Sustained Pain Relief Research Articles

Unusual Presentation of Trigeminal Neuralgia and its Surgical Management

Trigeminal neuralgia (TN) is a debilitating neuropathic condition characterized by excruciating, lancinating pain attacks. The standard first-line treatment of TN is carbamazepine medication, but some patients do not experience relief from this drug. For cases that do not respond to medication, surgical procedures that cut or remove portions of the peripheral nerves, such as the inferior alveolar and mental nerves, can be attempted. However, these neurectomysurgeries often have high rates of severe facial pain recurring over time. A 40-year-old man suffered from chronic, debilitating trigeminal neuralgia. He underwent multiple tooth extractions and took carbamazepine, but neither provided improvement in his agonizing facial pain. He then had surgical neurectomies of the mental and inferior alveolar nerves, which provided only partial pain relief. The patient was not relieved, so he underwent a surgical neurectomy of the lingual nerve. This third procedure successfully provided a significant reduction in his trigeminal neuralgia pain. Lingual neurectomy emerges as a potentially definitive treatment modality for trigeminal neuralgia refractory to medication or alternative neurectomy procedures. This minimally invasive surgical approach offers a valuable option for patients seeking sustained pain relief, particularly those who are not suitable candidates for or desire to avoid, more extensive or resource-intensive interventions.

Two-Centre Retrospective Analysis on Selective Sensory Denervation of Shoulder Joint by Means of Cooled Radiofrequency in Chronic Shoulder Pain.

Radiofrequency ablation has been used to treat chronic shoulder pain with mixed results. Thanks to recent anatomical studies, the precise location of articular branches of the suprascapular, lateropectoral and axillary nerves has been determined. Cooled radiofrequency is a neuroablative modality of treatment which has been demonstrated as efficient in different anatomical locations, and targeting the aforementioned nerves could result in a complete and efficient denervation of the shoulder. The aim of this study is to assess the efficacy of a fluoroscopic guided cooled radiofrequency technique for chronic shoulder pain. This is a retrospective observational study performed in two hospital in Wales and Italy (Wrexham NHS trust and Iseo Hospital). Forty-four patients were treated between December 2019 and January 2023. Follow-up was provided at 1-, 6- and 12-months post-procedure. Pain intensity was measured with a 0-10-point Numerical Rating Scale (NRS), and was assessed at rest and during movement. Disability was assessed with the Oxford Shoulder Score (OSS). All patients were treated with cooled radiofrequency under fluoroscopic guidance targeting the articular branches of the suprascapular, axillary and lateropectoral nerves. In the 44 patients treated, the mean NRS significantly decreased at all follow ups, pain relief of >50% was obtained in 70.4%, 61% and 51% of the patients at 1.6 and 12 month follow-ups, respectively. Disability improved significantly, with a mean OSS at 12 months follow up of 30 ±17.5, compared to 15 ± 3 at baseline. Medication intake (non-steroidal anti-inflammatory drugs (NSAIDS) and/or opioids) significantly decreased at all follow ups. Cooled radiofrequency denervation can be an effective procedure to manage chronic shoulder pain, providing sustained pain relief and functional improvement in more than 50% of the patients.

Investigating interactions between derivatives of graphene nanosheets and articaine for prolonged dental anesthetic effects: A multiscale modeling study

The controlled release of anesthetic molecules for extended local anesthesia has emerged as a promising strategy in pain management. In this context, we focus on the interactions between graphene nanosheet derivatives (GND) and the anesthetic molecule articaine (ART). Our motivation for studying ART adsorption stems from our previous extensive computational study, which demonstrated that among local anesthetic molecules, ART shows the strongest binding to pristine graphene. To understand the binding of articaine to graphene nanosheets, we conducted an extensive multiscale modeling study using modern levels of theory. We employed a combination of semiempirical (GFN-xTB) and density functional theory calculations (DFT and TD-DFT) to obtain reliable geometrical parameters, binding energies, and quantum-molecular descriptors, crucial for understanding the binding mechanism of articaine. Detailed electron density analysis within the considered systems provided important insights into the noncovalent binding between graphene derivatives and articaine. Additionally, to observe the dynamics and behavior of the system in a biologically relevant environment, we conducted molecular dynamics (MD) simulations based on the GFN-FF method. This study aims to advance the development of effective drug-carrier systems for sustained pain relief. We intend to identify the graphene modifications that could lead to stronger binding of articaine, thereby enabling slower release and prolonged anesthetic effect.

