Bardoxolone Methyl Ameliorates Chemotherapy-Induced Neuropathic Pain by Activation of Phosphorylated Nuclear Factor Erythroid 2-Related Factor 2 in the Dorsal Root Ganglia.

BACKGROUND: Many chemotherapeutic drugs, including paclitaxel, produce neuropathic pain in patients with cancer, which is a dose-dependent adverse effect. Such chemotherapy-induced neuropathic pain (CINP) is difficult to treat with existing drugs. Nuclear factor erythroid 2-related factor 2 (Nrf2) is a major regulator of antioxidative responses and activates phosphorylated Nrf2 (pNrf2). We determined the analgesic effects of bardoxolone methyl (BM), an Nrf2 activator, and the role of pNrf2 on CINP. METHODS: CINP was induced in rats by intraperitoneally injecting paclitaxel on 4 alternate days in rats. BM was injected systemically as single or repeated injections after pain fully developed. RNA transcriptome, mechanical hyperalgesia, levels of inflammatory mediators and pNrf2, and location of pNrf2 in the dorsal root ganglia (DRG) were measured by RNA sequencing, von Frey filaments, Western blotting, and immunohistochemistry in rats and human DRG samples. In addition, the mitochondrial functions in 50B11 DRG neuronal cells were measured by fluorescence assay. RESULTS: Our RNA transcriptome of CINP rats showed a downregulated Nrf2 pathway in the pain condition. Importantly, single and repeated systemic injections of BM ameliorated CINP. Paclitaxel increased inflammatory mediators, but BM decreased them and increased pNrf2 in the DRG. In addition, paclitaxel decreased mitochondrial membrane potential and increased mitochondrial volume in 50B11 cells, but BM restored them. Furthermore, pNrf2 was expressed in neurons and satellite cells in rat and human DRG. CONCLUSIONS: Our results demonstrate the analgesic effects of BM by Nrf2 activation and the fundamental role of pNrf2 on CINP, suggesting a target for CINP and a therapeutic strategy for patients.

The efficacy of high-intensity laser therapy in wound healing: a narrative review.

