on the NRS, as well as all other secondary endpoints, will be analysed according to the intention-to-treat (ITT) principle, incorporating all participants randomized irrespective of receiving treatment and having at least one efficacy measurement. For the primary analysis, the treatment effect will be determined in participants with a DOBRET-positive response at screening, evaluating the mean difference in NRS at week 2 between placebo and phenytoin 20% cream. Linear mixed-effects models (LME) will be used to account for the intra-individual clustering of observations. In brief, we will use an LME with fixed effects for time (week 1 or 2), treatment period (1 or 2 or 3), treatment (20% or 10% or placebo), the interaction between time and treatment, and NRS score at screening. The random part will be modelled with a random intercept and slope for time per individual, and an unstructured covariance matrix. The random slope for time will be kept in the model only if statistically significant. The likelihood ratio test will be used to test the significance of treatment; 95% confidence intervals will be based on the profile likelihood. Sensitivity analyses will be performed to evaluate (1) treatment-period interaction to assess potential carry-over effects and (2) per-protocol analysis involving all participants who completed the study. As secondary analysis, we will evaluate the treatment effect in all randomized patients irrespective of DOBRET, and explore the interaction between DOBRET outcome and treatment using additional interaction terms. Treatment effects on the NPSI, EQ-5D-5L, sBPI and PGIC will be evaluated in the same manner as the primary outcome.MPR30, at least 30% improvement as moderate pain improvementMPR50, at least 50% improvement as substantial pain improvementFurthermore, the number of participants with a minimal pain relief (MPR), defined as the minimal percentage of pain reduction in the 7-day average pain intensity, as measured by the NRS, over week 2, will be calculated, for phenytoin 10%, phenytoin 20% and placebo cream. The number of participants experiencing the following MPRs will be determined:Regression analyses will be performed to explore associations between DOBRET results and pain reduction during the intervention periods.www.R-project.org (R Development Core Team (2008). R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. ISBN 3-900051-07-0).The statistical analysis will be performed with SPSS 22  and with the R-project, No interim analyses will be performed.p < 0.05. For the subgroup analysis, we will correct the p-value according to Bonferroni.As an exploratory objective, we will determine the test accuracy for DOBRET to identify participants who benefited from treatment, where treatment benefit is defined as a 30% reduction from baseline NRS. The following factors will be tested in the models for confounding effects: pain duration, and intensity, use of co-medication and escape medication, pain characteristics, pain catastrophizing score, level of education and duration of effect of study medication. Linear regression analyses will be used to evaluate the correlation of pain reduction with pain duration, and intensity, use of co-medication and escape medication, pain characteristics, catastrophizing, level of education and duration of effect. For all analyses, results will be considered significant when As LME models are flexible in handling missing outcome data when this occurs at random, we will not impute any missing efficacy endpoints for the primary analysis. As a sensitivity analysis, we will evaluate the following strategies: (1) last-observation-carried-forward and (2) jump-to-reference. Missing data in any of the covariates will be handled by multiple imputation and pooled according to Rubins’ rules.Participant information will be kept confidential. Results of the clinical trial will be published in a scientific journal, on the ClinicalTrials.gov website and presented on conferences. Data concerning the daily NRS will be publicly available. Requested additional data and/or analyses will be considered by the corresponding author of the published article.This monocentric trial has the following trial steering committee: principal investigator and two research physicians, supervising the trial process, such as recruiting participants and performing the trial, and reporting any AE and SAE to the Institutional Review Board. At trial completion, the trial steering committee and data manager decide in which journals the results of the trial will be published.Data monitoring will be carried out by an independent auditor, who will inspect the presence of the informed consent, verification of the inclusion and exclusion criteria, the completion of all data, the accountability of the study drug, and laboratory data. The auditor will brief any issues to the principal and coordinating investigators, who will address and resolve these issues and report back to the auditor.All AEs and SAEs experienced by the trial participants will be monitored closely, properly documented and reported to the Institutional Review Board, which can terminate the trial immediately in case of serious life-threatening adverse events due to the study drug.The independent auditor will check the data after the first 5 inclusions, after the first participant completion of the 6-week double-blind period, and at closure of the trial. The auditor will inspect the process of data gathering.No changes in the execution of the trial according to the protocol are expected. In case of deviations in the execution of the protocol occur, detailed registration and reporting to the Institutional Review Board will be carried out. Any amendments to the protocol will be submitted to the Institutional Review Board for approval. After any approved amendment participants and all trial personnel will be informed.After completion trial results will be made available through scientific journals, clinicaltrials.gov and trialregister.nl websites.Painful CIAP results from damage of the peripheral nerves, which become hyperexcitable as a consequence of upregulation and sensitization of receptors and ion channels . For exaPhenytoin can influence the upregulated and sensitized receptors and ion channels in peripheral neuropathic pain. For example, phenytoin inhibits voltage-activated sodium channels, leading to reduced firing of depolarized neurons . InteresThis trial will mainly be executed during the COVID-19 pandemic, which could affect recruitment due to patients’ fear to visit the out-patient clinic and due to capacity reduction of the out-patient clinic. This will partly be resolved by visiting patients at home. Neurological departments in the Netherlands will be approached for referral of patients. Furthermore, on the websites of Muscle disease (spierziekten.nl), Prinses Beatrix Spierfonds (spierfonds.nl), the expertise centre for CIAP (ciapexpertisecentrum.nl) and the Institute for Neuropathic Pain (neuropathie.nu) the study with its main inclusion criteria is described.This protocol version 1.9, 4th of September 2020 has been approved by the Institutional Review Board Utrecht. The recruitment started on the 16th of December 2020 and is planned to be completed at the end of 2022.


