Pain Relief Research Articles

Low-dose ketamine as an adjunct to morphine: A randomized controlled trial among patients with and without current opioid use.

Pain is a common complaint among patients presenting to the emergency department (ED), yet pain treatment is frequently suboptimal. The aim of this study was to determine the effectiveness of low-dose ketamine (LDK) as an adjunct to morphine versus morphine alone for treatment of acute pain among ED patients with and without current opioid use. Adult patients presenting with acute pain of ≥5 on a numeric rating scale (0-10) who were deemed by their treating ED physician to require intravenous opioids were randomized to receive either 0.1 mg/kg ketamine (treatment group) or isotonic saline (placebo) as an adjunct to morphine. Patients with and without current opioid use were randomized separately. Pain was measured at baseline (T0) and 10, 20, 30, 45, 60, and 120 min after randomization. The primary outcome was pain reduction from T0 to T10. Secondary outcomes included pain intensity over 120 min, need of rescue opioids, side effects, and patient and provider satisfaction. A total of 116 patients were included from May 2022 to August 2023. Median (IQR) age was 51 (36.5-67) years; 58% were male and 36% had current opioid use. Pain reduction from T0 to T10 was greater in the LDK group (4 [IQR 3-6]) compared to the placebo group (1 [IQR 0-2]; p = 0.001). Pain intensity was lower in the LDK group at T10, T20, and T30, compared to the placebo group. There was a higher risk of nausea, vomiting, and dissociation in the LDK group during the first 10 min. LDK may be effective as an adjunct analgesic to morphine for short-term pain relief in treatment of acute pain in the ED for both patients with and without current opioid use.

The Effect of Antinociceptive Dose of Morphine on Cell Therapy in Rats with Spinal Cord Injury.

Spinal cord injury (SCI) is a sensory-motor injury. Today, combined treatments such as cell therapy along with drug therapy and their interactions are of interest. Morphine is an opioid drug used to relieve intolerable pain. This study aims to evaluate the impact of an antinociceptive dose of morphine (with minimal tolerance/dependence but effective pain relief) on cell therapy in SCI. The antinociceptive dose of morphine was determined in rats with SCI through the Hargreaves and naloxone-induced morphine withdrawal tests. The rats were then allocated to 5 groups: laminectomy, SCI, SCI + Morphine, SCI + cell therapy, SCI + Morphine + cell therapy. The antinociceptive dose (5 mg/kg) was administered on days 1, 4, 10, and 13 (i.p.) post-SCI. On day 7, Neural-like stem cells derived from adipose tissue were transplanted intraspinally into the injured animals, and they were monitored for 12 weeks. The outcomes were assessed using the BBB test, somatosensory evoked potential (SSEP), and histology. The BBB test indicated that morphine significantly hindered functional recovery post-cell transplantation compared to animals receiving only cell therapy (p < 0.05). In the SSEP test, the analysis of amplitude and latency of waves did not reveal a significant difference (p > 0.05). The histological results showed that cell therapy reduced the cavity size post-SCI, while morphine had no significant impact on it. Morphine at the antinociceptive dose significantly impairs motor recovery despite cell therapy. Nonetheless, there was no significant difference between groups in terms of sensory pathway outcomes.

NIR-Remote Selectively Triggered Buprenorphine Hydrochloride Release from Microneedle Patches for the Treatment of Neuropathic Pain.

Neuropathic pain is a prevalent form of intermittent chronic pain, affecting approximately 7-10% of the global population. However, the current clinical administration methods, such as injection and oral administration, are mostly one-time administration, which cannot achieve accurate control of pain degree and drug dose. Herein, we developed near-infrared (NIR) light-responsive microneedle patches (MNPs) to spatiotemporally control the drug dose released to treat neuropathic pain according to the onset state. The mechanism of action utilizes upconversion nanoparticles to convert NIR light into visible and ultraviolet light. This conversion triggers the rapid rotation of the azobenzene molecular motor in the mesoporous material, enabling the on-demand controlled release of a drug dose. Additionally, MNs are used to overcome the barrier of the stratum corneum in a minimally invasive and painless manner, effectively promoting the transdermal penetration of drug molecules. The effectiveness of these patches has been demonstrated through significant results. Upon exposure to NIR light for five consecutive cycles, with each cycle lasting 30 s, the patches achieved a precise release of 318 μg of medication. In a mouse model, maximum pain relief was observed within 1 h of one cycle of NIR light exposure, with the effects lasting up to 6 h. The same level of precise treatment efficacy was maintained for subsequent pain episodes with similar light exposure. The NIR-controlled drugs precision-released MNPs provide a novel paradigm for the treatment of intermittent neuropathic pain.

