Back pain is the single leading cause of disability worldwide. Despite the prevalence and morbidity of lower back pain, we still lack a gold-standard treatment that restores the physiological function of degenerated intervertebral discs. Recently, stem cells have emerged as a promising strategy for regenerative therapy for degenerative disc disease. In this study, we review the etiology, pathogenesis, and developing treatment strategies for disc degeneration in low back pain with a focus on regenerative stem cell therapies. A systematic search of PubMed/MEDLINE/Embase/Clinical Trials.gov databases was conducted for all human subject abstracts or studies. There was a total of 10 abstracts and 11 clinical studies (1 RCT) that met the inclusion criteria. The molecular mechanism, approach, and progress of the different stem cell strategies in all studies are discussed, including allogenic bone marrow, allogenic discogenic cells, autologous bone marrow, adipose mesenchymal stem cells (MSCs), human umbilical cord MSC, adult juvenile chondrocytes, autologous disc derived chondrocytes, and withdrawn studies. Clinical success with animal model studies is promising; however, the clinical outcomes of stem cell regenerative therapy remain poorly understood. In this systematic review, we found no evidence to support its use in humans. Further studies on efficacy, safety, and optimal patient selection will establish whether this becomes a viable, non-invasive therapeutic option for back pain. Back pain is the single leading cause of disability worldwide affecting people of all ages and socioeconomic statuses ,2,3,4,5.The cause of lower back pain is complex and multifactorial, and often the specific source of the pain cannot be identified. For a significant portion of patients with back pain, the symptoms are short-lived and self-limiting in nature, with occasional recurrent episodes. A small percentage of patients develop chronic and disabling LBP. Organic causes of back pain, such as infection, malignancy, inflammation, or trauma, are a rarity since most back pain is mechanical in nature.While diagnostic tests may not always accurately identify the precise source of LBP, several innervated structures of the spinal anatomy have been implicated as pain generators. It is becoming increasingly evident that one of the foremost causes of LBP is intervertebral disc degeneration . DegenerDespite the prevalence and morbidity associated with LBP in the setting of degenerative disc disease, there is no gold standard for the treatment of LBP, which restores the integrity and normal physiological function of degenerated intervertebral discs. Considering this, we reviewed some of the developing and new treatment strategies for low back pain that target disc degeneration in patients with severe back pain related to degenerative disc disease.Intervertebral discs are fibrocartilaginous in nature, contributing to their role in providing mobility and maintaining the integrity of the spine . There aAs a structural unit, the intervertebral disc, the NP, AF, and EPs are interconnected to form a crucial part of the motion segment of the spine. The discs function as shock absorbers and provide resistance to both the tensile and torsional forces. The matrix of the NP is approximately 80% water, which helps it resist compressive forces and provide flexibility to the spine . The NP Intervertebral discs are also the largest avascular tissue in the body as well as aneural. To maintain the viability of the NP cells, the intervertebral discs primarily attain their nutrients and metabolites by diffusion from vessels in the cartilaginous EP and outer AF  8,10].,10.8,10]Both the integrity and the structure of the discs change with age . DegenerWhile aging can contribute to disc disease, disc degeneration may also occur independent of the aging process. It is difficult to clearly differentiate the physiological process of disc aging from that of disc degeneration. As such, the main distinguishing factor in disc degeneration is the inherent structural and functional failure of the disc secondary to impaired cellular processes and extracellular matrix changes ,13. In tIntervertebral disc degeneration is a major cause of neck and back pain and a major cause of disability ,13. The Current approaches to treat discogenic back pain primarily target symptomatic relief through either conservative or invasive methods ,31,32. CStem cells are unspecialized cells with the ability to self-renew and differentiate into various cell types ,36. ReceMesenchymal stem cells (MSCs) have proven particularly attractive for regenerative cell therapy for degenerative disc disease. Given their capability of differentiating into various connective tissues cells and being readily obtained from several sources, including adipose tissue, muscles, umbilical cord blood, bone marrow, and dermis, MSCs could potentially provide the ideal treatment for degenerative disc disease and discogenic back pain ,46,47. IA systematic search of PubMed/MEDLINE was conducted for literature published until 17 October 2022 in the