A novel feature, named temporal grading index (TGI), was proposed to quantify the temporal deviation of each network property of a patient with CBP to the normal oscillation of the HCs. The TGI of the three features achieved outstanding performance in predicting pain intensity on three commonly used regression models  through a 5-fold cross-validation strategy, with the minimum mean square error of 0.25 ± 0.05; and the TGI was not related to depression symptoms of the patients. Furthermore, compared to the HCs, brain regions that contributed most to prediction showed significantly higher CC and lower PC across time windows in the CBP cohort. These results highlighted spatiotemporal changes in functional network topology in patients with CBP, which might serve as a valuable biomarker for assessing the sensation of pain in the brain and may facilitate the development of CBP management/therapy approaches.Chronic back pain (CBP) is a maladaptive health problem affecting the brain function and behavior of the patient. Accumulating evidence has shown that CBP may alter the organization of functional brain networks; however, whether the severity of CBP is associated with changes in dynamics of functional network topology remains unclear. Here, we generated dynamic functional networks based on resting-state functional magnetic resonance imaging (rs-fMRI) of 34 patients with CBP and 34 age-matched healthy controls (HC) in the OpenPain database  Pain and pain-related diseases are major contributors to disability –3. Amongvia functional magnetic resonance imaging (fMRI)  established g (fMRI) –16. The g (fMRI) –20. For g (fMRI) , 22 and g (fMRI) ; and theg (fMRI) . These ag (fMRI) , 26.Existing evidence has suggested that the perception of pain was influenced by maladaptive neuroplastic changes over time , 28, andThe present study aims to investigate whether CBP is associated with dynamic changes in the functional network topology and to find an effective feature that could accurately predict the intensity of pain in the brain of patients with CBP. Resting-state fMRI data of 34 patients with CBP and 34 age-matched healthy controls (HC) were used to estimate the dFC through a sliding window approach along the time sequence. Degree centrality, clustering coefficient (CC), and participation coefficient (PC) of dFC network were calculated at each time window and cascaded to represent the dynamic fluctuation of network topology from the perspectives of nodal importance, local efficiency, and modular communication, respectively. Temporal grading index (TGI), a new feature that quantifies the oscillation slope of each network metric of the CBP cohort relative to the normative oscillation sequence of the HCs, was proposed and utilized to predict the pain intensity of the patients. TGI of these network metrics were submitted to three commonly used regression models , with a 5-fold cross-validation strategy, to examine the effectiveness of dynamic network topology on explaining pain intensity of patients with CBP.www.openpain.org). The database was collected by the OpenPain Project (OPP) for scientific investigation, teaching, or the planning of clinical research studies. All patients with CBP have completed the Short-Form of the McGill Pain Questionnaire (SF-MPQ), including a visual analog scale (VAS) ranging from 0 (painless) to 10 (maximum imaginable pain). The Beck Depression Inventory (BDI) was used to access the depression scores of all participants. Questions of SF-MPQ and BDI were finished 1 h before the brain scan.In the study, MRI data of 34 patients with CBP and 34 healthy controls (HC) who had matched age and gender in patients with CBP were downloaded from the Open Pain database  = 2,500 ms, echo time (TE) = 3.36 ms, flip angle = 9°, number of slices = 160, field of view = 256 mm, in-plane matrix resolution = 256×256. Resting-state fMRI (rs-fMRI) data were acquired using an echo-planar imaging (EPI) sequence at the same scanner with the following scanning parameters: repetition time (TR) = 2,500 ms, echo time (TE) = 30 ms, flip angle = 90°, number of slices = 40, slice thickness = 3 mm, in-plane resolution = 64×64, number of volumes = 245 or 305. For images that had 305 volumes, we removed the last 60 volumes to make the time point consistent   , 45.via the statistical parametric map 8  using the general pipeline. Briefly, the pipeline included the following steps: (1) removing the first 5 volumes; (2) correcting slice timing and head motion; (3) registering the functional images to the corresponding T1-weighted images, and normalizing the acquisition to Montreal Neurological Institute (MNI) space with a resampling voxel size of 3×3 × 3 mm3 resolution; (4) smoothing the normalized images with a 5-mm full-width at half-maximum (FWHM) Gaussian kernel spatially according to previous literature  redterature , 48. Parterature , 50] werterature , leavingterature  was usedterature ].n×T) for each participant was obtained, where T = 240 denotes the number of time points and n = 274 denotes the number of brain regions. We used the DynamicBC toolbox (https://guorongwu.github.io/DynamicBC)  in preprocessing of bandpass filtering   to estimiltering –57. The ing step . Finally removed , were ob removed .http://www.brain-connectivity-toolbox.net) was used to calculate the network properties of dFC matrices w of each subject across time windows, including degree, clustering coefficient (CC), and participation coefficient (PC)  . The PC ent (PC) , subcortWh (the averaged dFC networks of the HCs) from the regional network property of each patient with CBP. Then a linear regression (equation 1) model, with the result of the subtraction as the dependent variable and the network property of average HC Wh as the independent variable, was performed to extract the temporal gradient index (TGI) of each brain region of CBP patients.As shown in k is the TGI that represents the alteration gradient of this patient relative to the HC group at the temporal scale. For each patient with CBP, we concatenated the TGI of each network property across brain regions. In addition, the combination of all the TGI features was calculated via the z-score strategy.The slope To examine the validity of TGI in assessing the pain intensity of patients with CBP, three commonly used regression models  were applied to predict pain intensity (VAS scores) using the TGI. Five-fold cross-validation repeated ten times was performed and mean square error (MSE) was used to evaluate the regression performance.The Linear SVR  we used ϵℝn1× and b are the parameters of the function. For the prediction of the pain intensity, xϵℝn×1and the output f(xi) denoted the TGI feature of each brain region extracted from patients and the prediction result for the i-th patient, respectively.where ωϵℝn×1 is the parameter of the regression function. The L1-norm regularization was used to make the coefficients sparse so that the irrelevant predictors could be excluded (The regression problem of Lasso  can be dexcluded .