Background and Objectives: Patients experience severe pain after surgical correction of ankle fractures. Although their exact mechanism is unknown, dexamethasone and epinephrine increase the analgesic effect of anesthetics in peripheral nerve blocks. This study aimed to compare the postoperative pain control efficacy of peripheral nerve blocks with ropivacaine combined with dexamethasone/epinephrine and peripheral nerve blocks with only ropivacaine and added patient-controlled analgesia in patients with ankle fractures. Materials and Methods: This randomized, controlled prospective study included patients aged 18–70 years surgically treated for ankle fractures between December 2021 and September 2022. The patients were divided into group A (n = 30), wherein pain was controlled using patient-controlled analgesia after lower extremity peripheral nerve block, and group B (n = 30), wherein dexamethasone/epinephrine was combined with the anesthetic solution during peripheral nerve block. In both groups, ropivacaine was used as the anesthetic solution for peripheral nerve block, and this peripheral nerve block was performed just before ankle surgery for the purpose of anesthesia for surgery. Pain , patient satisfaction, and side effects were assessed and compared between the two groups. Results: The patients’ demographic data were similar between groups. Pain scores were significantly lower in group B than in group A postoperatively. Satisfaction scores were significantly higher in group B (p = 0.003). There were no anesthesia-related complications in either group. Conclusions: Dexamethasone and epinephrine as adjuvant anesthetic solutions can effectively control pain when performing surgery using peripheral nerve blocks for patients with ankle fractures. Severe pain after orthopedic surgery contributes to fear of surgery and post-traumatic stress disorder . PostopeRopivacaine is usually used as an anesthetic solution for PNB. The analgesic effect of PNBs with ropivacaine is brief, generally lasting <24 h postoperatively . HoweverWe hypothesized that PNB with dexamethasone and epinephrine is more effective than other pain control methods after conventional PNB. Therefore, this study aimed to prospectively compare PNB combined with dexamethasone/epinephrine and patient-controlled analgesia (PCA) using ketorolac after PNB anesthesia in patients with ankle fractures.This single-center randomized, controlled prospective study enrolled patients aged 18–70 years surgically treated for ankle fractures between December 2021 and September 2022. Unilateral open reduction and internal fixation for ankle fractures were performed on the patients by a single surgeon who has been operating in this field for >10 years. Fracture types included fractures involving the articular surface of the distal tibia and fibula, including simple fibula fractures, bimalleolar fractures, trimalleolar fractures, and pilon fractures. Patients were blinded to their group assignment and hospitalized for at least three days for postoperative pain control.2, which is considered underweight according to the World Health Organization standard [The exclusion criteria were contraindication for PNBs; uncontrolled diabetes mellitus, peripheral vascular disease, renal or hepatic disease, or any neurologic disease; and contraindication for regional anesthesia (coagulopathy or injection site infection). Patients with body mass index <18.5 kg/mThis study was approved by the institutional review board (CNUSH 2021-11-003) and was conducted in accordance with the Declaration of Helsinki. This study was registered with the ISRCTN registry (ISRCTN17431025). Written informed consent was obtained from all patients. A single researcher explained and conducted the study. Patients understood, and agreed to be hospitalized for more than three days according to their will, which is common in this research institution for hospitalization of more than three days after ankle fracture surgery, and is related to the medical system. All authors approved the final version of this manuscript.All patients were anesthetized using ultrasound-guided PNB with ropivacaine. We randomly allocated 60 participants (1:1) into two groups using blinded randomization blocks. Group A received PCA with ketorolac for postoperative pain management after PNB. Group B received PCA with normal saline; instead, dexamethasone and epinephrine were added to ropivacaine during PNB. The allocation sequence was concealed from the researchers and participants in sequentially numbered, opaque sealed envelopes. The envelopes were opened only for the researchers after the enrolled participants had completed all baseline assessments, when it was time to perform the intervention in the operating room. A sample size of 59 patients was determined based on the following parameters: significance level (5%), statistical power (90%), sample ratio (1:1), variance (2.5), and difference between the two groups (1.5). To obtain a 1:1 ratio between groups, we included 60 cases (30 in each group).In group A, PCA was initiated approximately 10 h after PNB induction ,9. The t®, AstraZeneca AB, Sodertalje, Sweden) combined with dexamethasone disodium phosphate 5 mg  and epinephrine 0.1 mg ; epinephrine was added in a ratio of 1:200,000. The same PCA instrument was also used for all patients in group B. However, only normal saline was administered in the same way as in group A. We kept all patients unaware of which group they belonged to until the end of the study. To do so, the same PCA instrument was applied to all patients included in this study. In both groups, patients with visual analog scale (VAS) scores ≥ 5 received intravenous acetaminophen  for rescue analgesia. VAS scores obtained within 8 h of intravenous acetaminophen injection were excluded from the analysis. No other pain control medications or methods were used in either group.In group B, PNB was performed using an anesthetic solution of ropivacaine  was compared between the two groups at 6, 12, 18, 24, 32, 40, 48, and 60 h after PNB. The time at which the sensation began  and the time at which motor function was restored were recorded. After three days of administering pain control, a questionnaire was completed to assess patients’ satisfaction with the pain control method . The clinical researcher collected the questionnaires and confirmed that the patients had filled them correctly . The cliThe surgeon administered the anesthetic solution (30 mL 0.75% ropivacaine) via a 50-mL syringe connected to a venous catheter with a 100-mm, 23-gauge spinal needle. A registered nurse prepared the anesthetic solution by adding dexamethasone and epinephrine to the ropivacaine .A standard noninvasive monitor was used in the operating room, and an intravenous line was secured. A 3–12 MHz linear transducer with an ultrasonic device  was used. All patients received an ultrasound-guided single-injection sciatic nerve block at the mid-thigh level on the lateral side, and a femoral nerve block in the inguinal area. The femoral and sciatic nerves were each injected with 15 mL of the solution under aseptic conditions.The patients were placed in a supine position, and a femoral nerve block was performed. A spinal needle was inserted via an in-plane approach while ultrasonographically visualizing the short axis of the femoral nerve at the inguinal level. Ultrasound visualization helped confirm the correct needle position. Following this, a negative aspiration was performed and 15 mL of local anesthesia was injected in fractionated doses over a minute. A sciatic nerve block was performed in the proximal 15 cm of the popliteal fossa before separating the tibial and peroneal nerves, while the patient was in a supine position with their knee flexed at 60 degrees. Local anesthesia injection around the sciatic nerve was performed with the same technique employed for the femoral nerve block .After confirming the loss of a cold sensation in the ankle and lower leg, surgery was started. The same orthopedic team conducted all surgeries. At surgery commencement, patients complaining of mild pain in the medial malleolar area received 5 mL local injections of 1% lidocaine hydrochloride  for analgesia. A tourniquet was applied to the distal thigh in all patients. In some patients, thigh pain during the surgery was relieved by removing the tourniquet after a rubber bandage was wrapped around the proximal tibia. A scrub nurse recorded the operation start and end times.p ≤ 0.05.All statistical analyses were performed using SPSS software . VAS and satisfaction scores were compared between pain control methods using a Mann–Whitney U test. Sex and diagnoses were compared using a chi-square or Fisher’s exact test. Operation time and motor and sensory function recovery times were compared between the groups using an independent t-test. Results are considered statistically significant at All 60 enrolled patients completed the study. Patient characteristics were similar between the two groups. Group A included 20 men, and Group B comprised 19 men. The fracture types in both groups are shown in p < 0.001). There were no complaints of pain in both groups at 6 h. In group A, sensation began to return before PCA was applied in some cases, at approximately 10 h, but no cases of severe pain were reported until the beginning of PCA. If additional pain control was required postoperatively, intravenous acetaminophen was administered. In group A, five patients received intravenous acetaminophen between 12 and 18 h, and one had an additional same dose injection. In group B, three patients received intravenous acetaminophen, two between 24 and 32 h and one between 32 and 40 h. Satisfaction scores  differed significantly between the groups . Complications related to anesthesia or surgery were not reported in any group  was locally injected into the surgical site at the start of the operation due to medial malleolar pain. The average time between the groups from anesthesia initiation to surgery completion was similar. After surgery, the surgeon confirmed that all patients’ ankles and lower extremities were completely paralyzed. Analgesia duration and the time of recovery of motor function after surgery differed significantly between the groups. In group A, the analgesia time was an average of 11.6 h (8–14), and motor function recovery began at an average of 12.0 h (8–15.5). In group B, sensation was restored