High-intensity laser therapy (HILT) has recently been incorporated into wound management therapeutic protocols (Mosca RC et al. (2019) Photobiomodulation Therapy for Wound Care: A Potent, Noninvasive, Photoceutical Approach. Adv Skin Wound Care 32(4):157-167. https://doi.org/10.1097/01.ASW.0000553600.97572.d2 ). Laser therapy is increasingly used as an adjunct to therapeutic interventions in clinical practice (Dundar U et al. (2015) Effect of high-intensity laser therapy in the management of myofascial pain syndrome of the trapezius: a double-blind, placebo-controlled study. Lasers Med Sci 30(1):325-332. https://doi.org/10.1007/s10103-014-1671-8 ). This study aimed to evaluate the efficacy of HILT and the potential benefits of incorporating co- interventions alongside HILT in wound management. The following databases were searched up to April 2023: Embase, MEDLINE, PubMed, and Cinahl, as well as manual searches. The search keywords included high- intensity laser therapy, high-power laser therapy, laser therapy, wound, ulcer, and wound healing. The primary measures were decreased wound surface area (WSA) and improved wound appearance (WA) or other objective wound assessment tools containing these two values. Six human studies investigating HILT in wound healing treatment and one animal study assessing the wound-healing effects of HILT in acute wounds of mice were selected (Thabet AAE, Mahran HG, Ebid AA, Alshehri MA. Effect of pulsed high intensity laser therapy on delayed caesarean section healing in diabetic women. J Phys Ther Sci.;30(4):570-575. doi:, Ebid AA, Thabet A, Helal O (2018) (2011) Efficacy of pulsed high intensity Nd: Yag Laser in Treatment of Chronic Diabetic Foot Ulcer. Energy for Health pp. 25-30); (Ebid AA, El-Kafy EM, Alayat MS (2013) Effect of pulsed Nd: YAG laser in the treatment of neuropathic foot ulcers in children with spina bifida: a randomized controlled study. Photomed Laser Surg 31(12):565-570. https://doi.org/10.1089/pho.2013.3533 ); (Hong SE et al. (2016) Effects of neodymium-yttrium-aluminum garnet (Nd: YAG) pulsed high-intensity laser therapy on full thickness wound healing in an experimental animal model. J Cosmet Laser Ther 18(8):432-437. https://doi.org/10.1080/14764172.2016.1202421 ); (Lu Q et al. (2021) Clinical effects of high-intensity laser therapy on patients with chronic refractory wounds: a randomised controlled trial. BMJ Open 11(7):e045866. https://doi.org/10.1136/bmjopen-2020-045866 ); (Pereira FLC et al. (2020) Use of a High-Power Laser for Wound Healing: A Case Report. J Lasers Med Sci 11(1):112-114. https://doi.org/10.15171/jlms.2020.19 ); (Thabet AAE et al. (2018) Effect of pulsed high intensity laser therapy on delayed caesarean section healing in diabetic women. J Phys Ther Sci 30(4):570-575. https://doi.org/10.1589/jpts.30.570 ); (Nussbaum EL, Baxter GD, Lilge L (2003) A Review of Laser Technology and Light-Tissue Interactions as a Background to Therapeutic Applications of Low Intensity Lasers and Other Light Sources. Phys Therapy Reviews 8(1):31-44. https://doi.org/10.1002/lsm.20769 ). This limited number of studies exhibited varying treatment parameters, blinding procedures, wound etiologies, irradiation protocols, and testing areas (Thabet AAE, Mahran HG, Ebid AA, Alshehri MA. Effect of pulsed high intensity laser therapy on delayed caesarean section healing in diabetic women. J Phys Ther Sci. ;30(4):570-575. doi:, Ebid AA, Thabet A, Helal O (2018) (2011) Efficacy of pulsed high intensity Nd: Yag Laser in Treatment of Chronic Diabetic Foot Ulcer. Energy for Health pp. 25-30); (Ebid AA, El-Kafy EM, Alayat MS (2013) Effect of pulsed Nd: YAG laser in the treatment of neuropathic foot ulcers in children with spina bifida: a randomized controlled study. Photomed Laser Surg 31(12):565-570. https://doi.org/10.1089/pho.2013.3533 ); (Hong SE et al. (2016) Effects of neodymium-yttrium-aluminum garnet (Nd: YAG) pulsed high-intensity laser therapy on full thickness wound healing in an experimental animal model. J Cosmet Laser Ther 18(8):432-437. https://doi.org/10.1080/14764172.2016.1202421 ); (Lu Q et al. (2021) Clinical effects of high-intensity laser therapy on patients with chronic refractory wounds: a randomised controlled trial. BMJ Open 11(7):e045866. https://doi.org/10.1136/bmjopen-2020-045866 ); (Pereira FLC et al. (2020) Use of a High-Power Laser for Wound Healing: A Case Report. J Lasers Med Sci 11(1):112-114. https://doi.org/10.15171/jlms.2020.19 ); (Thabet AAE et al. (2018) Effect of pulsed high intensity laser therapy on delayed caesarean section healing in diabetic women. J Phys Ther Sci 30(4):570-575. https://doi.org/10.1589/jpts.30.570 ); (Nussbaum EL, Baxter GD, Lilge L (2003) A Review of Laser Technology and Light-Tissue Interactions as a Background to Therapeutic Applications of Low Intensity Lasers and Other Light Sources. Phys Therapy Reviews 8(1):31-44. https://doi.org/10.1002/lsm.20769 ). All selected studies demonstrated favorable results in improving wound conditions (Thabet AAE, Mahran HG, Ebid AA, Alshehri MA. Effect of pulsed high intensity laser therapy on delayed caesarean section healing in diabetic women. J Phys Ther Sci. ;30(4):570-575. doi:, Ebid AA, Thabet A, Helal O (2018) (2011) Efficacy of pulsed high intensity Nd: Yag Laser in Treatment of Chronic Diabetic Foot Ulcer. Energy for Health pp. 25-30); (Ebid AA, El-Kafy EM, Alayat MS (2013) Effect of pulsed Nd: YAG laser in the treatment of neuropathic foot ulcers in children with spina bifida: a randomized controlled study. Photomed Laser Surg 31(12):565-570. https://doi.org/10.1089/pho.2013.3533 ); (Hong SE et al. (2016) Effects of neodymium-yttrium-aluminum garnet (Nd: YAG) pulsed high-intensity laser therapy on full thickness wound healing in an experimental animal model. J Cosmet Laser Ther 18(8):432-437. https://doi.org/10.1080/14764172.2016.1202421 ); (Lu Q et al. (2021) Clinical effects of high-intensity laser therapy on patients with chronic refractory wounds: a randomised controlled trial. BMJ Open 11(7):e045866. https://doi.org/10.1136/bmjopen-2020-045866 ); (Pereira FLC et al. (2020) Use of a High-Power Laser for Wound Healing: A Case Report. J Lasers Med Sci 11(1):112-114. https://doi.org/10.15171/jlms.2020.19 ); (Thabet AAE et al. (2018) Effect of pulsed high intensity laser therapy on delayed caesarean section healing in diabetic women. J Phys Ther Sci 30(4):570-575. https://doi.org/10.1589/jpts.30.570 ); (Nussbaum EL, Baxter GD, Lilge L (2003) A Review of Laser Technology and Light-Tissue Interactions as a Background to Therapeutic Applications of Low Intensity Lasers and Other Light Sources. Phys Therapy Reviews 8(1):31-44. https://doi.org/10.1002/lsm.20769 ). Although insufficient data support using HILT in wound management, the promising results encourage further research. HILT appears effective in wound healing, but more high-quality studies are needed to identify optimal laser protocols.