ϵℝn×1) and the elastic net will turn into Lasso when setting α =0 (see equation 4). The L2-norm regularization enabled the model to select a subset rather than only one from the highly correlated features to overcome the deficit of using L1-norm regularization only.Compared to Lasso, elastic net  had one We used the grid search method to calibrate the λ in Lasso regression according to the previous study . For exaWe then adjusted the bias between predicted pain intensity and real pain intensity according to the bias-adjustment scheme proposed by Beheshti et al. . For eacoffset from individual predicted pain intensity  in brain regions that had high prediction power. The false discovery rate (FDR) correction with q < 0.05 was used to correct the results for multiple comparisons.Between-group differences in age and BDI score were estimated by using a two-sample DI score  to examiThe average TGI of each network property across patients with CBP is shown in We used the TGI of degree, CC, PC as well as their combination as input features of SVR, Lasso, and elastic net models to predict the VAS score via a cross-validation strategy. The results are visualized in The distribution of brain regions with the TGI that highly contributed to the regression process is shown in The present study aimed to (1) investigate whether CBP is associated with altered dynamics of topological organization of functional brain networks, and (2) develop a novel kind of feature (TGI) that could better characterize pain sensation from dynamic functional networks. We found CBP significantly altered the dynamics of functional network properties, and the gradient of these dynamics of CBP patients relative to the HCs accurately predicted pain intensity. These results suggested that CBP is accompanied by abnormal alterations of functional topology at the temporal scale, which may serve as an effective biomarker for estimating pain perception in the brain.Studies have shown that the degree gradient of patients with CBP relative to the HCs can characterize a unique neurological state of chronic pain , 69, sucInterestingly, we also found that the dynamics of CC and PC of brain regions that had TGI with high prediction power  showed distinct fluctuation patterns between patients with CBP and the HCs. Although previous studies have shown altered CC and PC of the static functional network in the CBP cohort , 75, ourThere were several limitations in the present study. First, the sample size was limited in this study. Here, we performed a 5-fold cross-validation strategy and employed three commonly used regression models  that showed high generalizability across studies –89 to reWe proposed a novel feature called TGI that was derived from the dFC network to represent the temporal deviation of network topology in patients with CBP relative to HCs. The TGI of network properties achieved outstanding performance in predicting the pain intensity of patients with CBP in three commonly used regression models, with a minimum MSE of 0.25 ± 0.05. Our findings suggested that the TGI can serve as a valuable biomarker for pain intensity evaluation and has potential application in CBP management/therapy.https://www.openpain.org/.The datasets presented in this study can be found in online repositories. The names of the repository/repositories and accession number(s) can be found at: The studies involving human participants were reviewed and approved by Northwestern University's Institutional Review Board Committee. The patients/participants provided their written informed consent to participate in this study. Written informed consent was obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article.ZL drafted the manuscript. LZ conducted data analysis. ZZ polished the manuscript. All authors provided feedback and revised the manuscript.This work is supported by the Science and Technology Innovation 2030-Major Project of China (2021ZD0202002) and the China Postdoctoral Science Foundation (2020M671726).The 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


Background Pain relief can be achieved by diversity of methods with analgesics being the basic form of treatment. Analgesic safety and clinical effectiveness are the core factors in determining the analgesic of choice. One adverse effect of concern with opioids is the postoperative ileus (POI).Objective In this study, we looked at the severity of postoperative pain, the type of analgesics used to control the pain, and the incidence of POI at Baghdad Teaching Hospital. We hypothesized that we would find an association between the type of analgesia used and POI.Methods This observational study was conducted among 100 patients who were residents at the general surgery wards of Baghdad Teaching Hospital. A structured questionnaire was employed focusing on types of analgesics, degree of pain control, and the presence of ileus.Results Sixty-nine percent of patients received a combination of opioids and nonopioids. Moderate-to-severe pain was the most commonly reported category on pain scales. More than half of the patients (57%) were found to have POI during their hospital stay and there was a statistically significant association between the type of analgesia and POI development (p=0.001).Conclusions A mix of analgesics (opioids and nonopioids) was the most common regimen at our center. The majority of the surgical inpatients reported having moderate-to-severe pain on both pain scales used in this study. Ileus incidence following abdominal surgeries (61%) was significantly higher than the reported incidence worldwide (10–30%). Postoperative ileus has multifactorial causes, one of which is the use of opioids for pain control. Considering the high incidence of ileus in our center and the association we found between the use of opioids and ileus, further studies should look at the doses of opioids used and whether alternative analgesic methods might result in less ileus. Pain relief can be achieved by a diversity of methods with analgesics being the basic form of treatment. The clinical use of different types of analgesics including opioids and nonsteroidal anti-inflammatory drugs (NSAIDs) is the standard through a proposed ladder for different types of pain; for example, the World Health