EMBASE and Clinical Tri-als.gov databases. Only studies in human subjects with abstracts written in English were considered for inclusion, while no other search limitations were included . We sougn = 542), 536 unique articles were identified. After the initial screening, 512 articles did not meet the inclusion criteria, most being related to preclinical models/mechanisms/methods, involving animal studies, commentary, or case reports . Gender was documented in all reports with a total number of 71 males and 48 females included in all articles. There was an average of 15 months of follow-up (ranging from 12 to 72). Validated patients reported outcomes comprising the Oswestry Disability Index (ODI) and visual analog scale for pain (VAS), except for one study, which reported the Japanese Orthopedic Association score (JOA), Functional Rating Index (FRI), and numeric pain scale (NPS). ODI is a validated outcome measure from 0 to 100, with 0 representing functional independence and 100 being severely disabled. The VAS is a pain-reported outcome scale with 0 being no pain and 10 being the worst pain possible. JOA is reported on a scale of 0 (severely disabled) to 17 (no disability). FRI is reported from 0  to 100 (severely disabled). NPS has a pain scale with a range from 0 (no pain) to 10 (worst possible pain).× 106 cells/disc, isolated from subcutaneous adipose tissue) for low back pain caused by degenerative disc disease (DDD), they reported reductions of 68% and 62.4% in VAS and ODI, respectively, at 6 months [In a prospective cohort study of 10 patients treated with autologous MSCs (10 6 months . These r6) were co-cultured in direct contact with NP cells for 7 days before these activated NP cells were transplanted into the degenerated disc adjacent to the interbody fusion segment. JOA scores were noted to have improved from 14.2 to 27.2 after 36 months, with a resolution of symptoms in all 9 patients involved in the study [6 cells) cultured in hypoxic conditions from a cohort of five patients with chronic back pain and injected them into the involved degenerated disc . They reported improvement in overall quality of life, strength, and mobility after 48–72 months [6, range 1.72–4.5 × 106) into the discs of 33 patients with low back pain and degenerative disc disease [p < 0.05). These findings support earlier work suggesting a clinical benefit from disc injections of autologous bone marrow-derived MSCs. This benefit is independent of MSC dose and does not correlate significantly with the disc hydration content post-injection. These studies are limited in that they are non-randomized, single-arm, cohort studies with no control group.In a separate study by Mochida et al., autologous bone marrow-derived MSCs  in 26 patients with indications of spinal fusion or disc replacement [In a prospective, non-randomized cohort study, Pettine et al. used autologous MSCs . Given that the most clinical benefit  was noted to occur within the first 3 months, it is difficult to fully attribute this effect to the degree of disc hydration, which becomes statistically different at 12 months. In addition, the absence of the appropriate control arms limits the ability to interpret this finding because not all the patients with improved disc hydration status benefited from the MSC injections. Further studies exploring the safety, efficacy, and long-term implications in different populations are warranted. Additionally, future studies will need to investigate the potential mechanisms of MSCs and their ability to induce local cellular proliferation in vivo or prevent further disc degradation by providing a better microenvironment for cell viability. Lastly, the biomechanical properties of the discs treated with MSCs need to be explored further to better understand the benefit of applying this approach in humans.Two main strategies have been employed for MSC-based therapies for back pain associated with degenerative disc disease: transplantation of undifferentiated stem cells in vivo with induction under the stimulation of local factors, or differentiation of stem cells in vitro prior to transplantation. In either case, modest improvement was noted in the reviewed studies . SignifiTo date, there is no clinical therapy that successfully targets and reverses disc degeneration. Treatment options for discogenic back pain involve non-surgical approaches or surgery for symptomatic patients requiring decompression of their neural elements and stabilization spinal stabilization. With the advent of cell-based strategies and new areas of investigation focusing on regeneration, significant advances have been made, yet more questions arise regarding the therapeutic advantage of stem cells.MSCs have been identified as being capable of potentially providing the ideal treatment for degenerative disc disease ,46,47. TClinical trials utilizing intradiscal injection of mesenchymal stromal cells (MSCs) from adipose tissue or bone marrow have successfully yielded promising results in patients with discogenic back pain. Emerging trends, as noted in several clinical trials using an