Case report of pharmacokinetic analysis of continuous intravenous infusion of fentanyl in a patient with severe burn: burn shock stage complicates pain management

BackgroundFentanyl is widely used as an analgesic and sedative for patients with severe burn injuries in intensive care units. However, pharmacokinetic (PK) data for fentanyl, particularly for continuous intravenous infusion during the acute phase of burn injuries, are limited. Here, we report the clinical course and changes in blood fentanyl concentrations during the acute phase in a patient with severe burns treated with continuous intravenous infusion of fentanyl.Case presentationA woman in her 40s, with burns caused by a gas cylinder explosion, was transported to our hospital. The patient had burn wounds on face, neck, shoulders, and all four extremities, with a total burn area of 39.0%. For pain relief, the patient received a continuous infusion of 0.01 mg/mL fentanyl (20–30 µg/h) with a target blood concentration of 1.0–1.5 ng/mL, but continued to suffer from pain due to burning during the acute phase. We measured the blood fentanyl concentrations and found that all concentrations obtained during the acute phase were subtherapeutic. Notably, during the burn shock stage, blood concentrations of fentanyl were 0.50 ng/mL on day 1 and 0.66 ng/mL on day 2, indicating that the blood concentration did not rise sufficiently for the dosage. From days 0 to 2, the patient was administered a massive fluid load for burn shock. After the burn shock stage resolved, fentanyl concentrations gradually approached the target range, and the pain rating scale improved, even though the fentanyl administration rate remained unchanged (30 µg/h).ConclusionsMajor changes in the fluid volumes of body compartments that occur with large burns might increase the volume of fentanyl distribution, thereby lowering its concentration when a standard dose is administered. Our findings indicate that the PK of fentanyl in patients with severe burns can be substantially affected, especially during the shock phase, implying the importance of titrating analgesics for clinical efficacy in the acute phase.

Pain prevalence and pain relief in end-of-life care – a national registry study

BackgroundDespite pain control being a top priority in end-of-life care, pain continues to be a troublesome symptom and comprehensive data on pain prevalence and pain relief in patients with different diagnoses are scarce.MethodsThe Swedish Register of Palliative Care (SRPC) was used to retrieve data from 2011 to 2022 about pain during the last week of life. Data were collected regarding occurrence of pain, whether pain was relieved and occurrence of severe pain, to examine if pain differed between patients with cancer, heart failure, chronic obstructive pulmonary disease (COPD) and dementia. Binary logistic regression models adjusted for sex and age were used.ResultsA total of 315 000 patients were included in the study. Pain during the last week of life was more commonly seen in cancer (81%) than in dementia (69%), heart failure (68%) or COPD (57%), also when controlled for age and sex, p < 0.001. Severe forms of pain were registered in 35% in patients with cancer, and in 17–21% in non-cancer patients. Complete pain relief (regardless of pain intensity) was achieved in 73–87% of those who experienced pain, depending on diagnosis. The proportion of patients with complete or partial pain relief was 99.8% for the whole group.ConclusionsThe occurrence of pain, including severe pain, was less common in patients with heart failure, COPD or dementia, compared to patients with cancer. Compared with cancer, pain was more often fully relieved for patients with dementia, but less often in heart failure and COPD. As severe pain was seen in about a third of the cancer patients, the study still underlines the need for better pain management in the imminently dying.Trial registrationNo trial registration was made as all patients were deceased and all data were retrieved from The Swedish Register of Palliative Care database.

Methylene Blue, a Unique Topical Analgesic: A Case Report.