Organization analgesic ladder for cancer pain or its modified one for acute pain in emergency departments and in postoperative situations.The combination of analgesic drugs has been augmented considerably in the last few years. The main concept is to use two or more drugs with different mechanisms of action to achieve synergistic interaction leading to a sufficient analgesic effect at lower doses, therefore reducing the intensity and frequency of adverse events. One example is the combination of NSAIDS and opioids which is more effective at controlling pain with lower doses of opioids.In the assessment of clinical effectiveness of analgesics, relief of pain is one of the most important variables. A set of factors must be met in pain relief interventions for optimum outcome. For example, appropriate clinician–patient interactions on the ward encourage patients to communicate unrelieved pain without feeling needy and weak. Quality assurance and frequent monitoring and displaying patient pain ratings are two other factors that improve the outcome.Analgesic safety is yet another important factor, alongside effectiveness, in making the analgesic of choice for postoperative pain relief. The consequences of overtreatment are often overlooked but can be life-threatening. An observation study done by Taylor and coworkers found that there are high rates of oversedation in the first 12 postoperative hours reaching dangerous levels in 72.7% of patients on patient-controlled analgesia.Acute kidney injury (AKI), ileus, and even death are also among the serious complications of inappropriate postoperative use of different classes of analgesics. NSAIDs were found to cause AKI through impairing renal homeostasis in around one in six patients following major abdominal surgeries and is associated in increased postoperative death at 30 days.The clinical and economic consequences of opioids are of concern as well through their adverse effect as postoperative ileus (POI). In fact, recent international data from developed countries have reported the overall consequence of POI to be an added cost of $8,300 and an increase in hospital length of stay (LOS) of 5 days.At our freestanding, urban, university-affiliated center, the overall image of postoperative pain control is hazy and the management of such cases is done on a case-by-case basis without stepping up the official analgesic ladder for acute/postoperative pain.Knowledge about the effectiveness of pain treatments is crucial to provide quality care for patients admitted to our wards, and to reduce the medical and economic adverse effects of inappropriate use of analgesics.The purpose of this study is to take first steps in looking at the types of analgesics used at our center and their adverse effects starting with ileus. We hope to collect the evidence for a more rational use of analgesic medications for the future. We hypothesized that there is an association with the type of analgesics used  and the incidence of POI.This observational study was conducted among 100 patients and residents at the general surgery wards of Baghdad Teaching Hospital. For patients to be included in the study, they had to be in their second day (or beyond) postoperatively, and have undergone open general surgery. Patients who have undergone minimally invasive surgery, those with an inpatient stay earlier than 2 days postoperatively and those who have taken opioids 1 month before surgery for any reason were all excluded from the study.Patients were sampled via a stratified random sampling for the period between October 2019 to January 2020. Gender  and the type of analgesia being given  were the characteristics used to stratify the source population into smaller groups. Thus, six strata were eventually reached which were, then, randomly sampled through random number method via using Stat Trek random number generator  to achieve equal chances for all eligible patients of being selected to participate in the study. The overall response rate was 99.3%.A structured questionnaire was employed for data collection purposes. This questionnaire was built in the English language and based on previous similar studies.The questionnaire contained three main items. First, the type of analgesia given to the patient. This was taken from the information recorded in the patients' files. Patients were, then, categorized into those who were receiving opioids, nonopioids , and both opioids and nonopioids.Second, the pain estimation scales including the visual analogue scale (VAS) and the numeric pain rating scale (NPRS), both of which were acquired through patients picking the face and number printed on the questionnaire form for the respective scale upon data collection. The numeric values of pain intensities were divided into three groups  for the NPRS and five groups  for the VAS. The two scales were presented in a sequential manner to all participants with the NPRS being presented first followed by the VAS to eliminate the carryover effect of one scale to another.Third, the presence of POI which was recorded based on the history of whether or not the patient passed feces/flatus postoperatively along with the presence or absence of bowel sounds which their lack for 72hours or more postoperatively was employed to define ileus.The questionnaire also included other data such as demographics, cause of surgery, sequence of postoperative day, history of previous surgeries, presence of nausea, vital signs, and wound examination findings making the questionnaire dependent on both, patients (history taking), and researchers (examination findings) for accurate data collection and addressing potential sources of bias, for example, recall bias.Data were collected through the aforementioned dates via a face-to-face interview between patients and researchers during the morning when patients were rested and not in distress for accurate pain estimation using the premade questionnaire. Questions with regard to the patient's history were translated into lay language for the patients to understand, then their responses were translated back into English on the questionnaire form with fixed operational definitions of the patients' spoken terms. Items that can only be addressed by the researcher were collected by a thorough examination of patients.p-value of <0.05 was considered as statistically significant throughout the analysis.The collected data were analyzed using Statistical Package for Social Sciences (SPSS) (version 25.0). Descriptive statistics were presented in frequencies and percentages using appropriate tables and figures for the purpose of comparison. For statistical