Drug-Free Noninvasive Thermal Nerve Block: Validation of Sham Devices.

Headache is a leading cause of disability and suffering. One major challenge in developing device treatments is demonstrating their efficacy given devices' often-high placebo rate. This paper reviews the importance of validating sham devices as part of finalizing the design for larger-scale prospective randomized controlled trials in patients with chronic headache as well as the results of a prospective, single-blind trial to validate two potential sham noninvasive thermal nerve block devices. Study participants were trained to self-administer thermal nerve block treatment using sham devices in an office visit. Two different sham systems with different temperature profiles were assessed. Devices were offered for patients to use daily at-home for one week to assess the durability of sham placebo effects before participants were given active treatment in a second office visit followed by another optional week of self-administered active treatment at-home use. Sham treatments reduced pain scores by an average of 31% from 6.0 ± 2.3 to 4.3 ± 3.3, including two participants who fell asleep during the in-office treatment and woke up with no pain, but whose pain recurred after returning home during at-home use of the sham system. In-office active treatments reduced pain scores by 52% from 6.7 ± 2.1 to 3.3 ± 2.9 with sustained pain relief during optional at-home use. Successful blinding for the study was confirmed with an ideal Bang's Blinding Index of 0 and an ideal James' Blinding Index of 1. Both the sham and active treatments were viewed by participants as highly credible, and credibility increased from the beginning to end of sham treatments on average.

Head-to-Head Comparison of Tapentadol Nasal Spray and Intravenous Tramadol for Managing Postoperative Moderate-to-Severe Pain: An Observational Study

Background: Tapentadol is known for its opioid-sparing effect, reducing adverse effects associated with opioids, particularly gastrointestinal issues. However, limitations in the oral formulation warrant exploration of alternatives like tapentadol nasal spray for enhanced efficacy and patient experience. Aims and Objectives: This investigator-initiated trial aimed to assess the safety of tapentadol nasal spray (45mg/dose, administered four times daily) compared to intravenous tramadol (50mg twice daily) in patients with post-operative moderate to severe pain over a 3-day period. Materials and Methods: A randomized, open-label real-world trial enrolled 600 patients. Pain management efficacy, sleep scores, and patient comfort and convenience were evaluated. Results: Tapentadol nasal spray demonstrated superior pain reduction compared to intravenous tramadol. Sleep scores were significantly better with tapentadol nasal spray. The nasal route provided enhanced comfort, convenience, safety, and efficacy, offering rapid pain relief. Conclusion: Tapentadol nasal spray presents a favorable option for post-operative pain management, offering improved pain reduction, better sleep outcomes, and enhanced patient comfort. The nasal delivery method proves efficient and patient-friendly, marking a significant advancement in achieving early and sustained pain relief.

Remote cognitive behavioral therapy utilizing an in-home virtual reality toolkit (Vx Therapy) reduces pain, anxiety, and depression in patients with chronic cervical and lumbar spondylytic pain: A potential alternative to opioids in multimodal pain management