intradiscal injection of bone marrow (BM)-MSCs, demonstrated significant pain relief with improvement approaching 71% of optimal during the first year ,39,40. In = 12) received intradiscal injections of 25 × 106 cells in 2 mL of saline per disc treated, while the control group (n = 12) received a sham infiltration of 2 mL of 1% mepivacaine anesthetic of paravertebral musculature close to the affected disc(s). The mean age of the patients was approximately 38 years and 30% were female. The authors reported the temporal evolution of pain and disability as being significantly improved and used ANOVA for pair populations. There was no significant improvement in SF-12, disc height, or water content by MRI. Yet the Pfirrmann scores improved in the MSC-treated patients when assessing several disc parameters for changes in apparent diffusion coefficient versus T2 quantitation. Upon calculation of the statistical testing, using unpaired t-tests to assess mean differences and corresponding confidence intervals, no differences between the treatment and control groups were noted. No major adverse events were identified in either treatment group. The authors reported allogenic MSC recipients required fewer nonsteroidal anti-inflammatory drugs versus sham , and 8.3% of both groups received opioids.Noriega et al. (2017) conducted a randomized controlled trial of 24 patients to determine if allogenic BM MSCs injected into degenerative IVD decreased pain and improved function. The primary outcome measures were self-reported pain on the visual analog scale, and enhanced function as measured using the Oswestry Disability Index, and Short Form quality of life (SF-12) functional scales. Outcomes were assessed at baseline, 3, 6, and 12 months. Clinical significance was not predefined in this study. MRI was used to assess disc height and water content. Study inclusion required patients to be healthy from a hematological and biochemical standpoint. The patients had low back pain with DDD at 1 or 2 levels and failed conservative measures for at least 6 months. Radiographic measurement of IVDs had decreased disc heights of greater than 20% and MRI Pfirrmann grades of 2 to 4. The indexed grades had enough degeneration to observe a treatment effect while permitting the annulus to hold the implanted cells. Under local anesthesia, the test group  group. Allogenic MSCs have advantages, including lower costs, possible higher homogeneity, and logistically more convenience for clinical applications. However, the limitations include a small sample size, which may account for the lack of statistical significance between the MSC and sham-control groups for pain, function, quality of life, and MRI disc height assessments.While these results are not yet published, another novel, allogenic BM MSC study, which used a more purified monoclonal population of stromal precursor antigen (STRO-3+) selected progenitor cells has been investigated . Preclin6 rexlemestrocel-L cells, 1 × 106 rexlemestrocel-L cells with hyaluronic acid (HA), or a saline solution (placebo) control. A primary endpoint was examined for the treatment success based on a composite of 50% or greater pain reduction in the VAS score, a 15-point or greater reduction in the ODI score, and a lack of post-treatment interventions at 12- and 24-months post-injection. These specific results and the analysis were not reported in the publication. Only the demographics, mortality, and serious and other adverse events were reported on clinicaltrials.gov. There were no deaths due to any cause during the clinical study. The percentage of serious adverse events in the group receiving 1 × 106 rexlemestrocel-L cells alone (n = 143), 1 × 106 rexlemestrocel-L cells with hyaluronic acid (n = 129), and saline placebo (n = 132) were 9.29%, 9.38%, and 5.38%, respectively. Other non-serious adverse events were reported among all three groups, including musculoskeletal and nervous system disorders, such as back pain, muscle spasms, and hypoesthesia or paresthesia. The outcome measures proposed for the analysis were similar to the Noriega study, in terms of assessing the VAS and ODI. In contrast, the rexlemestrocel-L study defined success based on composite responder analyses, which included the reduction in pain (VAS), improvement in function (ODI), and lack of post-treatment intervention (decrease in the need for another treatment for LBP).The Rexlemestrocel-L phase-3 trial was a multicenter, randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of a single injection of rexlemestrocel-L alone or in combination with hyaluronic acid in subjects with chronic low back pain. The study enrolled 404 patients with documented DDD, Pfirrmann scores from 3 to 6 at a single level from L1 to S1, and with low back pain for at least 6 months, which was not responsive to conservative treatments, including physical therapy. The patients were randomized to receive 1 × 10Similar to the Noriega study, cells were isolated from bone marrow and from mononuclear cells and expanded ex vivo. However, the rexlemestrocel-L cells originated from a single, young