analysis, exact tests were performed to test the significance of between the study variables. Spearman's correlation was used to clarify the type and strength of relationship between ordinal variables. AOf the 100 participants included in the study, the age was ranging from 13 to 83 with a mean (±standard deviation) of 42 (±18). Half of the participants were males and the other half were females. Most of the participants were in their third postoperative day (23%) among a range of postoperative days 2 to 17 with a mean of 5 (±3).Midline laparotomy was the most common incision among patients (39%), while the collar incision was the second most common type of incisions (12%). An overview of the sociodemographic data are given inThe most common types of analgesics used were both opioids and nonopioids (69%), followed by nonopioids only (26%).Most patients were assessed as having moderate pain (75%) on the numeric pain scale (NPRS) and severe pain (38%) on the VAS.Regarding the effects of the use of different types of analgesia on patients' postoperative mobilization,More than half of the participants (57%) were found to have ileus during their hospital stay. Sixty percent of those who were receiving opioids developed ileus, while only 27% of those who were given nonopioids developed it. Ileus was identified in 68% of patients who were receiving both types of analgesics .The incidence of ileus according to the type of surgery  is shown inp=0.001;There was a statistically significant difference between the type of analgesia used for pain relief and whether patients developed ileus during their hospital stay (p=0.017) and VAS (p=0.009). The correlation was weakly negative with correlation coefficient (–0.235) on the NPRS and (–0.318) on the VAS.There was a statistically significant difference between ileus development and the degree of pain control on the NPRS (p=0.545), past surgical history (p=0.602), ambulation postoperatively (p=0.627), and the type of surgery .Ileus development was independent of gender  among a range of postoperative days 2 to 17. Patients with earlier than 3 days of hospital stay were excluded, as they lack the proper recovery, also for proper assessment of analgesic complications such as ileus. This is in line with the study by Farhadi Hassankiadeh et al which suggested that most of the patients in the general surgery departments have no complications reported leaving the hospital before the third day postoperatively.Midline laparotomy was the most common incision among patients (39%), while the collar incision was the second most common type of incisions 12%). Clay et al in their randomized controlled trial found that patients following a midline laparotomy can have pain reaching up to 7 on the VAS, this pain is more likely to be ameliorated by either scaling up the analgesic choice or using an elastic griddle, if present.%. Clay eThere are many available analgesic agents postoperatively. In this study, they were classified into opioids and nonopioids classes. The majority of the patients (69%) were receiving both opioids and nonopioids to control the pain. Despite opioids are more potent, the addition of nonopioids will still provide 20 to 50% of opioids effect in pain control without opioids-related unwanted effects which delay patients' recovery.The supplemented use of opioids by nonopioids is the best strategy as suggested by previous studies.When it comes to exclusive nonopioids analgesia, only 26% of participants were receiving them. It was not a single-type medication but rather a mix of nonopioids. The combination of intravenous paracetamol with a NSAID results in better and longer lasting analgesia in some but not all patients with mild-to-moderate pain postoperatively.Looking atThe extent to which opioid consumption influences postoperative mobilization is still unknown.One of the common postoperative complications is ileus. At our center, the majority of the patients who received opioids analgesics developed ileus (60%), while only 27% of those who received nonopioids developed it . This iThe statistically significant association between ileus development along with the degree of pain control on both scales signifies that the pain control done by giving different types of analgesia is complicated by ileus development. This correlation has been shown to be a negative one. Although being weak, it means that the greater the ileus, the less pain reported on the scales and this indicates that analgesics and, especially, opioids are being given for the sole reason of pain relief without accounting for ileus, thus the high incidence of ileus at our center. Frants et al in their randomized clinical trial have highlighted the fact that NSAIDs are an acceptable and safe alternative to opioids for postoperative analgesia in rhinoplasty patients as an example.p=0.545) and past surgical history (p=0.602), the latter was positive in 74% of the patients participating in this study. Artinyan et al found them to be independent as well withp=0.81 and 0.43, consecutively.It is worth noticing that ileus development was independent of gender . This finding supports the aforementioned concept that POI at our center is being primarily influenced by the opioids' effects rather than the type of surgery, putting in mind that the type of analgesia given to surgical inpatients at our center was statically significant with ileus development in this study (p=0.001).The statistical association between ileus development and the type of surgery yielded a nonstatistically significantThis article primarily focuses on postoperative analgesics as a risk factor for ileus development among patients admitted to our center. However, the literature expands for other risk factors, such as the amount of blood loss. Artinyan and coworkers found a relationship between intraoperative blood loss and ileus.A mix of analgesics (opioids and nonopioids) constituted most of the regime at our center. The majority of the surgical inpatients reported having moderate-to-severe pain on both scales used to measure pain in this study. Ileus incidence following abdominal surgeries (61%) was significantly higher than the reported incidence worldwide (10–30%). Our results found an association between analgesics that included opioids and a higher incidence of POI. Further studies should look at the doses of opioids used and whether alternative analgesic methods might result in less ileus. Patients who were receiving opioids were better able to ambulate postoperatively; however, this finding cannot be taken for granted due to the poor control on the confounding variables associated in this study.