Background ContextVirtual reality (VR) reduces pain through visual and auditory distraction without narcotic-related side effects or dependency. Cognitive behavioral therapy (CBT) improves pain-related disability and quality of life, but patient access remains a challenge. We hypothesized that in-home weekly CBT coordinated with daily use of a proprietary VR toolkit will reduce pain, anxiety, and depression for patients with non-operative chronic cervical and lumbar spondylitic pain with and without radiculopathy. MethodsA total of 145 patients with chronic spondylitic pain (63 cervical, 46 noradicular lumbar, 36 radicular lumbar) were enrolled into a guided 14-week VR+CBT program (Vx Therapy) consisting of weekly encounters with a trained therapist and 50 modules. Pain/anxiety severity scores and time to pain recurrence were recorded prospectively by patients. PROMIS measures of overall daily pain intensity, behavior, interference, anxiety, and depression were recorded at baseline and conclusion of the program. ResultsA total of 52% of the 145 patients were male. The average (SD) age of the cohort was 51 (10.7) years (range: 24–76 years). Mean score for all PROMIS domains were significantly improved after 14 weeks of Vx Therapy (pain intensity 36±24 vs. 28±21, interference 39±25 vs. 24±21, behavior 35±21 vs. 25±16, anxiety 51±28 vs. 41±26, depression 58±32 vs. 48±32) for the entire cohort and each diagnosis group. Virtual reality acutely reduced pain on average by 33% (4.5±2.5 vs. 6.7±2.2, p<.05) across all 14 weeks, lasting a mean 2.8 hours after use. Duration of pain relief increased by the final vs. first month (4.5 hours vs. 2.5 hours, p<.05). Virtual reality acutely reduced anxiety on average by 46% (3.5±3 vs. 6.4±2, p<.05) across all 14 weeks lasting a mean 2.7 hours after use. The effect was similar for all 3 groups. ConclusionsFourteen weeks of a remote CBT guided in-home VR toolkit provided effective and sustained pain, anxiety, and depression relief in patients with chronic degenerative neck/back pain with and without radiculopathy. The non-invasive, non-pharmacological nature of Vx Therapy makes it an ideal option for pain management in the post-opioid epidemic era.

Ultrasound-Guided Electroacupuncture Treatment for Rotator Cuff Tendinopathy: Proposing an Effective Alternative to Nonoperative Medical Treatments.

Rotator cuff (RTC) tendinopathy is a common painful condition of the shoulder that impairs function and quality of life. Nonoperative treatments when physical therapy and oral medications have not resolved the issue often consist of different strategies to improve blood flow and promote growth factors, thereby creating regeneration and healing of injured tissue in the RTC tendons. Acupuncture could serve in a similar role when needles are strategically targeted into injured tissue utilizing ultrasound visualization. A 58-year-old male presented with over 1 year of symptomatic RTC tendinopathy involving the supraspinatus and infraspinatus tendons. He had not gotten sustained pain relief with physical therapy or a corticosteroid injection to the subacromial bursa and was not a surgical candidate for RTC repair due to only having small partial tearing of the tendons. He wanted to consider alternative treatment options and it was decided that he could pursue ultrasound-guided electroacupuncture. Treatment was successful and completed within 4 weekly sessions. He reported 85% improvement in symptoms two months after starting treatment and is now over 1 year out from treatment, with what the patient states as "minimal" residual discomfort with one stretching movement. Ultrasound guidance of acupuncture needles into areas of RTC tendon injury simulates many of the current nonoperative treatment modalities sports medicine has to offer for RTC tendinopathy. This short- and long-term successful case report provides a steppingstone for future research into this area.

Painful diabetic peripheral neuropathy of the feet: integrating prescription-strength capsaicin into office procedures.

Prescription-strength (8%) capsaicin topical systemisa USFDA-approvedtreatment for painful diabetic peripheral neuropathy of the feet. A 30min application of the capsaicin 8% topical system can provide sustained (up to 3months) local pain relief by desensitizing and reducing TRPV1-expressing cutaneous fibers. Capsaicin is not absorbed systemically; despite associated application-site discomfort, capsaicin 8% topical system iswell tolerated, with no known drug interactions or contraindications, and could offer clinical advantages over oral options. Capsaicin 8% topical systemare not for patient self-administration and require incorporation into office procedures, with the added benefit of treatment compliance. This article reviews existing literature and provides comprehensive, practical information regarding the integration of capsaicin 8% topical systems into office procedures.