Background: Rectal prolapse is a circumferential, full-thickness protrusion of the rectum through the anus, which, if not properly managed, may become incarcerated and pose a risk of strangulation. This pathology is rarely a medical emergency unless a complication is encountered. Such complications include infection, necrosis, perforation, incarceration, and uncontrolled pain. Case Presentation: We report a case of an elderly patient with pain associated with chronic rectal prolapse. Surgical intervention had been ruled out, and there had been no pain relief after using systemic analgesics. Case Management: Based on increasing reports of analgesic properties, topical methylene blue (MB) 0.1% was applied externally at the prolapsed organ, obtaining pain relief. Case Outcome: The patient experienced immediate and long-lasting pain relief; MB applications were continued every 12 hours as needed. After this therapy, the patient was no longer in need of systemic analgesics. No side effects were reported. Conclusion: Topical MB may be an effective analgesic for the management of pain associated with chronic rectal prolapse. This treatment might be extrapolated to other clinical scenarios of tegumentary pain. Similar use has been shown to be safe and effective in other pathologies, including pain in oral mucositis associated with cancer therapy.

Intra-operative hypertension as a predictor of surgical outcomes in microvascular decompression surgery for trigeminal neuralgia

PurposeThe trigeminocardiac reflex (TCR) has traditionally been characterized by a sudden decrease in heart rate, asystole, or hypotension during the manipulation of the trigeminal nerve (MTN) or its branches. While this classical TCR is well-documented, there is limited literature on alternative forms of TCR, such as the development of intraoperative hypertension (HTN) or tachycardia, and the underlying pathogenesis. Furthermore, a gap exists in understanding the correlation between intraoperative blood pressure readings and postoperative outcomes, particularly regarding pain relief in patients with trigeminal neuralgia (TN). Our study aims to examine intraoperative blood pressure trends during microvascular decompression (MVD) for TN and assess their impact on postoperative outcomes.MethodsWe selected 90 patients who underwent MVD for TN treatment. Blood pressure and heart rate were recorded both preoperatively and during the procedure, specifically during the MTN period, using an arterial line. The Barrow Neurological Institute (BNI) Pain Scale was calculated for all patients both pre- and post-operatively to evaluate pain relief after surgery.ResultsThe mean age of the patients was 61.0 ± 12.35 years, with 64.4% being females. Classical TCR (hypotension) was observed in only 2.2% of patients, whereas 80% of patients developed hypertension (≥ 140/90) during MTN. The mean preoperative systolic blood pressure was 128 ± 22.25, and the mean intraoperative systolic blood pressure during MTN was 153.1 ± 20.2. An analysis of covariance, utilizing either preoperative BNI or duration of symptoms as covariate variables, revealed a statistically significant association between intraoperative HTN and postoperative BNI. A linear regression model demonstrated that intraoperative HTN following MTN significantly predicted a lower postoperative BNI score (p = 0.006).ConclusionsIntraoperative HTN during MTN, an observed yet underexplored phenomenon, demonstrated a correlation with improved postoperative outcomes. Furthermore, it is recommended to conduct additional investigations into potential neurovascular conflicts in patients not manifesting intraoperative HTN following MTN. A comprehensive understanding of TCR, encompassing its various forms, is vital for optimizing surgical management. This study underscores the imperative for further research to unravel the mechanisms linking intraoperative HTN to surgical outcomes in TN patients.

Rate of graft retear is higher in over-the-top superior capsular reconstruction for massive posterosuperior rotator cuff tears with subscapularis tear.

To compare side-to-side superior capsular reconstruction (SCR) with over-the-top SCR in terms of functional outcomes, pain relief and allograft survival rates. Patients who had undergone arthroscopic dermal allograft SCR for massive irreparable rotator cuff tears and clinical follow-up for ≥2 years were recruited. All patients underwent postoperative assessment with routine radiographic analysis for acromiohumeral distances, ultrasound imaging 1 and 3 months after SCR and magnetic resonance imaging (MRI) at least 12 months after SCR. The outcome measures were visual analogue scale (VAS), American Shoulder and Elbow Surgeons (ASES), Constant and Single Assessment Numeric Evaluation (SANE) scores. SCR was performed in 56 patients including side-to-side SCR in 32 and over-the-top SCR in 24. Postoperative MRI showed that the grafts were intact in 46 patients (82.1%; 26 who underwent side-to-side SCR and 20 who underwent over-the-top SCR). The proportion of nonhealing grafts in the over-the-top group was significantly higher with concomitant subscapularis tears (60% vs. 5.3%; p = 0.02). VAS scores and functional outcomes improved postoperatively in both groups and postoperative VAS (1.4 vs. 1.7; n.s.), Constant (74.8 vs. 76.0; n.s.), mean ASES (87.4 vs. 89.1; n.s.) and mean SANE (81.7 vs. 84.3; n.s.) scores did not differ significantly. For massive rotator cuff tears, over-the-top and side-to-side SCR achieve similar pain relief and functional improvement, and the rate of healing allografts is high. However, over-the-top SCR is not recommended for massive posterosuperior rotator cuff tears with repairable subscapularis tendon tears due to a higher nonhealing rate. Level III.