at 35.8 h (20–42), and movement at 35.6 h (21–41) ; no significant difference was noted at 6 and 32 h   , Table 3The combined use of ropivacaine with dexamethasone and epinephrine for PNB provided significantly prolonged and better analgesic effects than PCA after PNB anesthesia with ropivacaine alone. Moreover, patients who received dexamethasone and epinephrine experienced significantly less pain than the controls, even after the anesthetic effect had worn off. This finding may be related to the drug effect of dexamethasone or epinephrine, or a psychological effect related to delayed pain onset after anesthesia. Two patients in the dexamethasone and epinephrine group reported VAS pain scores of 0 throughout the investigation, even after recovering motor and sensory nerve function.However, no significant difference was noted in VAS scores between the two groups at 32 h after surgery. In group A, patients complained of peak pain about 24 h after surgery, which gradually decreased. However, patients in group B complained of peak pain at around 32 h, when the effect of PNB disappeared; then, the pain level decreased further over time. Therefore, the pain difference between the two groups was considered to be the smallest at around 32 h. This finding is thought to be associated with some rebound pain, with complaints of high repulsive pain in some cases at the point at which the effects of PNB disappear .In orthopedics, morphine, non-steroidal anti-inflammatory drugs (NSAIDs), and acetaminophen are common postoperative pain control medications, but they all have limitations. Patients may experience severe pain after surgery, but morphine often has side effects and can be fatal when overused . NSAIDs Ropivacaine is a long-acting amide local anesthetic. The major concern when using high doses of local anesthetic is systemic toxicity, which develops when the free serum concentration of ropivacaine exceeds the toxic threshold . RopivacThere are conflicting reports on whether adding epinephrine to ropivacaine is effective. Most studies showing its effectiveness found that it reduced the risk of toxicity by slowing systemic absorption. However, the studies did not identify a significant effect on analgesic duration. Several researchers advocate the addition of epinephrine to large doses of local anesthetics to reduce the maximum plasma concentration . Adding The glucocorticoid, dexamethasone, appeared to be effective in one preclinical  and seveGiven the conflicting reports of the pharmacokinetic effects of the addition of dexamethasone or epinephrine to PNBs ,24,25,262) and those with systemic diseases were excluded. Second, we were careful not to cause toxicity reactions while administering the drugs to the patients. The authors restricted the use of additional drugs other than those approved in this study for patients. Additionally, 1% lidocaine administered during the surgery was minimized to 5 mL because of the aforementioned problems.During our study, we considered the possibility of anesthetic drug toxicity ,27. FirsAs expected, pain scores remained significantly different, with a block duration at most time points. The total number of additional analgesic injections administered over the first 60 h differed significantly between the groups. No significant complications occurred in either group; no neurological symptoms were reported.In cases in which sensation remained on the medial side after anesthesia induction, a part of the posterior division of the femoral nerve was not completely anesthetized . AdditioIn our study, both sensation and movement returned gradually. In group A, sensation returned first, whereas in group B, movement returned first. The sensation was determined based on when patients reported starting to feel pain. However, because the pain increased gradually, patients had difficulty specifying the point at which sensation was restored, and recovery of movement was often only identified after the patient had started moving their foot to some extent, which can be difficult to measure and can produce inaccuracies. In addition, accurate measurements were difficult when sensation and movement were recovered late at night or while the patient was sleeping. In some cases, the exact time point could not be identified. Therefore, investigating the exact time of motor and sensory function recovery was difficult in this study.Most patients with ankle fractures can be discharged immediately after surgery. Administration of dexamethasone and epinephrine with PNB may be useful in cases wherein patients with fractures require or want hospitalization. Moreover, when managing an ankle fracture, we thought this method could be beneficial for pain control at home after hospital discharge, even in non-hospitalized patients. However, delayed motor and sensory function recovery caused discomfort in some patients. The transfer process at discharge, motor and sensory function recovery progress after discharge, and related precautions should be sufficiently explained. Alternatively, a saphenous nerve block in the adductor canal, rather than a femoral block, can also reduce the above problems. An ankle block can be convenient and require little concern for patient safety in some cases.In addition, postoperative sensory loss can cause problems in terms of detecting if or when compartment syndrome occurs. We must be aware of the possibility of postoperative compartment syndrome and prepare diagnostic methods, because the period without motor and sensory functions lasts very long after PNB.Normal pressure within a compartment is less than 10 mmHg. An intra-compartmental pressure greater than 30 mmHg indicates acute compartment syndrome and the need for fasciotomy. However, a single normal intra-compartmental pressure reading does not exclude acute compartment syndrome. Intra-compartmental pressure should be monitored serially or continuously. Several methods can be used for monitoring. Before the 1960s, most measurements of intra-compartmental pressure used needles to inject saline. When intra-compartmental pressure increases to within 10 mmHg to 30 mmHg of the patient’s diastolic blood pressure, it indicates inadequate perfusion and relative ischemia of the involved extremity. A Stryker Intra-Compartmental Pressure Monitor System  has been used recently to evaluate compartment pressure. It is a portable monitor that uses a side port needle, a disposable syringe of saline flush, and a digital read-out manometer to allow for simple measurement of compartment pressure .If there is even a slight suspicion of compartment syndrome after PNB, one should be ready to apply these methods. This may reduce the risk to some extent. However, according to research, even this can often be inaccurate and insufficient . In concIt is important to note that complications may occur when applying PNB to patients and using anesthetic drugs. When high-dose local anesthetics are used, the main problem is systemic toxicity when the free ropivacaine serum concentration exceeds the threshold. However, when anesthetics are mixed with dexamethasone and epinephrine, they cause local vasoconstriction near the injection site, which slows the drug absorption, thus lowering the maximum plasma concentration of the free ropivacaine ,21. ThusThis study is considered a well-compared study, with no dropouts of patients and measurement errors. However, this study had limitations. First, our study only included a few patients. Second, we did not perform mid- to long-term observations; thus, longer-term complications and sequelae should be studied in larger study populations after using the combination of medicines. Further research is needed to determine whether this medication combination will be effective for other types of surgery, or if this combination can be applied to nerves in other body parts. In our study, we used ropivacaine with dexamethasone and epinephrine; hence, it was unknown which of the two drugs played a major role in sustaining the anesthetic effect. In addition, it was impossible to provide the dose of the drug combination appropriate for a single use of epinephrine or dexamethasone. Moreover, future comparative studies should determine the effect of adding only dexamethasone or epinephrine to ropivacaine, and the optimal concentration of these drugs for achieving the maximum effect while reducing side effects.PNB is a useful anesthetic method for patients with an ankle fracture. The adjuvant use of dexamethasone and epinephrine as anesthetic agents had an excellent effect on pain control by extending the duration of the anesthetic effect. The anesthesia method described herein could be useful if surgery is selected after carefully considering the exclusion criteria.


Celecoxib‐tramadol co‐crystal (CTC) is a first‐in‐class analgesic co‐crystal of celecoxib and racemic tramadol with an improved pharmacologic profile, conferred by the co‐crystal structure, compared with its active constituents administered alone/concomitantly.We evaluated CTC in moderate‐to‐severe acute postoperative pain.This randomized, double‐blind, factorial, active‐ and placebo‐controlled phase 3 trial (NCT03108482) was conducted at 6 US clinical research centers. Adults with moderate‐to‐severe acute pain following bunionectomy with osteotomy were randomized to oral CTC (200 mg [112 mg celecoxib/88 mg rac‐tramadol hydrochloride] every 12 h), tramadol (50 mg every 6 h), celecoxib (100 mg every 12 h), or placebo for 48 h. Patients, investigators, and personnel were blinded to assignment. The primary endpoint was the 0–48 h sum of pain intensity differences (SPID0–48) in all randomized patients. Pain intensity was assessed on a 0–10 numerical rating scale (NRS). Safety was analyzed in patients who received study medication. Funded by ESTEVE Pharmaceuticals.p < 0.001), celecoxib , or placebo . Total treatment‐emergent adverse events (TEAEs) were 358 for CTC and 394 for tramadol. Drug‐related TEAEs occurred in 37.7% patients in the CTC group, compared with 48.6% in the tramadol group. There were no serious TEAEs/deaths.In 2017 (March to November), 1323 patients were screened and 637 randomized to CTC (n = 184), tramadol (n = 183), celecoxib (n = 181), or placebo (n = 89). Mean baseline NRS was 6.7 in all active groups. CTC had a significantly greater effect on SPID0–48  than tramadol (−109.1 ; CTC provided greater analgesia than comparable daily doses of