Discal cysts and pseudocysts: Single center experience

IntroductionCurrent knowledge of intervertebral discal cysts is restricted to case reports and surgical case series, typically in young adult males presenting with back pain and radiculopathy. ObjectiveWe review our single-center experience to describe presentation, management, and outcomes of these rare lesions. MethodsWe performed a retrospective electronic search of our institution database using key words “discal cyst,” “disc cyst” and variations. Clinical presentation, imaging findings, management and outcomes were reviewed and tabulated. ResultsNine patients were identified (4 female), with mean age 49.1 years. Three patients had prior surgery at the level of the cyst. Seven patients presented with back pain, five with additional radiculopathy, one patient with radiculopathy alone, and one asymptomatic. Most discal cysts occurred at L5-S1, were left-sided, paracentral in location with a T2 hypointense rim and variable enhancement. One patient underwent primary cyst resection. Amongst 6 patients who underwent primary image-guided procedures, two had sustained pain relief, three proceeded to cystectomy, microdiscectomy and/or posterior decompressive surgery, and two were lost to follow-up. ConclusionOur retrospective cohort includes a wider age group with more heterogeneous clinical features, treatment approaches and response to therapy than that described in the literature. CT or fluoroscopy-guided steroid injection provided short-term symptomatic relief with several cases managed definitively with surgery. Further research is required to better understand and manage these rare lesions. Clinical impactDiscal cysts and pseudocysts occur in a wider range of patients and with more heterogenous presentations than previously described. Imaging-guided intervention can provide short-term symptomatic relief, but further research is required to optimize long-term management.

PVP with or without microwave ablation for the treatment of painful spinal metastases from NSCLC: a retrospective case-control study

Objective To compare the clinical efficacy of percutaneous vertebroplasty (PVP) alone and microwave ablation (MWA) combined with PVP for the treatment of painful spinal metastases from non-small cell lung cancer (NSCLC). Methods From October 2014 to October 2021, the data of 58 NSCLC patients with refractory painful spinal metastases (visual analog scale score ≥ 5) were retrospectively collected and analyzed. Patients in Group A (n = 30) and Group B (n = 28) received PVP alone and MWA combined with PVP, respectively. The primary endpoint was pain relief. The secondary endpoints were quality of life (QoL), local tumor progression (LTP), and complications. Results The technical success rate was 100% in both groups. Patients in both groups showed similar pain relief at 1–12 weeks, but patients in Group B still showed sustained pain relief at 24 weeks compared to those in Group A (p = 0.03). The assessment of QoL showed similar changes. LTP (33.00% vs. 7.14%, p = 0.02) and cement leakage rates (40.00% vs. 7.14%, p = 0.03) were lower in Group B. The multivariate analysis demonstrated spinal metastases with a maximum diameter ≤ 3.0 cm (p = 0.027) and MWA combined with PVP (p = 0.028) were two independent protective factors for LTP. For cement leakage, spinal metastases with vertebral body compression (p = 0.019) was an independent risk factor, while MWA combined with PVP (p = 0.042) was an independent protective factor. Conclusion MWA combined with PVP for painful spinal metastases from NSCLC performed more sustained pain relief (>6 months) and ultimately improved QoL with lower LTP and cement leakage rates, compared to PVP alone.