healthy donor, while in the Noriega study, they were isolated from four men and one woman, while the cells obtained from each donor were used for one to three recipients. In all cases, the cell products were examined for the presence of donor infectious diseases and screened for viability before use.7 autologous BM-MSCs to each affected disc. The sham comparators will have simulated bone marrow harvesting without insertion into the iliac crest and simulated local anesthetic without a disc or placebo injection. For the DREAM trial, primary outcome measures include pain relief as measured by a decrease in VAS and functionality by ODI. Secondary measures will assess the quality of life (SF36) and its evolution, interval disability and pain evolution, employment status, and pain medication consumption. For the ACTIVE occupational study, efficacy will be evaluated 12 months after treatment in terms of pain relief (VAS), function (ODI), quality of life (SF36), and work ability index (WAI).Two other investigations recruited patients to assess the efficacy of intradiscal injection of autologous bone marrow-MSCs. The DREAM trial is assessing intradiscal treatment injections in subjects with chronic LBP of >6 months, who have up to 3 levels of intervertebral disc degeneration (IVDD) and are unresponsive to conventional therapies . The ACTA unique clinical trial that is currently active involves the application of a novel cell population produced by expanding and modifying cells from adult intervertebral nucleus pulposus tissue . Since tThere is evidence that nucleus pulposus stem cells isolated from degenerated IVD have demonstrated impaired proficiency in proliferation and differentiation. When cultured in a simulated disc microenvironment, such cells are more resistant to hypoxic and acidic pH compared to other types of stem cells, such as adipose stem cells ,71. The 6/mL concentration solution of MSCs and 6 subjects receiving a high dosage treatment of 1–2 mL of a 4 × 106/mL concentration solution of MSCs. Primary outcome measures will be of TRAEs and SAEs, while secondary outcome measures include changes in VAS, ODI, SF-36, and changes in MRI monitoring of the transplant site. Inclusion criteria include the absence of infection and coagulopathy, symptoms despite conservative  management for >6 months, absence of facet joint pain involvement between 18 months and 2 weeks, confirmed by diagnostic medial branch block or facet joint injections, and a Pfirrmann score of 3 to 5. Some exclusion criteria include infection, cancer, severe spinal stenosis, pregnancy, contraindications to MRI and immunosuppression, and a BMI of >35. This study will add to the literature as a comparison between autologous BM-MSCs and allogenic MSC studies, using relatively similar study subjects. It will also provide insight into lessons learned from autologous preparation, handling, and delivery. Previous investigations have demonstrated morbidities such as chronic pain from the use of autologous iliac crest bone grafts, as well as limited quantity and quality dependent on the age and comorbid diseases of the patients.A new clinical trial will be conducted to assess the percutaneous fluoroscopic delivery of autologous BM MSCs for the treatment of symptomatic degenerated intervertebral disc disease . A total7 and HA and another five received a higher dose of 4 × 107 cells/disc. No control group was available for comparison. Outcome measures included SAEs, VAS, ODI SF-36, and MRI Pfirrmann ADC mapping to assess DD severity as well as an X-ray for disc height. There were reported improvements in VAS and ODI over time from baseline, 3-month, 6-month, and 12-month assessments. There was no significant difference between the groups receiving different doses at 12 months. SF-36 was not reported. One patient had an MRI Pfirrmann improvement from 4 to 3. Three patients showed increased water content through MSC application and no decrease in height on an X-ray. No observation of AEs or SAEs was related to the cell transplantation and abnormal blood tests were assessed during the first week and quarterly.Kumar et al. (2017) investigated the intradiscal injection of hyaluronic acid derivative and adipose-tissue-derived expanded MSCs from abdominal fat in patients with discogenic LBP ,72. The n = 15) with no comparison group, which makes it difficult to draw a conclusion that the effects observed are reflective of true effects. Future studies and larger, placebo-controlled investigations will be beneficial.Comella et al. (2017) examined the effects of intradiscal implantation of stromal vascular fraction (SVF) of adipose-derived MSCs plus platelet-rich plasma (PRP) in patients with degenerative diseases . While tA new clinical trial will assess the safety and efficacy of Matrilin-3 pretreated autologous AD MSC implantation. Matrilin-3 is an extracellular matrix (ECM) protein involved in cartilage development. The role of ECM components in the remodeling process of disc degeneration has garnered much attention as manipulation of these elements may provide adjunctive therapy