A COMPARATIVE STUDY OF TRANSDERMAL BUPRENORPHINE PATCH VERSUS TRANSDERMAL DICLOFENAC PATCH FOR POST-OPERATIVE ANALGESIA IN ELECTIVE BELOW UMBILICAL SURGERIES

Objective: Effective postoperative pain management is crucial for recovery and patient satisfaction. This study compares the efficacy and safety of transdermal buprenorphine, an opioid analgesic, with diclofenac, a non-steroidal anti-inflammatory drug (NSAID), for postoperative pain relief in elective below umbilical surgeries. Methods: Hundred patients undergoing elective below-umbilical surgeries were randomized into two groups to receive either a transdermal buprenorphine patch or a diclofenac patch. Pain scores using the Numeric Rating Scale (NRS), functional recovery assessed by the WOMAC Index, and patient satisfaction were measured at baseline, 1 w, 2 w, and 4 w post-application. Results: Both groups showed significant pain reduction over time. However, at 1 and 2 W post-application, the diclofenac group exhibited greater pain relief (p&lt;0.001) and higher patient satisfaction. By the 4 w, differences in pain scores and WOMAC Index between the groups were not statistically significant, indicating similar long-term efficacy. Conclusion: While both transdermal buprenorphine and diclofenac patches are effective for postoperative pain management, diclofenac patches offer superior short-term relief and patient satisfaction. Tailoring pain management strategies to individual patient needs and recovery phases is essential for optimizing postoperative care.

Management of Miller’s Class-III multiple recession defects in mandibular anterior teeth using vista technique and PRF membrane: A case report

Gingival recession, characterized by the displacement of gingival tissue towards the root surface, poses challenges like compromised aesthetics and heightened vulnerability to dental issues such as root caries and sensitivity. Various surgical techniques have been developed to address these concerns, with recent advancements like the Vestibular Incision Subperiosteal Tunnel Access (VISTA) technique showing promise, especially for multiple recession defects in the esthetic zone. VISTA reduces tissue trauma and promotes optimal healing by minimizing micromotion, thus enhancing the overall success of root coverage procedures. Integrating Platelet-rich fibrin (PRF) membranes aids in soft tissue healing and graft integration, offering a cost-effective and immune-friendly option to bolster procedure success.In a 31-year-old female patient with receding gums and mobile teeth, vestibuloplasty was performed after oral prophylaxis and stabilization of mobile teeth to address the inadequate vestibular depth and mucogingival deformity. Post-operative care included antibiotics and pain relief medications. Subsequently, a Miller’s Class-III multiple gingival defect (MRD) was corrected using the VISTA technique combined with Platelet-rich fibrin (PRF) membrane application. PRF was inserted into the tunnel to cover the denuded roots and to improve the gingival phenotype and the surgical site was sutured. One month later, successful healing was evident with increased vestibular depth, demonstrating effective treatment outcomes.

Application of reverse traction device in preoperative treatment of high-energy tibial plateau fracture