Zavegepant: a promising intranasal medication for migraine treatment

Migraine is the third most prevalent and seventh-highest specific cause of disability worldwide1. It is a neurobiological headache disorder that is caused by increased excitability of the central nervous system. This multifactorial ailment has various causes, including lack of sleep, hormonal imbalance, menstrual cycle, and emotional stress. Some individuals may even trigger migraine due to their choice of food, especially chocolate, milk, caffeine, cheese, and alcoholic beverages2. The variability seen in its clinical presentation includes the pattern of associated symptoms and pain intensity along with photophobia, osmophobia, phonophobia, vomiting, nausea, and movement sensitivity3. Considering the acute onset of this excruciating pain, patients demand rapid relief and the cure of all associated symptoms. Several medications have been introduced. However, nowadays, 5HT1B/1D receptor agonists (sumatriptan, zolmitriptan) and ergot alkaloids (dihydroergotamine mesylate) are being used as intranasal or parenteral medications for the immediate treatment of migraines. Many patients prefer intranasal medications over injectable ones because of their rapid action4. Triptans, one of the most effective treatment regimens for migraine, is unfortunately ineffective intranasally. Moreover, its contraindication for cardiovascular patients restricts its use in almost 10% of the migraine population. On the other hand, dihydroergotamine which is still less effective than triptans, the nasal spray is contraindicated in patients with uncontrolled hypertension, ischemic heart disease, and coronary artery vasospasm5. Co-administration with potent cytochrome P450 3A4 inhibitors may also result in potentially fatal peripheral and cerebral ischemia. Recent studies led to the discovery of novel modulators, like calcitonin gene-related peptide (CGRP), that are crucially implicated in the development and chronicity of migraine. This led to new medications known as gepants that can antagonize the CGRP receptor. Successive advances led to the introduction of first-generation and second-generation gepants. However, both were short-lived due to poor oral bioavailability6, associated liver injury, and less effectiveness, respectively. Zavegepant is the third generation but the first intranasally administered gepant. It is a high-affinity antagonist of the CGRP receptor, has adequate oral bioavailability, and, unlike triptans, does not induce active contraction of coronary arteries; therefore, it is safe for patients with cardiovascular comorbidities. Compared with the prior lead, the pharmacophore of zavegepant has a 2-quinolone and a 7-methylindazole, increasing oxidation stability and nasal irritancy potential while maintaining picomolar receptor binding potency7. In addition to that, it is also 10,000 times more selective for the CGRP receptor than for its counterpart, the amylin receptor8. It was FDA-approved in February 2020 for acute treatment, and results demonstrate that it is safe regarding hepatotoxicity9. Recently it cleared the phase 2 trials and now advancing to phase 3 ones. Zavegepant has a tmax of 15–20 minutes as it provides considerable efficacy over 48 hours, with ultra-rapid pain relief starting 15 minutes after a single therapeutic dose (P=0.0015), prolonged and persistent pain freedom for 2–24 hours and 2–48 hours, respectively, along with sustained pain relief for 2–24 hours10. This makes it highly potent and the safest in terms of side effects. Although the provided data gives ample proof that zavegepant is a revolutionary drug to combat migraine attacks but for definite, high-quality evidence about its efficacy and safety, results from the recent clinical trials and future research work are needed. Similarly, soft gel formulations of zavegepant also need more attention as it can be another option for the abortive treatment of migraine. Lastly, extensive trials are needed to see its effect on pregnant women and patients with severe liver and cardiovascular issues. For commercialization, it should be economically friendly so that it can compete with all the available formulas and a maximum number of patients can be benefitted from it. Rest assured. This third-generation gepant can be a promising medication in terms of timely relief from escalating pain, and further research may even help us find the ultimate cure for migraine. Ethical approval Not applicable. Sources of funding None. Author contribution The conceptualization was done by A.S. and B.S.R. The literature and drafting of the manuscript were conducted by A.S., T.N., A.W.K., S.D.E.Z.Z., A.Q. and H.S.R. The editing and supervision were performed by B.S.R. All authors have read and agreed to the final version of the manuscript. Conflicts of interest disclosure The authors declare that they have no financial conflict of interest with regard to the content of this report. Research registration unique identifying number (UIN) Not applicable. Guarantor All authors take responsibility for the work, access to data and decision to publish.

Treatment of Early Undifferentiated Chronic Monoarthritis of the Wrist by Arthroscopic Wrist Synovectomy Combined with Partial Denervation.

Undifferentiated chronic monosecarthritis (UCMA) is a group of inflammatory joint diseases that has the potential to progress to other diseases and can seriously affect patients' quality of life. There is yet no unified consensus regarding treatment of UCMA. This study aimed to investigate the efficacy of arthroscopic synovectomy combined with partial wrist denervation in treating Larsen 1-3 UCMA. In this case series, we reviewed 14 patients with UCMA treated by arthroscopic synovectomy combined with partial denervation from February 2017 to June 2020. The mean duration of symptoms was 17.4 months (range, 4-60 months), and the mean follow-up was 13.3 months (range, 6-23 months). The anterior and posterior interosseous nerves were severed at the distal forearm, and the radiocarpal, midcarpal, and distal radial ulnar joint synovial membranes were arthroscopically resected at the wrist. The clinical evaluation indices included the visual analogue scale score (VAS) for pain, grip strength, range of (active) motion of the wrist, total active motion, and Mayo wrist score. Larsen's scoring method was used as the imaging evaluation index. At the last follow-up, significant clinical improvements were observed in the visual analogue scale (VAS) score for pain (6.0 (5.0-6.3) vs 1.0 (1.0-2.3), P = 0.001) and Mayo wrist score (42.1 ± 9.7 vs 61.8 ± 12.3, P < 0.0001). No significant changes were found in grip strength (15.9 ± 4.5 vs 16.6 ± 4.7, P = 0.230) or the flexion-extension arc (58.9 ± 39.0 vs 64.3 ± 36.5, P = 0.317), although the mean and median did show positive changes. Among the three patients who showed progress in imaging, there was no significant difference in their pain and functional scores compared to those who did not progress. One patient underwent total wrist fusion 17 months after the operation. Arthroscopic wrist synovectomy combined with partial wrist denervation can provide sustained pain relief and functional recovery for patients with Larsen 1-3 UCMA.