Sphenopalatine ganglion (SPG) is a peripheral structure that plays an important role in cluster headache (CH). Hence, a reliable method to measure the volume of SPG is crucial for studying the peripheral mechanism of CH. Additionally, the association between the clinical profiles and the morphology of the SPG in CH remains undetermined. This study aims to use the manual measurement of SPG volume to investigate its associations with CH, including headache laterality, cranial autonomic symptoms (CASs), presence of restlessness or agitation, and other clinical profiles.We prospectively recruited consecutive CH patients at a tertiary medical center between April 2020 and April 2022. A total of eighty side-locked, in-bout, episodic CH patients and 40 non-headache healthy controls received 1.5 T brain MRI focusing on structural neuroimaging of the SPG. The manual measurement process for SPG was under axial and sagittal FIESTA imaging, with reference T2 weight images  for localization. The inter-observer agreement of the SPG volume (both sides of the SPG from CH patients and controls) between the two observers was calculated. In CH patients, clinical profiles and the number of CASs (range 0–5) were recorded to analyze their association with SPG volume.p < 0.001). The mean [SD] SPG volume was larger in CH patients than in non-headache controls . In CH patients, the SPG volume was larger on the pain side than on the non-pain side . The number of CASs was positively moderately correlated with the pain-side SPG volume  but not the non-pain side SPG volume .The inter-observer agreement between the two raters was excellent for the new SPG volumetry method at 0.88 (95% CI: 0.84–0.90, This proof-of-concept study successfully measured the SPG volume and demonstrated its associations with symptomatology in patients with episodic CH. The direct measurement of SPG provide insights into studies on peripheral mechanism of CH. Cluster headache (CH) is one of the most severe pain disorders, and has a significant impact on patient quality of life, affecting 1/1000 in the general population . The claSphenopalatine ganglion (SPG), the largest extracranial parasympathetic ganglion of the head, may play a role in CASs in patients with CH –10. In ard edition (ICHD-3)  width and height of the SPG were larger in CH patients than controls . Regarding the headache laterality of CH patients, the SPG volume (mean [SD]) was larger on the pain side than on the non-pain side . The measurements of the SPG in each group are shown in Table The mean [SD] bilateral average SPG volume was larger in CH patients (35.89 12.94] μL) than controls  tr = 0.320, p = 0.004) but not the non-pain side volume . On the other hand, presence of restlessness or agitation did not associate with the either pain side  or non-pain side SPG volume .In this study, only one (1.3%) CH patient did not have any CASs, and 54 (67.5%) CH patients had sense of restlessness or agitation. Regarding the association between the SPG volume and the CASs of CH patients, the total number of CASs was positively moderately correlated with the pain side SPG volume , attack duration , or attack frequency .There were no associations between the pain side or non-pain side SPG volumes and the duration of disease (pain side: Pearson Using the manual MR volumetry for SPG, we first demonstrated that the SPG volume was not only larger in patients with CH than in controls but also larger on the pain side than the non-pain side, but there were no differences in the shape of SPG between CH patients and controls, as well as pain-side and non-pain side. Moreover, we found a higher the number of CASs associated with a larger SPG volume.Prior studies proposed the importance of SPG in the pathophysiology of CH, mainly focusing on the CASs during CH attacks –27. HoweOur study demonstrated that the SPG volume was associated with headache laterality and CASs during CH attacks. Currently, little information is available about the association between SPG volume and CH symptomatology due to the difficulty in vivo measuring the size of SPG. However, enlargement of autonomic ganglia had been observed in the cardiac and pelvic ganglia –15. In tThe present study has several implications. First, this is one of the pioneering studies that developed a method for the quantitative measurement of the SPG and, moreover, disclosed its association with headache laterality and CASs. It would be interesting to test whether SPG volumetry might be useful in the future to diagnose patients with episodic CH or the development of a neuroimaging-based headache classification system. Second, this volumetry might be used to study disorders manifesting with CASs or other trigeminal autonomic cephalalgias. However, the study also has limitations that must be considered when interpreting the results. First, our study results could not be extrapolated to chronic CH because we only recruited patients with episodic CH. Because of the rarity of chronic CH in Asians , we, forCH patients had larger SPG volume than non-headache controls. In side-locked episodic CH patients, the SPG volume was larger on the pain side than on the non-pain side. Additionally, the number of CASs was positively correlated with the SPG volume. The direct measurement of SPG provides insights into future studies on the peripheral mechanism of CH.