for improving disease outcomes . SimilarTargeting ECM remodeling as an adjunct therapy may result in better disease outcomes. Inclusion criteria include an age of 19–70 years, ODI score ≥ 30%, VAS ≥ 4, MRI Pfirrmann classification 3–4 between lumbar-1 and sacral-1, and the confirmation of one or two degenerated discs, which have been confirmed by injection procedures . While tA clinical trial is actively recruiting to evaluate the safety and effectiveness of human umbilical cord mesenchymal stem cells (hUC-MSCs) for the treatment of lumbar DDD . This ph7 cells/mL) for refractory LBP was investigated [p = 0.0002) all improved significantly from the baseline and 10/13 patients had an improved MRI. HIZ was absent or improved in eight patients. The lack of a comparison group limits the quality of evidence. The investigation elucidates the use of chondrocytes, which synthesis and turnover a large volume of the extracellular matrix (ECM) in treating DDD. Breakdown of ECM and loss of proteoglycans and type II collagen are observed in the DDD.Intradiscal injection of expanded allogenic juvenile chondrocyte cells (density of 5 × 10stigated . Coric estigated . Fifteen® disc plus (ND plus) is a biologic-device combination product (combination of autologous disc chondrocyte and a self-polymerizing hydrogel) investigated for the treatment of lumbar DDD. ND basic is the device alone with no active chondrocyte cells. Tschugg et al. (2017) examined whether autologous disc chondrocyte transplantation is safe and feasible [Novocartfeasible . Twenty-Five of the research studies referenced were either withdrawn or terminated from current and emerging clinical trials. These included two autologous BM MSCs, two adipose-derived MSCs and an allogenic MSC study to be used with lumbar fusion ,83,84,85One clinical trial was performed to isolate and authenticate MSC-like progenitor cells from degenerated IVDs from the lumbar spine . While nStem cell-based therapies that integrate tissue-engineering technologies and biomaterials science are becoming fundamental pillars in regenerative medicine. Clinical success with animal model studies employing stem cell transplantation is promising and provides a good foundation for further studies on stem cell transplantation strategies. Ongoing clinical trials will be crucial in validating the results in humans and serve as a launch pad for further stem cell therapeutic strategies. However, the clinical outcomes of stem cell transplantation for specific symptoms, such as back pain, as well as other back-related disorders, while encouraging, remains poorly understood and warrant further studies.The use of stem cells for regenerative therapy has provided insight into potential therapeutic options for discogenic back pain. While cell-based strategies hold significant opportunity for regenerative medicine, its role in treating degenerative disc disease associated with discogenic back pain is still in the early stages of clinical trials and the overall efficacy has yet to be proven. Although stem cell therapy is a rapidly emerging field given its perceived potential, it should be emphasized that these preliminary research findings need to be approached with great caution from a patient’s perspective. Specifically, the Federal Drug Association (FDA) has not sanctioned or approved the use of stem cells for degenerative disc disease or associated discogenic back pain. On the contrary, the FDA has issued warnings and raised concerns about scams by clinics and companies marketing stem cell treatment without FDA approval. Undoubtedly, further randomized, long-term clinical studies are required to establish the full potential of stem cell regenerative therapy. Upon FDA approval, understanding how stem cells might be integrated into the current treatment guidelines and management strategies for patients with discogenic back pain.From a clinical perspective, being able to reliably identify candidates for intradiscal injection and having an objective means of assessing their improvement will prove challenging given the multifactorial complex nature of back pain. Height restoration of a degenerative disc might serve to effectively monitor or predict improvement, although it would have its limitations in that pain relief has been observed in patients receiving intradiscal stem cell injection with no disc height restoration. Thus, as we already know, not all back pain is discogenic in nature and the perceived potential mechanism for stem cell therapy would be for back pain associated with degenerative disc disease. Establishing non-invasive means for selecting patients that might benefit from stem cell injections will be paramount. Moreover, the long-term implications of stem cell transplantation with respect to safety and efficacy need to be better defined prior to making this tissue regenerative approach a standard of care. This underscores the need for future studies to focus on being able to evaluate the safety and efficacy of stem cell treatment when compared to current non-surgical treatment standards and perceived long-term outcomes.