tramadol and celecoxib, with similar tolerability to tramadol. CTC is approved in the United States. There is an unmet need for new multimodal treatment options that are well tolerated, with equal or superior efficacy, and reduced risk of adverse outcomes such as abuse and dependence, compared with current conventional opioid analgesics.Today, provision of multimodal analgesia is standard care. For appropriate patients with moderate‐to‐severe acute pain, opioids are often a useful component of multimodal regimens.Celecoxib‐tramadol co‐crystal (CTC) has been developed as a multimodal treatment option for the management of acute pain severe enough to require an opioid. CTC contains tramadol, a μ‐opioid agonist and norepinephrine and serotonin reuptake inhibitor, plus the cyclooxygenase‐2 selective inhibitor celecoxib.The co‐crystal structure of CTC changes the physicochemical properties of celecoxib and tramadol in a way not achieved by their fixed‐dose or free combination.CTC received US Food and Drug Administration approval in October 2021.rac‐tramadol hydrochloride 176 mg) compared with tramadol 50 mg four times daily or celecoxib 100 mg twice daily.Using an established model of acute pain, and comparable doses of active ingredients, the present study demonstrates the superior analgesic efficacy of CTC twice daily , and a safety profile similar to tramadol.Celecoxib‐tramadol co‐crystal (CTC) received US Food and Drug Administration approval in October 2021.Combining tramadol (a μ‐opioid agonist and norepinephrine and serotonin reuptake inhibitor) with celecoxib (a cyclooxygenase‐2‐selective inhibitor) in CTC provides multimodal analgesia via 4 complementary mechanisms of action in central and peripheral pain pathways. Multimodal pharmacologic analgesia may improve efficacy beyond that provided by single agents while minimizing dose requirements and dose‐dependent adverse events (AEs) and is recognized as an essential tool in pain management. CTC, therefore, targets an unmet need for efficacious and well‐tolerated multimodal analgesics. CTC also addresses an unmet need for analgesics that are suitable for treating acute pain severe enough to require an opioid and that might also reduce the risk of adverse effects associated with conventional opioids ; tramadol has a lower risk of these effects than conventional opioids.rac‐tramadol hydrochloride) every 12 h as needed for pain relief,CTC is formulated as a 100‐mg immediate‐release tablet containing 56 mg of celecoxib and 44 mg of tramadol for oral administration. The recommended dosing regimen is 200 mg  requirements for the design of factorial studies assessing fixed‐dose combinations.https://clinicaltrials.gov/ct2/show/study/NCT03108482. Trial registration (submission) date was March 30, 2017. Patients were screened between March 14 and November 1, 2017; randomization occurred between March 21 and November 7, 2017.This randomized, double‐blind, factorial, active‐ and placebo‐controlled, parallel‐group, phase 3 clinical trial (NCT03108482) was performed at 6 US clinical research centers. The protocol was approved by an Institutional Review Board; Sterling IRB . The study was conducted in accordance with the ethical principles originating from the Declaration of Helsinki, the International Council for Harmonization guidelines for Good Clinical Practice, and local regulatory requirements. The protocol and statistical analysis plan are available at Eligible patients were ≥18 years old with moderate‐to‐severe pain  within 8 h of popliteal sciatic block cessation, following primary unilateral first metatarsal osteotomy with internal fixation and no additional collateral procedure. Full criteria are described in the supplemental digital content. All patients provided written informed consent.Eligible patients were randomized 2:2:2:1 to oral CTC 200 mg every 12 h, celecoxib 100 mg every 12 h, tramadol 50 mg every 6 h, or placebo every 6 h. Each CTC dose was given as two 100‐mg immediate‐release tablets; each tablet contained 56 mg of celecoxib and 44 mg of racemic tramadol. Randomization was stratified by center and baseline pain score (moderate [NRS 5–6] or severe [NRS 7–9]). At study start, a computer‐generated randomization schedule was prepared and randomization numbers were assigned sequentially via central interactive response technology. No one involved in study conduct had access to the schedule before official unblinding. Patients, investigators, and study personnel were blinded to assignment. To maintain blinding, all medications, including placebo, were provided as over‐encapsulated tablets. In the CTC and celecoxib groups, placebo was administered at the 6‐h midpoint between active treatments.Study duration was ≤6 weeks, including a screening period of ≤28 days. Patients were admitted to the center on the morning of surgery, remained there for 3 nights , and returned for a follow‐up visit 5 to 9 days post‐surgery. The treatment period was 48 h.Patients underwent bunionectomy with osteotomy and internal fixation under standardized regional anesthetic, involving popliteal sciatic nerve block and continuous sciatic infusion via a catheter placed in the proximity of the popliteal sciatic nerve. Patients received midazolam and/or propofol for initial sedation, lidocaine 1% for local anesthesia, and ropivacaine 0.5% for popliteal sciatic nerve block. If popliteal sciatic nerve block was insufficient to provide adequate anesthesia, a standard Mayo block with lidocaine 2% was permitted. Regional anesthesia (mepivacaine 0.5% or ropivacaine 0.2%) was continued after surgery, via continuous infusion, and discontinued between 3:00 and 4:00 am the day following surgery. After this time, patients meeting the inclusion criteria for baseline pain intensity were randomly assigned to treatment. Supplemental analgesia with intravenous ketorolac was permitted until 1:00 am to help control breakthrough pain if the regional anesthetic infusion was insufficient to provide adequate analgesia.Patients could receive rescue medication for pain after discontinuation of anesthetic and initiation of study medication . Patients were encouraged to wait ≥1 h after the first dose of study medication before receiving rescue medication.Pain intensity was assessed using the NRS  at: 0 h (before study medication); 15, 30, and 45 min; 1, 1.25, 1.5, 1.75, 2, 2.5, 3, 3.5, 4, 5, 6, 7, 8, 10, 12, 14, 18, 22, 24, 26, 28, 30, 32, 34, 36, 38, 42, 46, and 48 h; and immediately before rescue medication. Pain relief scores were assessed at the same time points, using a 5‐point categorical scale. Patients were asked, “How much relief have you had since your starting pain?”, with response choices of none (score of 0), a little (1), some (2), a lot (3), and complete (4). The pain intensity assessment was completed before the pain relief assessment; patients were not permitted to compare their responses with previous responses. Pain intensity and pain relief results were recorded in patient diaries. Pain assessments were performed during the night only if the patient was awake (patients were awakened to administer study medication). Time to perceptible and meaningful pain relief was measured using the double stopwatch technique starting at time 0 . Patients were instructed to stop the first stopwatch when they perceived any pain relief, and to stop the second stopwatch when they experienced pain relief that was meaningful to them. Patients provided an overall assessment of study medication by answering the following global evaluation question at the end of the 48‐h treatment period: “How effective do you think the study medication is as a treatment for pain?” . Safety and tolerability were evaluated until follow‐up based on the incidence, severity, and relationship of treatment‐emergent adverse events (TEAEs) to study medication, physical examination findings, clinical laboratory test results, and changes in vital sign and electrocardiogram measurements. TEAEs were defined as AEs with onset at the time of or following the start of study medication, or starting beforehand but increasing in severity or relationship at the time of or following the start of study medication, occurring up to 7 days after the final dose of study medication.0–48). SPID was calculated as a time‐weighted sum of pain intensity difference values at each follow‐up time point (difference between starting pain intensity and pain intensity at the given assessment time point) multiplied by time (h) since the last non‐missing assessment.The primary efficacy variable was pain intensity measured by NRS. The primary efficacy endpoint was the sum of pain intensity differences (SPID) from 0 to 48 h (SPID0–48) were performed, the latter to permit estimation of the absolute efficacy of CTC.Secondary efficacy endpoints included SPID over 4, 6, 12, and 24 h; total pain relief  over 4, 6, 12, 24, and 48 h; pain intensity and change from baseline in pain intensity at each time point; response rates; time to onset of analgesia ; proportion of patients using rescue medication; time to first use of rescue medication; and patients' overall assessment of study drug. Post hoc analyses on use of oxycodone rescue medication and on placebo‐adjusted efficacy  of 124, at a 2‐sided alpha level of 0.05 and 90% power, 142 patients per group were required (71 for placebo). Allowing for a 20% rate of nonevaluable patients, 180 individuals per group (90 for placebo) were to be randomized—630 in total. For sample size re‐estimation, a planned blinded interim analysis was performed after about half the patients had completed the study. In this analysis, estimated pooled variance of the primary outcome measure was substantially lower than that used for sample size calculation; thus, it was concluded that the study was adequately powered and there was no need to increase sample size.The study aimed to demonstrate superiority of CTC 200 mg over tramadol and celecoxib. To determine sample size, power for both comparisons of CTC (vs tramadol and vs celecoxib) was set at 90%; therefore, overall study power was 81%. To detect a difference in SPIDThe full analysis set comprised all randomized patients. The per‐protocol analysis included all patients in the full analysis set with no major protocol deviations. The safety analysis included all patients who received study medication. Efficacy analyses were performed on the full analysis set, sensitivity analyses on