The quantity of opioids prescribed at discharge was associated with opioid consumption on the DpDC only in the Mucosal and FF groups, which had longer LOA (6–7 days) than the Neck and OP groups . Overall, 65% of patients required at least one dose of an opioid on the DpDC, yet 76% of patients received a prescription for an opioid medication at discharge. A longer LOA  and higher Charlson Comorbidity Index  were negatively associated with receiving an opioid prescription at the time of discharge despite no opioid use on the DpDC, respectively. HNC patients, particularly those with shorter LOA, may be prescribed opioids in excess of their post-operative needs, highlighting the need the for improved pain management algorithms in this patient population. Future work aims to use prospective surveys to better define post-operative and outpatient pain and opioid requirements following HNC surgery.Pain management is an important consideration for Head and Neck Cancer (HNC) patients as they are at an increased risk of developing chronic opioid use, which can negatively impact both quality of life and survival outcomes. This retrospective cohort study aimed to evaluate pain, opioid use and opioid prescriptions following HNC surgery. Participants included patients undergoing resection of a head and neck tumor from 2019–2020 at a single academic center with a length of admission (LOA) of at least 24 h. Exclusion criteria were a history of chronic pain, substance-use disorder, inability to tolerate multimodal analgesia or a significant post-operative complication. Subjects were compared by primary surgical site: Neck , Mucosal , Oropharyngeal (OP) and Free flap (FF). Average daily pain and total daily opioid consumption  and quantity of opioids prescribed at discharge were compared. A total of 216 patients met criteria. Pain severity and daily opioid consumption were comparable across groups on post-operative day 1, but both metrics were significantly greater in the OP group on the day prior to discharge (DpDC) (5.6 (1.9–8.6),  Prescription opioids have significantly contributed to the recent opioid epidemic. Multiple studies across surgical specialties have shown that patients are prescribed opioids in excess of their post-operative requirements , 2. WithPain management is an important consideration for quality of life as well as survival outcomes in Head and Neck Cancer (HNC) patients –8. TheseRecent efforts have been made across the United States to limit inappropriate prescribing of opioids, and clinical practice guidelines have been developed to improve management of pain in the perioperative setting –18. WithTo provide safer and more effective pain management guidelines for HNC patients, it is essential to better define post-operative pain and opioid requirements in this patient population. Herein we evaluate patterns of pain, opioid use, and opioid prescriptions following inpatient surgeries for HNC patients and highlight the need for improved pain management algorithms in this patient population.A retrospective review of patients undergoing surgery for tumors of the head and neck in the Otolaryngology – Head & Neck Surgery department was performed at a single academic institution. This project was reviewed and approved by our institutional review board (IRB00251111). Inclusion criteria were: (1) age 18 years or older, (2) surgery for tumor in the head and neck region, (3) surgery from January 1, 2019 – January 1, 2020 at Johns Hopkins Hospital, (4) length of admission (LOA) following surgery of at least 24 h (measured from the time the patient was awake and recovered from anesthesia) and (5) “opioid naïve,” defined as no opioid consumption within the 30 days prior to surgery. Exclusion criteria were: (1) past medical history of chronic pain or substance use disorder, (2) inability to tolerate multimodal analgesia  due to medical comorbidity  or intolerance or allergy and (3) post-operative complication requiring return to the operating room during admission. Patients were grouped by surgical procedure as follows: (1) Neck group: neck dissection (ND) alone or thyroidectomy or parotidectomy with or without ND), (2) Mucosal group: resection of tumor of the upper aerodigestive tract other than in the oropharynx, with or without ND, but without free flap reconstruction (3) Oropharyngeal (OP) group: resection of primary oropharyngeal tumor with or without ND, but without free flap reconstruction, (4) Free flap (FF) group: resection of tumor of upper aerodigestive tract requiring reconstruction with a free flap .Patient demographics, including age, sex and ethnicity, and past medical and surgical history were collected by chart review from our electronic medical record (EMR) system. Charlson Comorbidity Index (CCI) scores were calculated based on ICD-9 codes , 24. CanContinuous variables are reported as the median and range or mean and standard deviation (SD), where applicable. Kruskal-Wallis test was used to compare continuous measurements between multiple groups, and Fisher's exact and Chi-squared tests were used to compare categorical variables between two and more than two groups, respectively. Wilcoxon matched-pairs signed rank test was used to compare paired data from individual patients at different time points. Linear regression analysis was used to determine significant predictors of quantity of opioids consumed following surgery and quantity of opioids prescribed at discharge; this was performed for all patients as well as within each surgical group. Multivariable logistic regression analysis was used to evaluate factors associated with receiving an opioid prescription at the time of discharge in patients with no opioid use during the 24 h prior to discharge (DpDC). Independent variables evaluated include age, sex, race, cancer stage, CCI, surgical procedure, LOA, and average pain severity on the DpDC. Of note, the surgical procedure group OP was not included as an independent variable given the small number of OP patients in the subgroup evaluated in this regression analysis. Results are reported as the adjusted odds ratio (aOR) and 95% confidence interval (CI). All statistical analysis was performed using R Statistical Software .p < 0.001) and FF (61 (42–80) years, p < 0.001) groups. The proportion of females was significantly greater in the Neck group (68%) compared to all others, which averaged between 25-31% female (p < 0.001). The CCI was significantly lower in the Neck group (2–15) compared to the Mucosal (8 (2–19), p < 0.001) and FF (6 (2–15), p < 0.05) groups. Considering tumors able to be staged, the Neck and OP groups had a significantly higher proportion of Stage I or II tumors compared to the Mucosal and FF groups (p < 0.001). Similarly, a significantly lower proportion of patients had a history of radiation therapy (RT) in the Neck group (1%) compared to the Mucosal  and FF  groups. The median LOA was approximately 1 day for the Neck and OP groups, compared to 6–7 days for the Mucosal and FF groups (p < 0.001). Overall use of benzodiazepines and Z-drugs was low, 6% and 1%, respectively, and did not significantly differ between groups. A greater proportion of patients used SRIs (18%) and gabapentinoids (13%) while inpatient, with a significantly lower proportion of gabapentinoid-use in the Neck (5%) group compared to Mucosal  and FF  groups.A total of 216 patients met