To investigate the effectiveness of the reverse traction device in the preoperative treatment of high-energy tibial plateau fractures. A retrospective study was conducted to analyze the clinical data of 33 patients with high-energy tibial plateau fractures who met the selection criteria between December 2020 and December 2023. All patients were treated by open reduction and internal fixation. According to the preoperative traction method, they were divided into the observation group (16 cases, treated with a reverse traction device on the day of admission) and the control group (17 cases, treated with heel traction on the day of admission). There was no significant difference in baseline data such as gender, age, body mass index, affected side, cause of injury, fracture Schatzker classification between the two groups ( P>0.05). Preoperative waiting time, preoperative related complications (nail channel loosening, nail channel oozing, nail channel infection, soft tissue necrosis, soft tissue infection, deep vein thrombosis of the lower extremity, etc.), operation time, and total hospitalization time were recorded and compared between the two groups. On the 4th day after traction, visual analogue scale (VAS) score was used to evaluate the pain relief of the patients, the swelling value of the affected limb was measured, and the Immobilization Comfort Questionnaire (ICQ) score was used to evaluate the perioperative hospital comfort of the patients. Both groups of patients completed the operation successfully, and the operation time, total hospitalization time, and preoperative waiting time of the observation group were significantly less than those of the control group ( P<0.05). There was no preoperative related complications in the observation group; in the control group, 3 patients had nail channel loosening and oozing, and 2 cases had the deep vein thrombosis of the lower extremity; the difference in the incidence of complication between the two groups was significant ( P<0.05). On the 4th day after traction, the ICQ score, VAS score, and limb swelling value of the observation group were significantly better than those of the control group ( P<0.05). X-ray films showed that the tibial plateau fracture separation and lower limb alignment recovered after calcaneal traction in the control group, but not as obvious as in the observation group. The fracture gap in the observation group significantly reduced, the tibial plateau alignment was good, and the lateral angulation deformity was corrected. The use of reverse traction treatment in patients with high-energy tibial plateau fractures on admission can accelerate the swelling around the soft tissues to subside, reduce patients' pain, shorten the preoperative waiting time, improve the patients' preoperative quality of life, and contribute to the shortening of the operation time, with a good effectiveness.

Responders to first-line osteoarthritis treatment had reduced frequency of hip and knee joint replacements within 5 years: an observational register-based study of 44,311 patients.

First-line treatment (education, exercise) for patients with hip and knee osteoarthritis (OA) aims to reduce pain and improve function. We aimed to compare progression to joint replacement within 5 years between responders and non-responders to first-line treatment for hip and knee OA, respectively. This observational study included data for 30,524 knee OA and 13,787 hip OA patients from the Swedish Osteoarthritis Register, linked with the Swedish Arthroplasty Register, Statistics Sweden, and the Swedish Prescribed Drug Register. The primary prognostic factor was change in pain between baseline and 3-month follow-up, measured on a numeric rating scale (0-10, best to worst) where an improvement of ≥ 2 was classified as responder and ≤ 1 as non-responder. The main outcome was progression to joint replacement surgery within 5 years, assessed using baseline adjusted multivariable Cox regression analyses. At 5 years, in hip OA, 35% (95% confidence interval [CI] 32.2-37.2) of the responders and 48% (CI 45.9-49.5) of the non-responders and in knee OA 14% (CI 13.0-15.3) of the responders and 20% (CI 18.8-20.8) of the non-responders had progressed to joint replacement. Being a responder to the treatment was associated with having a lower probability of progression to surgery for both hip OA (hazard ratio [HR] 0.4, CI 0.4-0.5) and knee OA (HR 0.6, CI 0.5-0.6). Patients with hip or knee OA who experienced pain relief after a first-line OA treatment program were less likely to progress to joint replacement surgery.

Effects of exercise dosage on the treatment of fibromyalgia: A meta-analysis of randomised controlled trials.

Exercise intensity is a key component of an exercise prescription. This meta-analysis aimed to investigate the treatment effect of different exercise doses on fibromyalgia syndrome. PubMed, Embase, Web of Science, and the Cochrane Library were searched from their inception until 29 December 2023. The studies were subjected to screening using a 2-phase approach by 2 independent reviewers. Reference lists of the included studies were manually searched. Two independent reviewers extracted information regarding the origin, characteristics of study participants, eligibility criteria, characteristics of interventions, outcome measures, and main results using a pre-defined template. This meta-analysis encompassed a total of 19 randomized controlled trials comprising 857 patients. Compared with the low compliance/uncertain group according to ACSM, the high compliance group showed better effectiveness in general condition improvement (SMD: -1.15>-0.71), pain relief (SMD: -1.29>-1.04), sleep quality enhancement (SMD: -1.66>-1.08), and fatigue relief (SMD: -1.72>-1.32). However, there was no difference in the improvement of mental health between the two groups (SMD: -0.93>-0.92). Compared to the ACSM group with compliance uncertainty (<70%), the high compliance group showed improvement in general conditions, pain, sleep quality, and fatigue. However, there was no difference in terms of mental health.