the per‐protocol analysis set, and safety analyses on the safety analysis set.0–48 across treatment groups using an analysis of covariance (ANCOVA) model, adjusting for center and baseline pain intensity. To account for use of rescue medication, a pain intensity assessment was performed upon each request for rescue medication, with the score used to replace all scores for timed assessments taken in the subsequent 4 h (considered to be the period over which rescue medication was active). ANCOVA analyses were performed for all quantitative efficacy outcomes; p‐values and 95% confidence intervals (CIs) for the least‐squares (LS) means for pairwise treatment differences were derived.The primary efficacy analysis compared SPIDAn additional analysis of pain intensity difference from baseline by time point was conducted using a mixed model for repeated measures analysis on the full analysis set using type 3 tests of fixed effects.The proportion of patients requiring rescue medication and of responders, and patients' overall assessment of study drug, were analyzed by logistic regression, adjusted by baseline pain and center. Time to onset of analgesia and first use of rescue medication were analyzed using time‐to‐event statistical methods. Safety data were analyzed and reported using descriptive statistics.Additional sensitivity analyses were conducted to assess the impact of rescue medication use and missing data imputation due to study discontinuation. Efficacy analyses were also performed by subgroups defined by baseline pain intensity, sex, age, body mass index (BMI), and race.All statistical analyses were conducted using SAS 9.4 .n = 184), tramadol (n = 183), celecoxib (n = 181), or placebo (n = 89)  discontinued treatment or withdrew from the study.Of 1323 patients screened, 637 were randomized to CTC  and white (74%). Mean age was 46 years, mean body weight was 76 kg, and mean BMI was 28 kg/m2 Table . Mean  provided a significantly greater analgesic effect than tramadol 50 mg administered 4 times daily , celecoxib 100 mg twice daily , and placebo  versus placebo .For SPID0–48 was approximately 1.9 and 2.2 times larger than that of tramadol and celecoxib, respectively , celecoxib , and placebo . In patients with moderate pain, CTC provided a significantly greater effect versus celecoxib  and placebo ; the comparison versus tramadol was not statistically significant . Results of subgroup analyses by sex, age, and BMI generally mirrored those of the main analyses, although treatment differences did not always reach statistical significance, particularly in smaller subgroups for which statistical power was low , over celecoxib at 1.25 h , and over tramadol at 3.5 h . Analyses of SPID and TOTPAR at 4, 6, 12, and 24 h and TOTPAR at 48 h were consistent with primary endpoint findings  reported that analgesia was good, very good, or excellent, versus 70.0% for tramadol, 59.7% for celecoxib, and 48.3% for placebo  and 3 in the tramadol group ; all events resolved. The most common TEAEs were nausea, dizziness, vomiting, and headache. No safety concerns were observed in laboratory tests, electrocardiograms, or vital sign assessments.Table 0–48 than comparable daily doses of tramadol or celecoxib, and placebo, thereby meeting the study's primary endpoint. SPID0–48 was selected as the study's primary efficacy endpoint as it provides a summary of treatment effects on pain intensity over a clinically meaningful time period. Results of sensitivity analyses using different imputation procedures for missing data and rescue medication use, and of a placebo‐adjusted analysis of treatment effects on SPID0–48, were consistent with those of the primary analysis. Subgroup analyses for the primary endpoint  were also generally consistent, although treatment differences did not always reach statistical significance, particularly in smaller subgroups.We evaluated the efficacy of CTC, a novel API–API co‐crystal containing celecoxib and tramadol, for the management of moderate‐to‐severe postoperative pain following bunionectomy with osteotomy. CTC was approved by the FDA in October 2021 and, to our knowledge, is the first API–API co‐crystal for analgesia to be specifically acknowledged as such within the prescribing information.Secondary efficacy endpoints supported primary findings, with most reaching statistical significance in favor of CTC. Reductions in mean pain intensity difference from baseline were statistically significantly greater for CTC over placebo, celecoxib, and tramadol at 1, 1.25, and 3.5 h post‐dose, respectively. Due to study medication, rescue medication, and/or natural post‐surgery resolution of pain, most study patients were classified as responders at some point during the 48‐h dosing period; response rates were not significantly different between groups but were highest in the CTC group. Most patients used first‐line rescue pain medication (intravenous acetaminophen), and about half used second‐line (oxycodone). Patients in the CTC group used less rescue medication, and used it later, than patients in other groups. Most patients in the CTC group (58%) did not require oxycodone, compared with 30% to 45%  in other groups, suggesting that CTC may have an opioid‐sparing effect while improving overall analgesia versus other treatments.The overall rate of TEAEs was similar in the CTC and tramadol groups and lower in the celecoxib and placebo groups. The most common TEAEs were consistent with known safety profiles of tramadol and were as expected in the acute postoperative setting. TEAEs included all events occurring from enrollment to follow‐up and, therefore, captured AEs arising from confounding factors . In phase 1 studies designed to avoid such factors, AE rates were lower with CTC than with tramadol alone, or with tramadol and celecoxib in free combination.This study used an established model of acute surgical pain (bunionectomy with osteotomy) associated with pain of sufficient intensity to warrant opioid use, and of sufficient duration to measure efficacy over multiple days; the model provides good sensitivity for approximately 72 h post‐surgery.Given ongoing problems with opioid misuse and abuse,The recommended CTC dose translates into a maximum daily dose of 224 mg of celecoxib and 176 mg oftramadol—about half the maximum daily doses of its individual active components based on the full prescribing information of celecoxib and tramadol for acute pain.Tmax [h] of 1.5, 3.0, and 2.5 from CTC, celecoxib alone, and free combination with tramadol, respectivelyThe study represents a well‐designed and fair comparison between CTC and its individual APIs. However, possible limitations should be acknowledged. First, doses of tramadol and celecoxib used in comparator groups may have been lower than full therapeutic doses. Although differences in tramadol and celecoxib dosage between CTC and comparator groups mean that the study might not be a true factorial study, the FDA considered that the study met requirements for a well‐controlled, full‐factorial, phase 3 study and proposed the dosing used . Second, most patients enrolled were female, although this is typical for the clinical population seeking treatment for bunionectomy. Subgroup analysis of the primary endpoint by sex showed no significant interactions, albeit this analysis was not well powered due to the small number of males. Third, the study did not include a head‐to‐head comparison versus the individual reference products taken together. However, earlier data show that the pharmacokinetics of the APIs in CTC are different to those observed when commercially available celecoxib and tramadol are administered in free combination.In conclusion, the API–API co‐crystal CTC provided greater analgesic efficacy than did comparable daily doses of tramadol and celecoxib alone. This was accompanied by lower utilization of rescue pain medication, including significantly lower use of opioid rescue medication. The safety profile of CTC 200 mg (112 mg celecoxib/88 mg tramadol) administered every 12 h was similar to that of tramadol 50 mg administered every 6 h. Our findings suggest that CTC could be an efficacious and well‐tolerated alternative for appropriately selected adult patients with acute pain severe enough to require an opioid, by providing multimodal analgesia with an anti‐inflammatory component, via a means not replicated by free or fixed‐dose combination.E.R. Viscusi, O. de Leon‐Casasola, J. Cebrecos, A. Jacobs, A. Morte, M. Sust, A. Vaqué, M.E. Kuss, S. Videla, N. Gascón, and C. Plata‐Salamán conceived or designed the study. J. Cebrecos, E. Ortiz, I. Gottlieb, S. Daniels, J.S. Gimbel, D. Muse, P. Winkle, and S. Videla contributed to data collection. J. Cebrecos, A. Jacobs, E. Ortiz, and M. Sust analyzed the data. E.R. Viscusi, O. de Leon‐Casasola, J. Cebrecos, A. Jacobs, A. Morte, M. Sust, A. Vaqué, I. Gottlieb, M.E. Kuss, and C. Plata‐Salamán interpreted the data. All authors drafted, edited, or reviewed drafts of the manuscript and approved the final version. All authors had access to the underlying data. E.R. Viscusi, J. Cebrecos, A. Jacobs, A. Morte, E. Ortiz, M. Sust, A. Vaqué, I. Gottlieb, S. Videla, N. Gascón, and C. Plata‐Salamán verified the underlying data.This study was supported by ESTEVE Pharmaceuticals S.A. E.R. Viscusi reports consulting fees for ESTEVE Pharmaceuticals, Fresenius, Heron Therapeutics, Innocoll Pharmaceuticals, Merck, and Salix Pharmaceuticals. O. de Leon‐Casasola reports personal fees for advisory board membership for ESTEVE Pharmaceuticals during the conduct of the study, and for ESTEVE Pharmaceuticals, Stimgenix, and Medtronic outside the submitted work. J. Cebrecos, A. Morte, E. Ortiz, M. Sust, A. Vaqué, and N. Gascón are employees of ESTEVE Pharmaceuticals. A. Jacobs is an employee of Premier Research . I. Gottlieb reports grants for ESTEVE Pharmaceuticals for participation as a principal investigator in the current study and personal fees for ESTEVE Pharmaceuticals for consulting projects. S. Daniels is an employee of Optimal Research . M.E. Kuss was an employee of Premier Research during the conduct of the study. S. Videla was an employee of ESTEVE Pharmaceuticals during the conduct of the study. C. Plata‐Salamán was an employee of ESTEVE Pharmaceuticals and has pending or issued patents relevant to CTC. The remaining authors have no conflicts of interest to declare.Appendix S1Click here for additional data file.