Several new ultrasound-guided superior cervical ganglia blocks (U-SCGBs) have been proposed to overcome the shortcomings of conventional superior cervical ganglia blocks; however, their clinical utility and practicality have not yet been demonstrated. The aim of this study was to evaluate the safety and utility of a new method of U-SCGB.We retrospectively collected data on patients who underwent U-SCGB for the treatment of headaches and orofacial pain at a single center. U-SCGB was performed by injecting 2–3 mL of 1% mepivacaine posterior to the internal carotid artery, just above the bifurcation. The Wilcoxon signed-rank test was used to compare pain scores. Numerical data are expressed as the mean ± standard error.p = 0.014).The total number of U-SCGB procedures was 43. All procedures were accompanied by Horner’s sign. The numerical rating scale score for pain  was reduced predominantly from 7.0 ± 0.7 before treatment to 4.5 ± 0.7 at the follow-up (U-SCGB was considered a clinically useful and accurate treatment for headaches and orofacial pain in this study. Headaches and orofacial pain may be caused by abnormalities in autonomic innervation and/or function. The cervical sympathetic ganglia consist of the superior, middle, intermediate, and inferior cervical sympathetic ganglia. Stellate ganglion block (SGB) refers to the blocking of the sympathetic chains/ganglia of the cervical and upper thoracic regions and is utilized to diagnose and treat pain-related diseases of the head, neck, mouth, face, and upper extremities . AlthougThe superior cervical ganglia (SCG) are cervical sympathetic ganglia located cephalad to the common carotid artery bifurcation. Although the effectiveness of SCG blocking alone has been reported in the cervical sympathetic nerve for trigeminal neuralgia, postherpetic neuralgia, and chronic facial pain , conventhttps://www.kuaccm.med.kyushu-u.ac.jp).We conducted a retrospective cohort study by reviewing the clinical records of patients diagnosed with headache and orofacial pain who underwent an ultrasound-guided SCG block at the pain management unit of Kyushu University Hospital. This study was approved by the Kyushu University Hospital Ethics Committee on August 30, 2022 (ID number 2106901) and performed in accordance with the 1964 Helsinki Declaration and its later amendments. Due to the retrospective design of this study, the requirement for written consent was waived for treated patients unless they refused. Moreover, an opt-out approach was implemented by publishing the information explaining the study on our website and guaranteeing the opportunity to refuse the use of information whenever possible until March 31, 2023  for approximately 30 min. The reduction in pain and signs of Horner’s syndrome were examined as the primary endpoints, and the secondary endpoint was the number of adverse events after the procedures. The patient was evaluated for signs of Horner’s syndrome 15–30 min after each ultrasound-guided SCG block. The level of pain was graded on a numerical rating scale (NRS) ranging from 0 to 10, 3 months after the start of treatment. On the day of evaluation, the physician asked the patient about the maximum and minimum NRS scores for the past few days; this information was noted in the patient’s medical record, and these scores were extracted.The patients were placed in the lateral decubitus position with the affected side up, following which the mastoid process, hairline, and neck were disinfected. The common carotid artery was identified via ultrasound; a high-resolution linear probe  was positioned vertically to the blood vessel. The probe was gradually moved in the cranial direction to the position of the carotid bifurcation. A representative ultrasound image is presented in Fig. p < 0.05.All values are expressed as the mean ± standard error. Statistical analysis was performed using the Wilcoxon signed-rank test for changes in NRS scores before and after the completion of the nerve blocks. Statistical significance was set at p = 0.014) and from 3.4 ± 0.7 to 1.4 ± 0.4 (p = 0.018), respectively. Table This study consisted of 43 ultrasound-guided SCG block procedures (the average number of blocks was 4.3 ± 0.4) performed on 10 patients, with a female predominance . The patient’s diagnoses were persistent idiopathic facial pain (PIFP), occipital neuralgia, painful post-traumatic trigeminal neuropathy, burning mouth syndrome, and postherpetic trigeminal neuropathy. The average age of the patients was 51.3 ± 4.5  years. The disease period, namely the time from disease onset to ultrasound-guided