Efficacy and Safety of Stempeucel in Osteoarthritis of the Knee: A Phase 3 Randomized, Double-Blind, Multicenter, Placebo-Controlled Study

Background: Osteoarthritis is a chronic, progressive, and degenerative condition with limited therapy options. Recently, biologic therapies have been an evolving option for the management of osteoarthritis. Purpose: To assess whether allogenic mesenchymal stromal cells (MSCs) have the potential to improve functional parameters and induce cartilage regeneration in patients with osteoarthritis. Study Design: Randomized controlled trial; Level of evidence, 1. Methods: A total of 146 patients with grade 2 and 3 osteoarthritis were randomized to either an MSC group or placebo group with a ratio of 1:1. There were 73 patients per group who received either a single intra-articular injection of bone marrow–derived MSCs (BMMSCs; 25 million cells) or placebo, followed by 20 mg per 2 mL of hyaluronic acid under ultrasound guidance. The primary endpoint was the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) total score. The secondary endpoints were WOMAC subscores for pain, stiffness, and physical function; the visual analog scale score for pain; and magnetic resonance imaging findings using T2 mapping and cartilage volume. Results: Overall, 65 patients from the BMMSC group and 68 patients from the placebo group completed 12-month follow-up. The BMMSC group showed significant improvements in the WOMAC total score compared with the placebo group at 6 and 12 months (percentage change: −23.64% [95% CI, −32.88 to −14.40] at 6 months and −45.60% [95% CI, −55.97 to −35.23] at 12 months P < .001; percentage change, −44.3%). BMMSCs significantly improved WOMAC pain, stiffness, and physical function subscores as well as visual analog scale scores at 6 and 12 months (P < .001). T2 mapping showed that there was no worsening of deep cartilage in the medial femorotibial compartment of the knee in the BMMSC group at 12-month follow-up, whereas in the placebo group, there was significant and gradual worsening of cartilage (P < .001). Cartilage volume did not change significantly in the BMMSC group. There were 5 adverse events that were possibly/probably related to the study drug and consisted of injection-site swelling and pain, which improved within a few days. Conclusion: In this small randomized trial, BMMSCs proved to be safe and effective for the treatment of grade 2 and 3 osteoarthritis. The intervention was simple and easy to administer, provided sustained relief of pain and stiffness, improved physical function, and prevented worsening of cartilage quality for ≥12 months. Registration: CTRI/2018/09/015785 (National Institutes of Health and Clinical Trials Registry–India).

ID: 207021 Significant and Sustained Relief of Shoulder Pain Following 60-day PNS Treatment: A Real-World Retrospective Review

Chronic shoulder pain commonly results in disability and reduced quality of life, with frequent causes including post-surgical pain, inoperable musculoskeletal injury or joint degeneration, and stroke. Temporary percutaneous peripheral nerve stimulation (PNS) has demonstrated significant and sustained relief of chronic shoulder pain in previous clinical trials. This study presents the first real-world, retrospective review of patient outcomes through up to 6 months following the start of a 60-day PNS treatment for chronic shoulder pain.

ID: 198326 Pain Relief Using an Interspinous Spacer for Treatment of Lumbar Spinal Stenosis Among Severe-Pain Patients

Patients with impaired physical function who experience leg, buttock and/or groin pain due to lumbar spinal stenosis (LSS) may be ideally suited for treatment using Indirect Decompression Systems (IDS) or Interspinous Spacers. Excellent long-term clinical benefit with sustained pain relief, improved quality of life, and medication reduction up to 5-years post-implant has been recently reported.1-3 Additionally, real-world reports demonstrated excellent long-term clinical benefit for patients including leg pain responder rate and pain severity of 75% and 60% respectively at 12-months post operation.4 Here, we provide real-world outcomes in patients with severe pain who received an Indirect Decompression System (IDS) for LSS related pain and symptoms as part of an ongoing multi-center observational case series