A systematic appraisal and statistical aggregation of primary studies.Scopus/ELSEVIER, PubMed/MEDLINE, Clarivate Analytics’ Web of Science , and Cochrane Central Register of Controlled Trials (CENTRAL) via the Cochrane Library.The complementary searches consisted of OpenGrey, Google Scholar (first 100 returns), Networked Digital Library of Theses and Dissertations, Open Access Theses and Dissertations, DART-Europe E-theses Portal—DEEP, Opening access to UK theses—EThOS.Human clinical trials studies in English language with at least 10 patients with mature or immature permanent teeth with pulpitis characterized by spontaneous pain in each arm  at the end of the study, comparing the patient-  and clinical-reported outcomes .Two independent review authors conducted study selection, data extraction and risk of bias (RoB) assessment and a third reviewer was consulted for solving disagreements. When insufficient or absent information, the corresponding author was reached out to for further explanation. The Cochrane RoB tool for randomized trials (RoB 2.0) was evaluated the quality of studies.The meta-analysis was performed on a fixed-effect model to estimate pooled effect size such as odds ratio (OR) and 95% confidence intervals (CIs) were performed using the R software. The quality of evidence assessed by the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) approach .2 = 0%).The study design, risk of bias, inconsistency, indirectness, imprecision, and publication bias domains were used to grade the quality of evidence for postoperative pain between RCT and full pulpotomy, resulting in a ‘High’ grade. In the first year, clinical success was high for both interventions, with a rate of 98%. However, the success rate declined over time, with pulpotomy showing a 78.1% success rate and RCT showing a 75.3% success rate at the 5-year follow up.Five primary studies were included. Four studies referred to a multicentre trial assessing postoperative pain and long-term success rate after pulpotomy compared with one-visit RCT in 407 mature molars. The other study was a multicentre trial assessing postoperative pain in 550 mature molars treated with pulpotomy and pulp capping with the calcium-enriched mixture (CEM), pulpotomy and pulp capping with mineral trioxide aggregate (MTA) and one-visit RCT. Both trials primarily reported first molars from young adults. When looking at the results of postoperative pain, all the trials included had a low RoB. However, when evaluating the clinical and radiographic outcomes of the included reports, it was determined that there was a high RoB. The meta-analysis found that the likelihood of experiencing pain  at the 7th postoperative day was not affected by the type of intervention (OR = 0.99, 95% CI 0.63–1.55, IThis systematic review was limited by the inclusion of only two trials, indicating a lack of sufficient evidence to draw definitive conclusions. Nonetheless, the available clinical data suggests that patient-reported pain outcomes do not differ significantly between RCT and pulpotomy at Day 7 postoperatively, and that the long-term clinical success rate of both treatments is comparable, as demonstrated by a single randomized control trial. However, to establish a more robust evidence base, additional high-quality randomized clinical trials, conducted by diverse research groups, are needed in this field. In conclusion, this review underscores the insufficiency of current evidence to draw solid recommendations. Tomson P L, Vilela Bastos J, Jacimovic J, Jakovljevic A, Pulikkotil S J, Nagendrababu V.Int Endod J 2022; 10.1111/iej.13844.Effectiveness of pulpotomy compared with root canal treatment in managing non-traumatic pulpitis associated with spontaneous pain: A systematic review and meta-analysis. GRADE Rating:2. In cases of irreversible pulpitis (IP), the clinician is typically limited to either root canal treatment (RCT) or extraction as treatment options. While extraction is always effective, RCT can also be highly successful if performed correctly. However, RCT is a technically challenging and time-consuming procedure that weakens the tooth’s structure and leaves it more vulnerable to infection and caries7. These concerns highlight the need for less invasive and biologically based treatment options.Untreated caries in permanent teeth is a prevalent global health condition that can lead to inflammation of the pulp, resulting in reversible or irreversible pulpitis, which may or may not cause pain8. A pulpotomy is a technique used to preserve pulp tissue and has been revisited as a permanent treatment modality, especially in cases of irreversible pulpitis. The use of calcium silicate cements has further increased the success rates of pulpotomy in such cases. High short-term success rates  have been reported for both partial10 and full pulpotomy11. The removal of some or all the coronal pulp tissue is a clinical approach to manage irreversible pulpitis by eliminating inflamed tissue, relieving pain, and inducing hard tissue barrier using a calcium silicate cement that stimulates the pulp’s natural reparative mechanisms12.Vital pulp treatment is now considered a reliable treatment even in cases with carious pulp exposure17.Therefore, the appraised systematic review by Tomson et al. (2022) aimed to evaluate whether a pulpotomy  could result in better patient and clinical reported outcomes compared to root canal treatment (RCT) in permanent teeth with pulpitis characterized by spontaneous pain. The review included five studies, three of which reported longer-term data on the same cohort of patients at different time points and two clinical trials with shorter-term outcomes. The results suggested that patients experience similar levels of pain postoperatively, irrespective of whether they are treated with RCT or full pulpotomy. The success rates for both interventions were high at 12-month follow-up and were reduced at 24 and 60-month follow-up, but there was no significant difference in success between both interventions. These findings are supported by previous reviews that reported that pulpotomy with calcium silicate cements is an effective treatment option for patients with pulpitis characterized by spontaneous pain managed by vital pulp therapy (VPT)18, which may impact the strength of the results.The review identified the benefits of pulpotomy, including its reduced aggressiveness, ability to maintain pulp functions, and improved cost-effectiveness compared to RCT. However, the review notes that the number of studies on this topic is limited, which makes it challenging to establish a strong evidence-based recommendation. Thus, no publications bias was performed. The study finds that patients experience similar levels of postoperative pain with both pulpotomy and RCT. Additionally, patients with apical periodontitis or periodontal ligament (PDL) widening had significantly more postoperative pain regardless of the treatment modality. The review identifies the limitations of the studies, including the fact that RCTs performed in a single visit are not typical in everyday dental practice. Furthermore, 33% of patients were lost to follow-up in one study21. Additionally, the use of calcium silicate cement, namely calcium-enriched mixture (CEM) cement, was limited to the country of manufacture. Furthermore, the study does not indicate any quality assurance for the general standard of treatment performed in either arm. However, the review acknowledges that the study was performed in a primary care setting, making it possible to extrapolate the results to a setting where most of the treatment for pulpitis with spontaneous pain is performed.The strength of the results is weakened by the fact that the longer-term outcomes are derived from the analysis of only one cohort of patients at different postoperative time pointsFuture research is required to establish a more robust evidence-based clinical practice for managing pulpitis characterized by spontaneous pain. It is necessary to conduct more clinical trials to assess the effectiveness of different agents to control hemostasis, cleanse the cavity/exposed pulp, or interface with the pulp. Further research is required to determine the optimal follow-up period for treatment outcomes, which should consider the high loss of patients during the long-term follow-up. Establishing standardized protocols for RCT and pulpotomy that consider patients with different periapical conditions is also essential. Additionally, future research should assess the cost-effectiveness of pulpotomy and RCT in different healthcare settings. Overall, more research is necessary to inform solid evidence-based clinical recommendations for managing pulpitis with spontaneous pain.To sum up, this well-conducted systematic review with quantitative analysis concluded that pulpotomy is a viable alternative to RCT. However, more high-quality clinical studies are required to provide reliable clinical practice recommendations.Practice pointsInsufficient evidence exists to establish clear differences between root canal treatment and pulpotomy in terms of patient-reported pain at day 7 postoperatively and long-term clinical success rate.If the comparative effectiveness of pulpotomy as a definitive treatment modality was demonstrated to be on par with that of root canal treatment on permanent teeth with spontaneous pain, it would retain a vital pulp, obviate the need for root canal treatment, and lower treatment cost and duration.


Over the years, endoscopic carpal tunnel release (ECTR) has gained significant interest as an alternative to surgery. However, no consensus has been reached on the necessity of postoperative wrist immobilization. This study aims to compare the outcomes of wrist immobilization for a period of 2 weeks to immediate wrist mobilization after ECTR.A total of 24 patients with idiopathic carpal tunnel syndrome undergoing dual-portal ECTR from May 2020 to Feb 2022 were enrolled and randomly divided into two groups postoperatively. In one group, patients wore a wrist splint for 2 weeks. In another group, wrist mobilization was allowed immediately after surgery. The two-point discrimination test (2PD test); the Semmes–Weinstein monofilament test (SWM test); the occurrence of pillar pain, digital and wrist range of motion (ROM); grip and pinch strength; the visual analog score (VAS), the Boston Carpal Tunnel Questionnaire (BCTQ) score; the Disabilities of the Arm, Shoulder, and Hand (DASH) score; and complications were evaluated at 2 weeks and 1, 2, 3, and 6 months after the surgery.All 24 subjects finished this study with no dropouts. During the early follow-up, patients with wrist immobilization demonstrated lower VAS scores, lower occurrence of pillar pain, and higher grip and pinch strength compared with the immediate mobilization group. No significant difference was obtained between these two groups in terms of the 2PD test, the SWM test, digital and wrist ROM, BCTQ, and the DASH score. In total, two patients without splints reported transient scar discomfort. No one complained of neurapraxia, injury of the flexor tendon, median nerve, and major artery. At the final follow-up, no significant difference was found in any parameters between both groups. The local scar discomfort mentioned above