The impact of scrambler therapy on pain and quality of life for chemotherapy-induced peripheral neuropathy: A pilot study.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a debilitating disturbance among patients who received chemotherapy, with no effective treatment available. Scrambler therapy (ST) is a noninvasive treatment capable of improving multiple quality-of-life symptoms beyond pain. We aimed to evaluate the efficacy of ST for pain and nonpain symptoms related to CIPN. METHODS: Ten patients with moderate to severe CIPN symptoms for >3 months were enrolled in a single-arm trial of ST for 10 daily sessions. CIPN-related symptoms were measured throughout the treatment period and up to 6 months thereafter. RESULTS: The worst pain was reduced by 6 months (p = 0.0039). QST demonstrated the greatest improvement in pressure of 60 g (p = 0.308, Cohen's d = 0.42) and cold temperature threshold of 2.5°C (p = 0.9375, Cohen's d = 0.51) in the gastrocnemius area. Symptoms of numbness, tingling, trouble walking, and disturbed sleep had significant improvements at 6 months. Pain medication use decreased by 70% at the end of treatment and by 42% at 6 months. Patient satisfaction was high (82%) and no adverse events with ST treatment were reported. CONCLUSIONS: The results of this pilot trial support the use of ST by demonstrating improvement in multiple domains of quality of life for CIPN patients during an extended follow-up of 6 months. However, further large-scale studies are needed to confirm our findings.

Effectiveness of Facet Joint Nerve Blocks in Managing Chronic Axial Spinal Pain of Facet Joint Origin: A Systematic Review and Meta-Analysis.