Therapeutic antagonism of the neurokinin 1 receptor in endosomes provides sustained pain relief

The hypothesis that sustained G protein-coupled receptor (GPCR) signaling from endosomes mediates pain is based on studies with endocytosis inhibitors and lipid-conjugated or nanoparticle-encapsulated antagonists targeted to endosomes. GPCR antagonists that reverse sustained endosomal signaling and nociception are needed. However, the criteria for rational design of such compounds are ill-defined. Moreover, the role of natural GPCR variants, which exhibit aberrant signaling and endosomal trafficking, in maintaining pain is unknown. Herein, substance P (SP) was found to evoke clathrin-mediated assembly of endosomal signaling complexes comprising neurokinin 1 receptor (NK1R), Gαq/i, and βarrestin-2. Whereas the FDA-approved NK1R antagonist aprepitant induced a transient disruption of endosomal signals, analogs of netupitant designed to penetrate membranes and persist in acidic endosomes through altered lipophilicity and pKa caused sustained inhibition of endosomal signals. When injected intrathecally to target spinal NK1R+ve neurons in knockin mice expressing human NK1R, aprepitant transiently inhibited nociceptive responses to intraplantar injection of capsaicin. Conversely, netupitant analogs had more potent, efficacious, and sustained antinociceptive effects. Mice expressing C-terminally truncated human NK1R, corresponding to a natural variant with aberrant signaling and trafficking, displayed attenuated SP-evoked excitation of spinal neurons and blunted nociceptive responses to SP. Thus, sustained antagonism of the NK1R in endosomes correlates with long-lasting antinociception, and domains within the C-terminus of the NK1R are necessary for the full pronociceptive actions of SP. The results support the hypothesis that endosomal signaling of GPCRs mediates nociception and provides insight into strategies for antagonizing GPCRs in intracellular locations for the treatment of diverse diseases.

Ultrasound-Guided Lumbar Peri-Facet Joint Blocks: A Therapuetuic Approach to Chronic Lower Back and Referred Leg Pain Management

Intra-articular fluoroscopically-guided facet joint (FJ) blocks are performed with diagnostic-therapeutic aims, whereas the main focus of ultrasound guided peri-facet joint blocks (USG-PFJB) is pain relief. USG-PFJB will therefore typically utilize higher injection volumes to potentially offer injection spread to other pain-generating structures. This study explores the potential role of USG-PFJBs in the outpatient management of chronic low back pain with our without leg symptoms in patients with MRI-confirmed mild to severe lower lumbar FJ arthrosis. USG-PFJBs were performed on 19 patients, (4 male and 15 females, mean age 55) at the L4/5 and/or L5/S1 segments at paraspinal points of palpable focal pain. All procedures were performed by the same clinician. One patient was lost to follow up and telephone reviews at 2-6 months on the remaining 18 patients, noted that 59.73% experienced significant &amp; sustained pain relief. In conclusion, lower lumbar segment USG-PFJBs appear to be effective treatment option in patients with mild to severe MRI-confirmed FJ degeneration and palpable paraspinal lower back pain and with or without lower limb pain.

Repeat CyberKnife Radiosurgery for Trigeminal Neuralgia: Outcomes and Complications.

CyberKnife radiosurgery (RS), as an initial first treatment, is recognized as an efficient and safe modality for trigeminal neuralgia (TN). However, knowledge on repeat CyberKnife RS in refractory cases is limited. The objective was to evaluate the clinical outcomes of repeat CyberKnife RS for TN. A retrospective review of 33 patients with refractory TN treated a second time with CyberKnife RS from 2009 to 2021. The median follow-up period after the second RS was 26.0 months (range 0.3-115.8). The median dose for the repeat RS was 60 Gy (range 60.0-70.0). Pain relief after the intervention was assessed using the Barrow Neurological Institute scale for pain (I-V). Scores I to IIIb were classified as an adequate pain relief and scores IV-V were classified as a treatment failure. After the second RS, initial adequate pain relief was achieved in 87.9% of cases. The actuarial probabilities of maintaining an adequate pain relief at 6, 12, 24, and 36 months were 92.1%, 74.0%, 58.2%, and 58.2%, respectively. Regarding sustained pain relief, there was no significant difference between the first and the second RS. Sensory toxicity after the first RS was predictive of a better outcome following the second RS. The onset of hypesthesia rate was the same after the first or the second RS (21%). Repeat RS is an effective and safe method for the treatment of refractory TN.