disappeared and left no serious sequela.Wrist immobilization during the early postoperative period demonstrated significant pain alleviation along with stronger grip and pinch strength. However, wrist immobilization yielded no obvious superiority regarding clinical outcomes at the final follow-up. Carpal tunnel syndrome (CTS) is the most common peripheral compressive neuropathy worldwide . Carpal However, postoperative immobilization is still subject to much controversy. Earlier studies showed comparable outcomes and even worse prognosis of splint immobilization after open release compared with initial active motion –19. AccoThis study was approved by the Ethics Committee of WuXi No.9 People's Hospital Affiliated to Soochow University. All subjects provided informed consent before this study started.Outpatients at the WuXi No.9 People's Hospital Affiliated to Soochow University from May 2020 to Feb 2022 diagnosed with CTS clinically or by electrodiagnostic testing were recruited in our study. Inclusion criteria were severe idiopathic CTS with an electromyography (EMG) test and failure of conventional intervention or symptom recurrence. We defined severe CTS according to the AAEM grading criteria: prolonged median motor and sensory distal latencies, with either an absent SNAP or mixed NAP or low amplitude or absent thenar CMAP. Needle examination often reveals fibrillations, reduced recruitment, and motor unit potential changes . ExclusiAll subjects received one sealed envelope prepared by a person who was not involved in this trial after inclusion. The envelope contained the subject's sequential number and group and was opened just before the skin preparation of the surgical area. All subjects underwent dual-portal ECTR by the same operator. After surgery, one group was provided with a plaster splint put in the volar side of the wrist and half of the forearm and wrapped with bandage gauze. The wrist was immobilized in the neutral position for 2 weeks while the metacarpophalangeal joint and elbow could be moved immediately after surgery. Thereafter, the splint and bandage were removed after 2 weeks at the outpatient. For another group, an elastic bandage was applied to cover the incision, with no limitation of active wrist motion. All subjects were discharged on the first or second postoperative day with no analgesics and were required to visit the outpatient clinic five times at 2 weeks and 1, 2, 3, and 6 months.® Hand Evaluation kit.Outcome parameters contained the 2PD test, SWM tests, the occurrence of pillar pain, digital and wrist range of motion, grip and pinch strength, VAS for pain, BCTQ, DASH score, and complications. All data were measured and recorded by an independent therapist with the JamarSensibility testing was measured by the 2PD and SWM tests. The 2PD test was used to evaluate the threshold capacity to distinguish two different pressure points applied on the fingertip via a particular discriminator. The SWM test was used to evaluate the touch threshold of the fingertip via five standardized filaments . The tactile senses of the first to fourth digital fingertips were measured three times, and the median value was obtained.Postoperative pain was assessed by VAS and the occurrence of pillar pain. VAS of the wrist was measured during active motion without any load with a 100 mm visual analog scale ranging from 0 to 10 (0: absence of pain and 10: worst pain).Postoperative strength was measured by the grip and pinch strength. Grip strength was measured in a seated position with the shoulder and wrist in a neutral position, with the elbow in a 90-degree flexed position, using the Jamar dynamometer. Key pinch strength measured the pressure between the thumb pad and the middle phalanx of the index digit with a pinch gauge dynamometer. All tests were measured three times, and the best value was recorded to decrease bias.Postoperative flexibility was assessed by digital and wrist ROM. Each digital ROM was measured with a finger goniometer, and the interphalangeal joint of thumb value was recorded for further comparison. Wrist ROM during flexion and extension was measured in a seated position with elbow flexion and the hand placed in a resting position using a wrist goniometer.n responses)/n – 1] * 25 and recorded for further comparison  and a functional status scale (BCTQ-F) , 23. Themparison .t-test. Data were expressed in the form of mean ± standard deviation. The 2PD test, SWM test, VAS, BCTQ, and DASH score were analyzed with Wilcoxon's rank sum test. Non-parametric data were expressed as median values. The occurrence of pillar pain was analyzed with the Fisher exact test. Data were expressed in the form of occurrence. The level of significance was set at a P-value of < 0.05.Data were analyzed using SPSS software, v.25 . Digital and wrist ROM and grip and pinch strength were analyzed using a Student's n = 18, 75%) aged 26–82 years old. The duration of symptoms ranged from 1 to 120 months. In addition to gender, there was no significant difference between the two groups regarding demographic data (The outcome measures were assessed in all subjects, and none were lost during the follow-up period. The subjects exhibited a female predominance (hic data .The 2PD and SWM tests showed an apparent improvement compared with preoperative values although no significant difference was found between both groups at each time point. Moreover, the wrist immobilization group yielded better VAS and lower occurrence of pillar pain compared with the wrist mobilization motion group at 2 weeks postoperatively. No difference in pillar pain was observed at 1 month postoperatively. In addition, nearly 80% of subjects were pain-free at the final follow-up in both cohorts. Moreover, grip and pinch strength decreased in early follow-up and got restored to preoperative levels at 2 months postoperatively. At 3 months postoperatively and the final follow-up, strength was slightly stronger than preoperative values in both groups. When these two groups were compared, the wrist immobilization group showed stronger grip and pinch strength than the wrist mobilization group at 2 weeks postoperatively. Subsequently, the strength of both groups was comparable. Digital and wrist ROM showed no obvious difference between preoperative and final follow-up and in both cohorts at any time. For the BCTQ and DASH questionnaire, both groups showed decreased scores at 2 weeks postoperatively and returned to preoperative levels at 1 month. Although the DASH scores of wrist immobilization at 1 month were greater, the difference showed no statistical significance. In total, two subjects in the wrist mobilization group complained of scar discomfort in the distal wound during early follow-up, which disappeared at 1 month postoperatively. No severe complications, including wound dehiscence, lesion of the superficial palmar arch, or median nerve, occurred during the whole follow-up. All data are shown in This study assessed postoperative outcome measures of wrist immobilization for 2 weeks following ECTR, compared to active mobilization with no restriction. Our results demonstrated that wrist immobilization significantly improved postoperative pain and strength rehabilitation at early follow-up, whereas there was no significant difference between the two groups regarding postoperative sensibility, flexibility, and self-evaluation. Interestingly, there was no significant difference between both groups in any outcome measure at the final follow-up.ECTR has increasingly become popular worldwide –3. ThougIn this study, the outcome measures of sensibility improved sustainably in both groups, especially 1 month after ECTR, consistent with the literature. All patients benefited from ECTR and showed no obvious indication of incomplete release. Moreover, the sensibility of both groups at every time point was comparable, which suggested compressive nerve recovery after release was not disturbed by external splint casting.Postoperative pain peaked at 2 weeks and was initially alleviated at 1 month after ECTR in both groups. At 2 weeks after ECTR, the wrist immobilization group exhibited better outcomes in VAS and pillar pain occurrence than the active motion group. Although pillar pain occurrence between the two groups differed by almost 30% at 1 month postoperatively, this difference did not reach statistical significance, which might be attributed to inadequate sample size. Subsequently, the two groups showed comparable outcomes regarding postoperative pain and achieved satisfactory results at the final follow-up. This difference could be related to stimulation by tiny subcutaneous hematoma and palmar cutaneous branches . The preThe change in postoperative strength showed a similar tendency to postoperative pain , 28. It Postoperative flexibility and self-evaluation demonstrated no significant difference between these two groups in the whole follow-up. The DASH outcome measures at 2 weeks after ECTR was superior in the wrist immobilization group although this difference was not significant. This finding implied that pain and slight strength did not influence the daily routine.No severe complications like bowstringing of the flexor tendons occurred, which showed the safety of ECTR. In total, two subjects in the wrist mobilization group complained of scar discomfort, which got worse during grip. Moreover, they both felt discomfortable with a scar on the palm rather than the forearm. Despite a lack of theoretical support, we considered that premature active motion, especially grip, would stimulate the cutaneous nerve in this region and cause discomfort.The outcome measures of ECTR in this study are in accordance with the literature –32. ThisSeveral limitations in this study should be given attention. First, the sample size was relatively small, which could easily cause bias and error. Moreover, this is a single-center study, and the findings only represent this single-center, which limits the generalization of our conclusions. Some outcome measures assessed are subjective, while objective outcome measures, such as EMG, were not analyzed. Hence, further multiple-center studies with large sample sizes are warranted for a more comprehensive investigation of outcome measures.Wrist immobilization for 2 weeks contributes to pain alleviation and improved grip and pinch strength during early follow-up. It brings no significant benefits in terms of improvement of sensibility, flexibility, and self-evaluation. At the final follow-up, wrist immobilization yielded no obvious significance compared with initial active motion. Therefore, wrist immobilization for 2 weeks is warranted after ECTR of idiopathic carpal tunnel syndrome.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding authors.The studies involving human participants were reviewed and approved by Ethics Committee of WuXi No. 9 People's Hospital Affiliated to SooChow University. The patients/participants provided their written informed consent to participate in this study.GZ and YR designed this study. HJ, ZL, HY, QZ, and JM worked on data acquisition. FZ and HJ created tables and charts. FZ analyzed the data and drafted this manuscript. GZ revised and finished this manuscript. All authors contributed to the article and approved the submitted version.