BACKGROUND: Chronic axial spinal pain is one of the major causes of disability. Literature shows that spending on low back and neck pain and musculoskeletal disorders continues to escalate, not only with disability, but also with increasing costs, accounting for the highest amount of various disease categories. Based on the current literature utilizing controlled diagnostic blocks, facet joints, nerve root dura, and sacroiliac joints have been shown as potential sources of spinal pain. Therapeutic facet joint interventional modalities of axial spinal pain include radiofrequency neurotomy, therapeutic facet joint nerve blocks, and therapeutic intraarticular injections. OBJECTIVE: The objective of this systematic review and meta-analysis is to evaluate the effectiveness of facet joint nerve blocks as a therapeutic modality in managing chronic axial spinal pain of facet joint origin. STUDY DESIGN: A systematic review and meta-analysis of randomized controlled trials (RCTs) and observational studies utilizing the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) checklist. METHODS: The available literature on facet joint nerve blocks in axial spinal pain was reviewed. The quality assessment criteria utilized were the Cochrane review criteria to assess risk of bias, the Interventional Pain Management Techniques - Quality Appraisal of Reliability and Risk of Bias Assessment (IPM-QRB) for randomized therapeutic trials, and the Interventional Pain Management Techniques - Quality Appraisal of Reliability and Risk of Bias Assessment for Nonrandomized Studies (IPM-QRBNR) for nonrandomized studies. The evidence was graded according to Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) assessment criteria. The level of evidence was based on best evidence synthesis with modified grading of qualitative evidence from Level I to Level V. A comprehensive literature search of multiple databases from 1966 to July 2023, including manual searches of the bibliography of known review articles was performed. Quality assessment of the included studies and best evidence synthesis were incorporated into qualitative and quantitative evidence synthesis. OUTCOME MEASURES: The primary outcome measure was the proportion of patients with significant relief and functional improvement of greater than 50% of at least 3 months. Duration of relief was categorized as short-term (less than 6 months) and long-term (greater than 6 months). RESULTS: This assessment identified 8 high-quality and one moderate quality RCTs and 8 high quality and 4 moderate quality non-randomized studies with application of spinal facet joint nerve blocks as therapeutic modalities. However, based on the Grading of Recommendations, Assessment, Development and Evaluations (GRADE) assessment, only 3 of the 21 studies showed high levels of evidence and clinical applicability, with 11 studies showing moderate levels of GRADE evidence and clinical applicability. LIMITATIONS: Despite the availability of multiple studies, the paucity of literature is considered as the major drawback. Based on Grading of Recommendations, Assessment Development, and Evaluations (GRADE) assessment, only 3 of the 21 studies showed high levels of evidence and clinical applicability. CONCLUSION: Based on the present systematic review and meta-analysis with 9 RCTs and 12 non-randomized studies, the evidence is Level II with moderate to strong recommendation for therapeutic facet joint nerve blocks in managing spinal facet joint pain.

Use of corticosteroids for adult chronic pain interventions: sympathetic and peripheral nerve blocks, trigger point injections - guidelines from the American Society of Regional Anesthesia and Pain Medicine, the American Academy of Pain Medicine, the American Society of Interventional Pain Physicians, the International Pain and Spine Intervention Society, and the North American Spine Society.

BACKGROUND: There is potential for adverse events from corticosteroid injections, including increase in blood glucose, decrease in bone mineral density and suppression of the hypothalamic-pituitary axis. Published studies note that doses lower than those commonly injected provide similar benefit. METHODS: Development of the practice guideline was approved by the Board of Directors of American Society of Regional Anesthesia and Pain Medicine with several other societies agreeing to participate. The scope of guidelines was agreed on to include safety of the injection technique (landmark-guided, ultrasound or radiology-aided injections); effect of the addition of the corticosteroid on the efficacy of the injectate (local anesthetic or saline); and adverse events related to the injection. Based on preliminary discussions, it was decided to structure the topics into three separate guidelines as follows: (1) sympathetic, peripheral nerve blocks and trigger point injections; (2) joints; and (3) neuraxial, facet, sacroiliac joints and related topics (vaccine and anticoagulants). Experts were assigned topics to perform a comprehensive review of the literature and to draft statements and recommendations, which were refined and voted for consensus (≥75% agreement) using a modified Delphi process. The United States Preventive Services Task Force grading of evidence and strength of recommendation was followed. RESULTS: This guideline deals with the use and safety of corticosteroid injections for sympathetic, peripheral nerve blocks and trigger point injections for adult chronic pain conditions. All the statements and recommendations were approved by all participants after four rounds of discussion. The Practice Guidelines Committees and Board of Directors of the participating societies also approved all the statements and recommendations. The safety of some procedures, including stellate blocks, lower extremity peripheral nerve blocks and some sites of trigger point injections, is improved by imaging guidance. The addition of non-particulate corticosteroid to the local anesthetic is beneficial in cluster headaches but not in other types of headaches. Corticosteroid may provide additional benefit in transverse abdominal plane blocks and ilioinguinal/iliohypogastric nerve blocks in postherniorrhaphy pain but there is no evidence for pudendal nerve blocks. There is minimal benefit for the use of corticosteroids in trigger point injections. CONCLUSIONS: In this practice guideline, we provided recommendations on the use of corticosteroids in sympathetic blocks, peripheral nerve blocks, and trigger point injections to assist clinicians in making informed decisions.