Bioadhesive and drug-loaded cellulose nanofiber/alginate film for healing oral mucosal wounds

Recurrent oral ulcers are common oral mucosal lesions that severely reduce patients' quality of life. Commercial mucoadhesive films are easily disrupted due to oral movement and complex wet environments, thus reducing drug utilization and even causing toxic side effects. Herein, we report a mucoadhesive film composed of Ca2+-crosslinked carboxymethylated cellulose nanofibers and alginate, in which two drugs of dexamethasone (DXM) and dyclonine hydrochloride (DYC) are loaded for the treatment of oral ulcers. The wet films have a high Young's modulus of 7.1 ± 2.6 MPa and a large strain of 53.6 ± 9.8 % and adhere to tissue strongly, which allows them to resist the deformation caused by frequent oral movement. The films also have nice durability against water and excellent biocompatibility. Moreover, the drug release was controlled at different rates. The fast release of DYC facilitates the quick relief of pain, while the slow release of DXM benefits the long-term treatment of wounds. Finally, the animal experiment demonstrates the films displayed excellent therapeutic efficacy in healing oral ulcers.

Gamma Knife radiosurgery for multiple sclerosis-associated trigeminal neuralgia

BackgroundGamma Knife radiosurgery (GKRS) has well-known efficacy in the treatment of idiopathic trigeminal neuralgia (TN). However, few studies have evaluated the effects of GKRS in the treatment of multiple sclerosis (MS)-related TN. This study analyzed the efficacy and complications of GKRS for MS-related TN. MethodsThis retrospective study included 28 MS-related TN patients who underwent GKRS with a median follow-up of 27 (range, 12–181) months. The cisternal segment of the trigeminal nerve was targeted with a median radiation dose of 80 (80–90) Gy. Pain intensity was assessed using Barrow Neurological Institute (BNI)-Pain Intensity Scores (BNI-PIS). Before GKRS, all patients suffered from BNI pain levels of 4 or 5. A reduction in pain to BNI 3b or below was deemed as adequate pain relief. ResultsThe initial proportion of patients who experienced adequate pain relief was 71.4%, with a median interval of 21 (1–45) days. At the final follow-up, 50% of patients had achieved adequate pain relief. Ten patients (35.7%) suffered from complications, including four with facial sensorial dysfunctions, four with a decline in their corneal reflexes, and two with jaw weakness. Among the 20 initial responders, six (30%) patients suffered pain recurrence after a median interval of 35 (12–180) months. ConclusionsGKRS is an effective means of pain relief in MS-related TN, but has side effects that are relevant to other ablative treatments. The benefits and risks of GKRS should be discussed with patients who wish to avoid surgery or when previous treatments fail.

Clinical Application of Different Doses of Hydromorphone Slow-Release Analgesia in Lumbar Fusion in Elderly Patients.

The aim of this study is to examine the analgesic efficacy of varying doses of hydromorphone hydrochloride in conjunction with absorbable gelatin sponge for postoperative pain management in elderly individuals undergoing lumbar fusion surgery. Additionally, the study aims to assess the sustained release analgesic properties of this combination and to determine the optimal dosage of hydromorphone hydrochloride for effective pain relief. A total of 113 elderly patients (aged≥65years old) meeting the criteria for 1-2-level posterior lumbar fusion surgery at Ganzhou City People's Hospital between July 2022 and August 2023 were randomly assigned to four groups: group A (0.2mg hydromorphone hydrochloride 1ml), group B (0.3mg hydromorphone hydrochloride 1.5ml), group C (0.4mg hydromorphone hydrochloride 2ml), and group D (0.9% normal saline 2ml) for standard anesthesia induction and maintenance. Prior to suturing the incision, gelfoam was utilized to administer epidural analgesia to each group. Following the surgical procedure, an intravenous analgesia pump was utilized for pain management. The baseline infusion rate was set at 0.5ml/h. Patient-controlled analgesia (PCA) was administered at a dose of 2ml, with a lockout interval of 20min, allowing the patient to self-administer as needed. Pain relief was assessed using the visual analogue scale (VAS) prior to surgery, as well as at 1day and 3days post-operation. The frequency of PCA requests within the initial 48-h postoperative period, the remedial analgesia with dezocine, postoperative adverse reactions, and duration of hospitalization were documented for analysis. The VAS scores of groups B and C were found to be significantly lower than those of group D 1day after the operation. Additionally, VAS scores at 3days post-operation, remedial rate of dezocine and PCA follow-up times at 48h in groups A, B, and C were significantly lower compared to group D (P<0.001). There was no statistically significant difference between group B and group C in VAS scores at 1day and 3days post-operation, as well as PCA follow-up times at 48h post-operation (P<0.001). Furthermore, the VAS scores of groups B and C were lower than those of group A at 1day and 3days post-operation (P<0.05). The PCA frequency of group C was also lower than that of group A at 48h post-operation (P<0.05). The combination of hydromorphone hydrochloride and absorbable gelatin sponge epidural analgesia has been shown to enhance postoperative pain management. A dosage of 0.4mg of hydromorphone hydrochloride may be considered an appropriate analgesic dose, as it can provide effective pain relief without eliciting adverse reactions. ChiCTR.org.cn(ChiCTR2200064863). Registered on October 20, 2022.