Maxillary bone contraction is caused by genetics or ambiental factors and is often accompanied by dental crowding, with the possibility of canine inclusion, crossbite, class II and III malocclusion, temporomandibular joint disorder, and obstructive sleep apnea (OSAS). Transverse maxillary deficits, in which the maxillary growth is unusually modest, are frequently treated with maxillary expansion. The purpose of this study is to compare the dental and skeletal effects of different types of expanders, particularly the Leaf Expander, rapid and slow dental-anchored or skeletal-anchored maxillary expanders. Methods: We chose studies that compared effects determined by palatal expansion using a rapid palatal expander, expander on palatal screws, and leaf expander. Results: Reports assessed for eligibility are 26 and the reports excluded were 11. A final number of 15 studies were included in the review for qualitative analysis. Conclusions: Clinically and radiographically, the outcomes are similar to those obtained with RME and SME appliances; Therefore, it might be a useful treatment choice as an alternative to RME/SME equipment in cases of poor patient compliance or specific situations. Finally, all of the devices studied produce meaningful skeletal growth of the palate. The use of skeletally anchored devices does, without a doubt, promote larger and more successful growth in adolescent patients. Transverse maxillary deficits, which are characterized by abnormally low maxillary growth, are frequently treated with a rapid maxillary expansion (RME) ,2,3. A tTherefore, the most precise method for assessing the palatine suture and detecting dentoskeletal alterations following RME is CBCT. Cone-beam computed tomography (CBCT) can be used to evaluate the palatine suture bone bridges’ interdigitation quality and density, which is a crucial factor in the device selection process ,7,18.The most contentious choice in treating transverse disparities in adolescent patients is how to expand the upper jaw. Depending on the situation, the orthodontist should select a “patient-oriented” appliance that can reduce the variety of potential side effects, including appliance breakage, functional issues, periodontal tissue problems, and discomfort . The hyrNext to the conventional HEX, the Leaf expander (LEX) has been proposed as an alternative without parental cooperation . The patWhile HEX and LEX expanders are intended to act orthopedically, they invariably result in unintended tooth movements. These tooth motions have the potential to change how well the teeth and their roots are supported by the periodontal ligaments, but they can also create space. From a biological perspective, the prognosis is really uncertain when such extension is sought in adult patients or those who have otherwise reached their maximal growth because of the increased interdigitation of the maxillary sutures and the rigidity of the surrounding structures.Rapid palatal expansion by skeletal anchoring (MARPE) can be employed on patients who are in advanced phases of skeletal development to avoid unfavorable dentoalveolar consequences and maximize skeletal expansion potential ,26. Lee The purpose of this study is to compare the dental and skeletal effects of different types of expanders, particularly the Leaf Expander, rapid and slow maxillary expanders with dental or skeletal anchorage to determine whether there is one method that is more effective and efficient than the others and to evaluate the pain they cause patients.This study was carried out in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses Extension for Scoping Reviews (PRISMA-ScR) guidelines and submitted to PROSPERO  with ID 430622 ,35,36,37With a restriction on English-language studies published between 1 January 2013 and 13 April 2023, we searched PubMed, Scopus, and Web of Science. To undertake an evaluation that is current with the recent 10 years, this time frame was selected. The search approach included the following Boolean keywords: (“hyrax” OR “rep on screws” OR “leaf expander”) AND “treatment”. These phrases were chosen because they most accurately reflected the aim of our investigation, which was to find out more about the expansion brought about by employing various palatal expanders.®, Leone Ortodonzia e Implantologia, Via del Ponte di Quaracchi, 50, 50019 Sesto Fiorentino FI) were used in the research and we chose to compare the effects of palatal expansion. The two steps of the selection process were the appraisal of the title and abstract and the complete text. Any article that fit the following requirements was taken into consideration: (a) clinical trials including human intervention; (b) comparison of the therapy to other interventions; (c) English language complete text. Publications  that lacked original data were not included. Titles and abstracts from the preliminary search were retrieved and evaluated for relevance. Full articles from pertinent research were acquired for further analysis. The retrieved studies were assessed for inclusion using the aforementioned criteria by two different reviewers (R.M. and A.P.).A quick palatal expander, an expander on palatal screws, and a leaf expander  was consulted in order to address any disagreements between the two writers.The PICOS  criteria, which are used in this evaluation, encompass population, intervention, comparison, outcomes, and study design .n = 675, Scopus n = 1, and Web of Science n = 332); no papers were found using a manual search. After 211 duplicate studies were removed, 797 studies were evaluated by looking at the title and abstract. A total of 26 records were chosen out of 771 items that failed to fulfill the requirements for inclusion. Reports requested for retrieval totaled 30, while reports not found totaled 0. There were 26 reports evaluated for eligibility, and 11 reports were removed. In the end, 15 studies were reviewed for the qualitative analysis. The selection process and the summary of selected records are shown in A total of 1008 publications were found in the online database  .It was immediately considered safe and efficient and met with great success .Since then, the interest in the RPE has gradually increased.Maxillary expansion can be achieved with slow (SME) or rapid (RME) expanding devices. RME is typically the first-choice treatment for transverse skeletal discrepancies  Figure .® Leaf Spring Activated Expander (MLSAE) influences dental health in young patients with orthodontics who have reduced transverse dimensions of the upper jaw. The Ni-Ti MLSAE was used by 22 patients (mean age of 12 years) compared to 22 untreated controls. Digital dental casts were taken at the pretreatment, one-week, monthly, and post-expansion time periods. The maxillary dental arch’s inter-canine, inter-premolar, inter-first molar, arch depth, arch perimeter, and molar angulation measures were evaluated .Pain caused by expansion is closely related to the activation protocol and lifestyle of the patient. The analysis was performed through patients’ completion of a questionnaire on the analysis of pain and discomfort caused by the apparatuses. For the analysis of pain intensity, the Wong–Baker scale was used, during the first week of apparatus placement. As shown in the table, it can be seen that subjects treated with leaf expander experienced less pain both from the point of view of intensity and duration than subjects treated with standard Hyrax .In the following study of Nieri et al., 2021 the difference in pain generated in the first S12 weeks of treatment in leaf expander patients and conventional RME patients was analyzed. Patients and parents were asked to fill out a questionnaire, as a result of which the following results were obtained. Pain was analyzed according to the VAS scale, and it was reported that the subjects with conventional RME showed a higher mean of pain (0.6 ± 0.5), compared with the mean of the leaf expander-treated group (0.3 ± 0.4), and that the maximum difference in pain was noted mainly in the first week of treatment. Based on these data, we conclude that leaf expander causes fewer complications than conventional RME. The pain originated from the inflammation of the mediopalatine suture during its expansion and the pressure generated on the periodontal ligament, and it was shown that the pain fee decreased significantly with the use of ketoprofen or with the reduction of the number of daily apparatus activations ,57.In the following study, conducted by Feldmann et al., 2017, conventional hyrax and hybrid hyrax are compared, evaluating their pain at day 1 and day 4 after activation. There was not a statistically significant variation between the two groups, although hybrid hyrax showed slightly lower levels of pain, the only difference reported in the hyrax hibrid treated group compared to conventional hyrax was pain at the molars and incisors .It was noted that patients treated with RME apparatology reported pain mainly during the first 10 activations, reaching a maximum level at day 3–4 and decreasing on subsequent days. Pain was analyzed with the VAS scale, and patients were asked to answer questions associated to jaw function impairment during free time, use of analgesics, overall discomfort, and pain severity .After analyzing these studies, we can state that both rapid and slow expansion methodologies achieve similar expansion effects and, therefore, the choice of therapeutic means is individualized based on the patient’s degree of collaboration. The differences in expansion obtained between RME and Leaf expander are not clinically relevant. Therefore, the choice of the therapeutic means is the responsibility of the clinician.In conclusion, all devices analyzed promote relevant skeletal expansion of the palate. Certainly, the use of skeletally anchored devices promotes greater and more effective expansion in the adult patient.


Ketamine is a phencyclidine (PCP) derivative, which primarily acts as a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. Ketamine serves as an analgesic and a dissociative sedative that produces potent analgesia, sedation, and amnesia while preserving spontaneous respiratory drive. It is rapidly gaining acceptance in the management of pain as multiple studies have demonstrated its reliable efficacy and a wide margin of safety. This article reviews some of these studies, the history of ketamine, and its pharmacological and pharmacokinetic properties. The article also discusses the use of ketamine in the trauma setting, including joint reductions, procedures, sedation, and pain control, as well as dosing recommendations. Physical pain caused by trauma can be a challenging problem for professionals involved in trauma care. Pain may not be controlled for several reasons, such as being underappreciated by physicians, hemodynamic instability concerns, respiratory depression, and addiction fears. Cohen et al. discussed the importance of adequate pain control in the trauma setting and how persistent and severe pain can alter the nervous systems’ anatomical and physiological functions . They stOpioids are considered the cornerstone for the treatment of severe pain in emergency trauma patients . These mMedical professionals often prescribe opioids to treat pain. It has been demonstrated that over 50% of patients will receive a narcotic prescription upon discharge after traumatic injuries ,5. As thAnalgesic options that reduce opioid use while managing acute pain are being sought by trauma surgeons to combat this epidemic as it is essential for optimal outcomes. The purpose of this article is to review the use of ketamine in trauma patients.HistoryThe history of ketamine began in the 1950s when phencyclidine (PCP) was first synthesized as a general anesthetic by the pharmaceutical company Parke-Davis in Detroit, Michigan. It was described as a potent general analgesic that did not cause cardiovascular or respiratory depression; however, it was known to have a high rate of side effects, including frequent hallucinations, postoperative delirium, and confusion . AttemptPharmacologyKetamine is a phencyclidine (PCP) derivative, which primarily acts as a noncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist. It serves as a dissociative sedative that produces potent analgesia and amnesia by direct action on the cortex and limbic system while preserving spontaneous respiratory drive . The mecIn subanesthetic doses, ketamine affects the release of γ-amino-butyric acid (GABA) on inhibitory interneurons. GABA is the most prevalent inhibiting neurotransmitter. In normal physiology, glutamine can bind to receptors on inhibitor neurons, causing a release of GABA from neurons. GABA inhibits the release of glutamine from the presynaptic neuron resulting in no excitability of the postsynaptic neuron Figure . At subaPharmacokineticsKetamine is liposoluble resulting in a wide distribution throughout the body, including lipid-rich tissues and the central nervous system. This is advantageous for trauma patients as it can be administered in