inclusion criteria. Demographics and clinical information about the patient cohort are shown in p < 0.01), Mucosal , and FF  groups. On POD 1, 86% of all patients required at least one dose of an opioid medication for pain control. By the DpDC, only 65% of all patients consumed at least 1 dose of an opioid medication. Average daily opioid consumption on the DpDC was significantly greater in the OP group (49 ± 44 MME/day) compared to the Neck  and FF  groups.Average daily pain and total daily opioid consumption were compared between surgical groups on the first post-operative day (POD 1) and the day prior to discharge from the hospital (DpDC) . Pain se2 = 0.49, p < 0.001) and OP  groups, and on the DpDC within the Neck group . Older age was weakly associated with lower opioid consumption within the FF group on the DpDC . Additionally, subgroup analysis showed significantly higher average pain levels and daily opioid consumption in the subgroup of all patients taking SRIs (N = 39) versus those not taking SRIs (N = 177) on POD 1  and the DpDC . Similarly, the subgroup of all patients taking gabapentinoids (N = 27) while inpatient had higher average pain levels than those not taking gabapentinoids (N = 189) on POD1  and the DpDC ; with no difference in opioid consumption between subgroups. Otherwise, sex, ethnicity, CCI score, cancer stage, history of RT and LOA were not associated with average opioid consumption within each surgical group or overall.Linear regression analysis showed a weak association of pain levels with the quantity of opioids consumed on POD1 in the Neck (Rp < 0.001), Mucosal  and FF groups . Additional subgroup analysis showed no difference in the quantity of opioids prescribed at discharge between subgroups of all patients taking SRIs versus those not taking SRIs while inpatient; with similar findings for subgroups based on gabapentinoid-use while inpatient. Multivariable logistic regression analysis was used to evaluate factors associated with receiving an opioid prescription at the time of discharge in patients with no opioid consumption during the 24 h prior to discharge ; this was 2–3 times greater than the quantity prescribed to the Neck  (p < 0.05)   and base < 0.05) , which rThis study analyzes post-operative pain and opioid consumption in a cohort of patients undergoing resection of tumors of the head and neck. Overall, we found that most patients (86%) consumed at least one dose of opioid medication on the first post-operative day. By the day prior to discharge, this had decreased to only 65% of all patients, and only 60% of patients had substantial opioid requirements of 7.5 MME/day (5 mg oxycodone/day). Despite these modest numbers, 76% of all patients received an opioid prescription at discharge. There was also discrepancy in the quantity of opioids prescribed between groups with similar pain levels as demonstrated by the FF group receiving nearly twice as much opioid than the Neck group. While the length of admission varied between patients, all patients had at least 24 h of data of pain levels and opioid consumption prior to discharge.The American Academy of Otolaryngology recently published a comprehensive Clinical Practice Guideline providing evidence-based recommendations for opioid prescribing after common Otolaryngology procedures . These gPain severity did not strongly correlate with opioid consumption or quantity of opioid prescribed at discharge overall or within each surgical group. However, the Mucosal and FF groups had a moderate association between opioid consumption on the day prior to discharge and the quantity of opioids prescribed at discharge. Both groups also had longer lengths of admission, of 6–7 days, compared to 1 day in the Neck and OP groups. This further suggests that prescribing patterns may better represent inpatient opioid requirements as more longitudinal data about patients is available.Numerous efforts have been made to further our understanding of factors affecting post-operative pain since the role of prescription opioids in the opioid epidemic has been elucidated –21, 27. Multimodal analgesia with NSAIDs has become the standard of care following most Otolaryngology procedures, including tonsillectomy, since studies have shown no increased risk of bleeding ; the useDespite the aforementioned progress, opioid medications continue to be prescribed in excess of patients' needs following tonsillectomy  and otheThe above findings highlight potential to improve our estimation of patients' opioid requirements following discharge from the hospital. Recent efforts by a General Surgery group showed that in patients undergoing inpatient general surgery procedures, opioid consumption on the day prior to discharge was correlated with outpatient use, suggesting this information could be used as a metric for prescribing . Follow-This study is limited by the relatively small sample size and retrospective nature of the EMR review. As guidelines have been implemented to limit the quantity of opioids physicians can initially prescribe, we aimed to evaluate data from a recent and limited time period for consistency. Patients with specific comorbidities preventing the use of multimodal analgesia with scheduled acetaminophen and ibuprofen were excluded to compare a more homogenous population, which may limit external validity. While total quantity of opioids prescribed at discharge may be influenced by concern about access to refills, this is less likely as all prescribers at our institution are able to electronically prescribe scheduled medications and an on-call physician is available around the clock for patient phone calls. Finally, this current study is limited to the evaluation of inpatient data.Effective and safe pain management following HNC surgery is imperative for both quality of life and survival outcomes in this patient population. Despite recent progress in decreasing prescription opioids, our study shows that these medications continue to be prescribed in excess of patients' post-operative needs. Future work aims to better define post-operative pain and opioid requirements following HNC surgery. Our group is currently collecting data on daily opioid consumption after discharge from the hospital with prospective surveys in a comparable patient population. This information will allow us to investigate patient and surgical factors, such as opioid consumption on the day before discharge from the hospital or surgical procedure, associated with outpatient opioid consumption. The ultimate goal of these studies is to develop a model to improve our prediction of a patient's opioid requirements, thereby limiting the risk associated with excess opioid prescriptions.The raw data supporting the conclusions of this article will be made available by the authors, without undue reservation.The studies involving human participants were reviewed and approved by Johns Hopkins IRB. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.DT, CP-H, and PV contributed to conception and design of the study. DT and CP-H organized the database and performed the statistical analysis. DT wrote the first draft of the manuscript. All authors contributed to the article and approved the submitted version.This research was supported by NIH T32DC000027-32 grant.The 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.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.