Altered Monocyte and Lymphocyte Phenotypes Associated with Pathogenesis and Clinical Efficacy of Progestogen Therapy for Peritoneal Endometriosis in Adolescents.

Background: Immunological imbalances characteristic of endometriosis may develop as early as the primary manifestations of the disease in adolescence. Objective: To evaluate subpopulation dynamics of monocytes and lymphocytes in peripheral blood and peritoneal fluid of adolescents with peritoneal endometriosis at diagnosis and after 1-year progestogen therapy. Methods: This study included 70 girls, 13-17 years old, diagnosed laparoscopically with peritoneal endometriosis (n = 50, main group) or paramesonephric cysts (n = 20, comparison group). Phenotypes of monocytes and lymphocytes of the blood and macrophages of the peritoneal fluid were analyzed by flow cytometry at diagnosis and during progestogen therapy. Results: Differential blood counts of CD16+ (p < 0.001) and CD86+ (p = 0.017) monocytes were identified as independent risk factors for peritoneal endometriosis in adolescents. During the treatment, cytotoxic lymphocytes CD56dimCD16bright (p = 0.049) and CD206+ monocytes (p < 0.001) significantly increased while CD163+ monocytes decreased in number (p = 0.017). The CD56dimCD16bright blood counts before (p < 0.001) and during progestogen therapy (p = 0.006), as well as CD206+ blood counts during the treatment (p = 0.038), were associated with the efficacy of pain relief after 1-year progestogen therapy. Conclusions: Adolescents with peritoneal endometriosis have altered counts of pro- and anti-inflammatory monocytes and lymphocytes both before and after 1-year progestogen therapy, correlating with treatment efficacy and justifying long-term hormonal therapy.

Peptide and Peptidomimetic Inhibitors Targeting the Interaction of Collapsin Response Mediator Protein 2 with the N-Type Calcium Channel for Pain Relief.

Ion channels serve pleiotropic functions. Often found in complexes, their activities and functions are sculpted by auxiliary proteins. We discovered that collapsin response mediator protein 2 (CRMP2) is a binding partner and regulator of the N-type voltage-gated calcium channel (CaV2.2), a genetically validated contributor to chronic pain. Herein, we trace the discovery of a new peptidomimetic modulator of this interaction, starting from the identification and development of CBD3, a CRMP2-derived CaV binding domain peptide. CBD3 uncouples CRMP2-CaV2.2 binding to decrease CaV2.2 surface localization and calcium currents. These changes occur at presynaptic sites of nociceptive neurons and indeed, CBD3 ameliorates chronic pain in preclinical models. In pursuit of a CBD3 peptidomimetic, we exploited a unique approach to identify a dipeptide with low conformational flexibility and high solvent accessibility that anchors binding to CaV2.2. From a pharmacophore screen, we obtained CBD3063, a small-molecule that recapitulated CBD3's activity, reversing nociceptive behaviors in rodents of both sexes without sensory, affective, or cognitive effects. By disrupting the CRMP2-CaV2.2 interaction, CBD3063 exerts these effects indirectly through modulating CaV2.2 trafficking, supporting CRMP2 as an auxiliary subunit of CaV2.2. The parent peptide CBD3 was also found by us and others to have neuroprotective properties at postsynaptic sites, through N-methyl-d-aspartate receptor and plasmalemmal Na+/Ca2+ exchanger 3, potentially acting as an auxiliary subunit for these pathways as well. Our new compound is poised to address several open questions regarding CRMP2's role in regulating the CaV2.2 pathways to treat pain with the potential added benefit of neuroprotection.