many ways including intravenous, intranasal, intramuscular, oral, and rectal. Ketamine is hepatically cleared through enzymes belonging to the cytochrome P450 system, which metabolizes ketamine into norketamine, which is further metabolized and excreted in bile and urine ,14.Because of the hepatic clearance, the effect of ketamine differs by the route being utilized. With intravenous and intramuscular administration, ketamine bioavailability reaches nearly 100% and 93%, respectively. This results in an expedited time to onset, less than one minute, with peak effect achieved at five minutes. Due to first-pass metabolism, ketamine administered orally has approximately 17%-29% bioavailability and reaches peak concentration in 20-30 minutes. Intranasal and intrarectal bioavailability are approximately 50% and 25%, respectively. Ketamine elimination half-life is two to three hours with a duration of action lasting between 10 and 25 minutes depending on the dose .Ketamine produces rapid and reliable analgesia without causing prolonged sedation, which can be particularly useful in monitoring neurologic and hemodynamic changes in the trauma setting.Ketamine in researchAnnals of Emergency Medicine. In this prospective, clinical trial, 108 children aged 14 months to 13 years underwent various procedures under ketamine sedation. It was noted that a single injection of ketamine achieved acceptable conditions in 97% of patients with 86% of patients not requiring adjunctive restraints or local anesthesia. Adequate sedation was produced within five minutes in 83% of patients, and the mean duration from injection to dischargeable recovery was 82 minutes (range: 30-175 minutes). One 18-month-old child vomited shortly after injection and experienced transient laryngospasm with cyanosis, but intubation was not required and there were no adverse sequelae. All other patients were able to maintain airway patency and independent respiration [Ketamine is rapidly gaining acceptance in the management of pain in trauma patients as multiple studies have demonstrated its reliable efficacy and a wide margin of safety. Green et al.'s study was the first landmark study that changed the trajectory of ketamine use, which was published in 1990 in the piration .Since 1990, several studies have been published, which have demonstrated that ketamine inhibits the development of opiate tolerance, enhances opiate analgesia, and provides a safe and effective alternative adjunct to opioid analgesics -21. The In addition to intravenous (IV) and intramuscular (IM) ketamine administration, intranasal ketamine also has proven to be safe and effective. It is gaining popularity due to its ease of use as it obviates the need for invasive routes of administration in patients without intravenous access, in patients who are seizing or combative, or in cases where obtaining intravenous lines is difficult and time-intensive. Furthermore, it provides a relatively painless alternative to IV or IM access, which is especially useful for children ,24. IntrIntranasal ketamine is shown to be as effective as intranasal narcotics in treating pain. Graudins et al. conducted a prospective, randomized controlled, double-blind equivalence study comparing IN ketamine to IN fentanyl for relief of moderate to severe pain due to limb injuries in children aged three to 13 years. The investigators compared IN ketamine (1 mg/kg) to IN fentanyl (1.5 μg/kg) in conjunction with ibuprofen (10 mg/kg) and assessed overall reduction in pain. There were similar pain reductions between groups at all points in addition to similar sedation scores between groups. There were more adverse events in the ketamine group , although all were considered minor and insignificant ,26. FreyIntranasal ketamine has also been shown to reduce the number of narcotics used for acute traumatic pain. Bouida et al. performed a prospective, multicenter, randomized controlled, double-blind trial comparing IN ketamine to placebo saline in adult patients with moderate to severe acute limb trauma pain in the ED. The need for opioids was significantly lower in the IN ketamine group compared to the placebo group . They also demonstrated that patients in the IN ketamine group required less non-opioid analgesics compared to the control counterpart  .Ketamine in traumatic brain injuriesTraditionally, ketamine has been contraindicated in patients at risk for increased intracranial pressure (ICP). The theory was that ketamine administration increased cerebral blood flow and thus increased ICP. Shaprio et al. conducted a small study in 1972 to investigate how ketamine affects ICP in patients with abnormal cerebrospinal fluid dynamics and/or space-occupying lesions compared to neurologically normal patients . The stuIn 1996, Kolenda and team performed a prospective study in which adult ventilated patients with moderate or severe traumatic brain injury (TBI) were prospectively allocated to receive treatment either with a combination of ketamine and midazolam or fentanyl and midazolam. The ICP was 2 mmHg higher in the ketamine group; however, this was not seen until day eight, and it was statistically insignificant. Interestingly, the ketamine group had higher cerebral perfusion pressure (CPP) by 8 mmHg. A similar prospective study was completed by Godoy et al. in which adult mechanically ventilated patients with severe TBI were allocated to receive treatment either with a combination of ketamine and midazolam or sufentanyl and midazolam. Again, there was no difference between the groups  .This phenomenon was also studied in children. Laws et al. studied the acute effects of ketamine on ICP and CPP in children with severe TBI. This was a prospective study of 82 ketamine administrations in 30 children with severe TBI. Ketamine was given for sustained ICP greater than 18 mmHg. They found that there was no increased ICP, and in fact, the ICP decreased after ketamine administration. One downfall of this study is that the Glasgow Coma Score (GCS) was not reported, thus limiting its generalizability .In addition to several studies demonstrating that ketamine is safe to administer to TBI patients, there are also new findings that suggest ketamine has neuroprotective properties in adults. Multiple mechanisms have been described in which ketamine attenuates excitotoxicity, reduces calcium-mediated cell death process, reduces proinflammatory cytokine release by microglial cells, reduces microthromboses through inhibition of platelet aggregation, and upregulates the density of dendritic spines, leading to the sprouting of new neuronal synapses during the recovery period .Considering the emerging evidence that ketamine does not increase ICP, the trauma foundation guidelines for the management of severe TBI in 2019 suggested reconsideration of ketamine use in that patient population. Clinicians should still use a pragmatic approach based on the clinical situation and their knowledge of the potential advantages and disadvantages before administering ketamine to TBI patients.Ketamine dosingThere are several opportunities to utilize ketamine in traumatic and non-traumatic patients Table . KetaminAnalgesia is generally achieved with lower dosing without inducing dissociative symptoms, while dissociation is achieved with higher dosing. Dissociation can be achieved by any dose greater than 0.5 mg/kg administered intravenously. Intramuscular doses greater than 5 mg/kg should be avoided as this could potentially cause agitation or psychosis without inducing sedation. Due to the volume limitation of the nasopharynx, intranasal doses greater than 40 mg per dose should also be avoided. If intranasal doses greater than 40 mg are administered, part of the dose will be delivered to the oropharynx and ingested orally, which may decrease effectiveness.AdministrationBefore administration of ketamine, providers should ensure patients do not have any contraindications to the drug Table . The admDuring administration, vitals should be taken every 15 minutes for one hour, then every two hours for four hours, followed by every four hours if stable. Pain assessments should be done hourly. If dissociative dosing is desired, medical personnel should expect loss of consciousness in patients within 30-60 seconds after IV administration and two to four minutes after IM administration. Return of consciousness should occur 10-20 minutes after injection. Amnesia persists 60-90 minutes after recovery of consciousness. The systolic blood pressure (SBP) of patients may also increase by 20-40 mmHg.Administration of the drug should stop immediately if any of the following events occur: SBP less than 85 mmHg, heart rate less than 60, respiratory rate less than 10 breaths per minute, suspected anaphylactic reaction, the patient experiences intolerable psychomimetic effects, or the patient requests to stop administration due to unpleasant side effects.Side effectsDespite minimal effects on the respiratory drive, ketamine maintains the protective airway reflexes, which allows spontaneous ventilation to continue. However, when the dosage is very high or the medication is given too quickly, respiratory depression can occur. Ketamine is also responsible for bronchodilation, increased salivation, pulmonary vasodilation, and increased cardiac output, along with increased mean arterial pressure and heart rate. Other potential side effects of ketamine include dizziness, feeling of unreality, disorientation, nausea, vomiting, fatigue, headache, changes in hearing, mood change, hallucination, general discomfort, sedation, unpleasant taste, itchiness, rash, nystagmus, nasal irritation, euphoria, or agitation. Following infusion, emergence delirium occurs in 10%-20% of patients. Fifteen percent of patients experience disorientation, crying, or restlessness. Laryngospasms can occur in 0.4% of patients ,28,33.Ketamine use in trauma management has a wide range of potential benefits, both physical and psychological. In a multifaceted approach to trauma care, ketamine plays a valuable role in amnesia, analgesia, and sedation, especially when other pain medications are contraindicated, ineffective, or unable to be administered due to insufficient IV access. It can provide rapid sedation to facilitate patient management and treatment in patients who are agitated, combative, or delirious. It is useful for short-duration procedural sedation such as for chest tube insertions, complex laceration repairs, or reductions in fractures or joint dislocations. It is particularly helpful when the use of opioid medication is risky due to respiratory depression or hemodynamic instability. Lastly, ketamine can be used as an induction agent in patients who require emergency airway management and intubation. As stated in this article, the range of utilization of ketamine is substantial as it provides reliable and effective amnesia, sedation, and analgesia while preserving respiratory drive and maintaining cardiovascular stability and the patients’ protective reflexes. To further expand the use of ketamine in diverse clinical settings, continued research and careful evaluation are essential.


Bipolar Disorder (BD) is a common psychiatric disease. It has been demonstrated a long time ago that bipolar patients are more painful than the healthy subjects. Substance use disorder is a frequent comorbidity in BD, but also in painful patients. The aim of our study was to analyze if bipolar patients with a painful expression have more substance use disorder than bipolar patients without pain.The aim of our study was to analyze if bipolar patients with a painful expression have more substance use disorder than bipolar patients without painWe included all bipolar patients from the FACE-BD cohort which is a prospective cohort of French outpatients with BD enrolled at the 12 advanced Centers of Expertise in Bipolar Disorder (CEBD). Pain has been evaluated by the “pain item” of the EQ-5D scale and we divided subjects in four categories: “no pain”, “slight pain”, “moderate pain”, “severe or extreme pain”. A multivariate analysis was performed to identify differences between each pain’s groups according to the kind of substance use disorder, psychiatric comorbidities and clinicals data.The cohort enrolled 1897 bipolar patients, 970 had no pain (51.1%), 507 had slight pain (26.7%), 298 had moderate pain (15.7%) and 122 had severe or extreme pain (6.4%). We found significant differences according to age, comorbidities and clinicals data with older, more anxious, and more severe patients more represented in the more painful groups. Painful bipolar patients had also more frequently lifetime substance use disorders  and we were able to characterize different profiles in bipolar patients.Bipolar patients with a painful expression had more risks to have a lifetime substance use disorder, an anxiety disorder, and a higher score on MADRS. Interestingly, subjects seemed to prefer substances with anxiolytic or antalgic effects during the acute intoxication as alcohol, marijuana, opioid and sedatives.None Declared