Efficacy and Safety of Zavegepant Nasal Spray for the Acute Treatment of Migraine: Results of a Phase 3 Double-Blind, Randomized, Placebo Controlled Trial (PL5.002)

Efficacy and Safety of Zavegepant Nasal Spray for the Acute Treatment of Migraine: Results of a Phase 3 Double-Blind, Randomized, Placebo Controlled Trial (PL5.002)

A Cross-Sectional Survey of Prevailing Opinions from Headache Specialists Regarding Status Migrainosus Management (P11-12.001)

<h3>Objective:</h3> To gather the prevailing opinions of headache specialists regarding status migrainosus (SM) management based on clinical experience and exposure to scientific data. <h3>Background:</h3> SM is a debilitating migraine complication with intense symptoms lasting &gt;72 hours. Although SM epidemiologic data are unclear, a recent population-based study in Minnesota reported that 15% of individuals experienced a recurrent SM attack during the following year. Although no evidence-based treatment guidelines for SM exist, treatment can include steroids, nerve blocks, nonsteroidal anti-inflammatory drugs, triptans, ergotamine, neuroleptics, and dihydroergotamine mesylate (DHE). Consensus on defining clinical trial endpoints for SM to improve future research and outcomes is an unmet need. <h3>Design/Methods:</h3> A cross-sectional phone survey was conducted with 33 headache specialists from tertiary headache centers across the United States. Verbal responses to 8 questions asked at random about SM patterns observed and treatment protocols used for SM management were given. <h3>Results:</h3> Most headache specialists reported treating SM patients every week, sometimes several patients per day. Cases were frequently observed at the clinic, but some required hospital admission when clinics were considered inadequate for SM treatment. Most headache specialists used drug infusions, the Raskin or modified DHE protocol, or steroids to treat SM. While DHE is considered the gold standard to completely break recurrence, drug inaccessibility and hesitation to send patients to hospitals limit its use. Most headache specialists reported refractory patients being more prone to recurrent SM attacks. Treatment goals included avoiding emergency room (ER) visits and providing patients with autonomy and at-home treatments (eg, self-injections, oral steroids). <h3>Conclusions:</h3> Headache specialists treat multiple SM patients per week and value treatments that break the headache and offer sustained pain relief while avoiding ER visits. Although DHE was viewed favorably for SM, it was underutilized and often only as a last resort due to accessibility issues. <b>Disclosure:</b> Dr. Robblee has received personal compensation in the range of $5,000-$9,999 for serving as a Consultant for Impel. Dr. Robblee has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Abbvie. An immediate family member of Dr. Robblee has received personal compensation in the range of $0-$499 for serving as an officer or member of the Board of Directors for Scottsdale Providence. The institution of Dr. Robblee has received research support from Eli Lilly. The institution of Dr. Robblee has received research support from AbbVie. The institution of Dr. Robblee has received research support from Barrow Neurological Institute. Dr. Robblee has received publishing royalties from a publication relating to health care. Dr. Robblee has received publishing royalties from a publication relating to health care. Dr. Vann has received personal compensation for serving as an employee of Impel Neuropharma. Dr. Vann has received personal compensation for serving as an employee of Biogen. Dr. Fitzpatrick has received personal compensation for serving as an employee of Impel Pharmaceuticals. Dr. Murphy has nothing to disclose. Dr. Ray has received personal compensation for serving as an employee of Impel Pharmaceuticals. Dr. Ray has stock in Impel Pharmaceuticals. Dr. Shrewsbury has received personal compensation for serving as an employee of Impel NeuroPharma. Dr. Shrewsbury has received stock or an ownership interest from Impel NeuroPharma. Dr. Aurora has received personal compensation for serving as an employee of Impel Neuropharma. Dr. Aurora has stock in Impel Neurpharma.