The dual amylin and calcitonin receptor agonist KBP-336 elicits a unique combination of weight loss, antinociception and bone protection – a novel disease-modifying osteoarthritis drug

BackgroundDespite the extensive research to provide a disease-modifying osteoarthritis drug (DMOAD), there is still no approved DMOAD. Dual amylin and calcitonin receptor agonists (DACRA) can provide metabolic benefits along with antinociceptive and potential structural preserving effects. In these studies, we tested a DACRA named KBP-336 on a metabolic model of OA in meniscectomised (MNX) rats.MethodsWe evaluated KBP-336’s effect on pain-like symptoms in Sprague Dawley (SD) rats on high-fat diet (HFD) that underwent meniscectomy using the von Frey test to measure the 50% paw withdrawal threshold (PWT) and analyzed using one-way ANOVA. Short in vivo studies and in vitro cell receptor expression systems were used to illustrate receptor pharmacology.ResultsAfter 30 weeks on HFD, including an 8-week treatment, female MNX animals receiving KBP-336 4.5 nmol/Kg/72 h had lower body weight and smaller adipose tissues than their vehicle-treated counterparts. After 20 weeks on HFD, including an 8-week treatment, male rats receiving KBP-336 had lower body weight than the vehicle group. In both the female and male rats, the MNX groups on KBP-336 treatment had a higher PWT than the vehicle-treated MNX group. Aiming to identify the receptor influencing pain alleviation, KBP-336 was compared to the long-acting human calcitonin (hCTA). Single-dose studies on 12-week-old male rats showed that hCTA lowers CTX-I without affecting food intake, confirming its calcitonin receptor selectivity. On the metabolic OA model with 18 weeks of HFD, including 6-week treatment, hCTA at 100 nmol/Kg/24 h and KBP-336 at 0.5, 1.5, and 4.5 nmol/Kg/72 h produced significantly higher PWT in MNX animals compared to MNX animals on vehicle treatment. hCTA and KBP-336 at 0.5 nmol/Kg did not affect body weight and fat tissues.ConclusionOverall, KBP-336 improved the pain observed in the metabolic OA model. Calcitonin receptor activation proved to be essential in this antinociceptive effect.

A sham-controlled, randomized trial of spinal cord stimulation for the treatment of pain in chronic pancreatitis.

Spinal cord stimulation (SCS) has emerged as a treatment option for patients with chronic pancreatitis (CP) who experience pain that does not respond to standard interventions. However, there is a lack of sham-controlled trials to support its efficacy. This randomized, double-blinded, sham-controlled, cross-over trial enrolled 16 CP patients with insufficient pain relief from standard therapies. Patients underwent high-frequency (1000 Hz) paraesthesia-free SCS or sham for two 10-day stimulation periods, separated by a 3-day washout period. The primary outcome was daily pain intensity registered in a pain diary based on a numeric rating scale (NRS). Secondary outcomes included various questionnaires. Quantitative sensory testing was used to probe the pain system before and after interventions. The average daily pain score on the NRS at baseline was 5.2 ± 1.9. After SCS, the pain score was 4.2 ± 2.1 compared to 4.3 ± 2.1 in the sham group (mean difference -0.1, 95% CI [-1.4 to 1.1]; P = 0.81). Similarly, no differences were observed between groups for the maximal daily pain score, secondary outcomes or quantitative sensory testing parameters. During an open-label, non-sham-controlled and non-blinded extension of the study, the average daily NRS was 5.2 ± 1.7 at baseline, 3.2 ± 1.8 at 3 months, 2.9 ± 1.9 at 6 months and 3.4 ± 2.2 at 12 months of follow-up (P = 0.001). In this first sham-controlled trial of SCS in painful CP, we did not find evidence of short-term pain relief with paraesthesia-free high-frequency (1000 Hz) stimulation. However, evaluation of the long-term effect by larger sham-controlled trials with long-term follow-up is warranted. In this first sham-controlled trial to apply high-frequency (1000 Hz) spinal cord stimulation in patients with visceral pain due to chronic pancreatitis, we did not find evidence for clinically relevant pain relief. Taken together with potential procedure-related complications, adverse effects and costs associated with spinal cord stimulation, our findings question its use for management of visceral pain.