SCG block, was 21.6 ± 5.7  months. Signs of Horner’s syndrome were observed after all 43 procedures (100%). The maximum and minimum NRS were significantly reduced after 3 months of the first ultrasound-guided SCG block, from 7.0 ± 0.7 to 4.5 ± 0.7 ; larger studies are required to verify the utility of our procedure for the treatment of headaches and orofacial pain.This study has several limitations. First, we included only patients with pain refractory to conservative treatment and who were treated with ultrasound-guided SCG block, with no control group. Thus, the degree of superiority of the ultrasound-guided SCG block procedure compared with other treatments or the natural course of the disease with conservative therapy is unknown. Second, as with other chronic pain, psychosocial considerations are important in the management of headaches and orofacial pain ; howeverThe SCG can be reliably blocked via ultrasound-guided injection of a small amount of local anesthetic posterior to the internal carotid artery. Our results suggest that ultrasound-guided SCG block is a promising alternative to conventional SGB for the treatment of sympathetically maintained headache and orofacial pain, as the latter may cause fatal complications such as retropharyngeal hematoma.


In the female group, all outcomes except for the FIM were statistically significantly worse (p ≤ 0.004). Dividing our sample into four groups based on gender and the BPI, a statistically significant difference was found for FSS between the two groups with BPI-II ≥ 4  (p < 0.002). Pain in DM1 patients is highly reported and gender related, with increased fatigue and poor balance/gait in the female group.Pain is an underestimated finding in myotonic dystrophy type 1 (DM1). We provide a characterization of pain in terms of functional implications through a multidimensional assessment in patients with DM1, focusing on gender differences. We assessed pain through the Brief Pain Inventory (BPI) and its indexes (the Severity Index (SI) and the Interference Index (II)), balance/gait (the Tinetti Performance-Oriented Mobility Assessment (POMA)), functional abilities ), and fatigue ). We divided our sample into a mild (<4) and a moderate–severe group (≥4) based on BPI indexes. A between-group analysis was performed. We recruited 23 males and 22 females with DM1. A statistically significant difference was found for the FSS and the BPI-SI ≥ 4, and for all outcomes in the BPI-II ≥ 4 ( Myotonic dystrophy type 1 (DM1), also known as Steinert’s disease, is the most common adult-onset muscular dystrophy . DM1 is As in other neuromuscular disorders (NMD) ,10, painIn DM1 patients, a significant contribution of the neuropathic mechanism as a pain generator has also been postulated, considering that peripheral neuropathy was reported in this population .As typically observed in other NMDs, the chronicization of pain in patients with myotonic dystrophy may adversely affect quality of life and social participation, with increased impact on the health care system ,18. FinaHowever, despite the huge disabling and socio-economic impact of pain in NMDs, this impairment is often overlooked in DM1 patients. Moreover, pain in DM1 has not yet been investigated from a multidimensional perspective, and less is known about its potential association with some disabling aspects of the disease such as gait and balance disturbances. The aim of this study is to provide a better characterization of pain in terms of both intensity and functional implications through a multidimensional assessment in a cohort of patients with DM1, particularly focusing on gender differences.In our observational, cross-sectional study, we recruited patients with a genetic diagnosis of DM1, classic phenotype, referred to our outpatient rehabilitation service. All patients provided written informed consent, in accordance with the guidelines of the Declaration of Helsinki. The Ethical Committee of the Università della Campania “Luigi Vanvitelli” approved the study protocol (Committee’s reference number: 0017390/2020).All patients were assessed by a dedicated evaluation protocol, including the collection of anamnestic and anthropometric data, and the administration of the following outcome measures:The Brief Pain Inventory is a self-reported questionnaire used to evaluate pain intensity and its interference with activities of daily living (ADLs) with two indexes (the Severity Index (SI) and the Interference Index (II)) . The BPIAccording to the World Health Organization (WHO) classification of pain ,22, we dThe Tinetti Performance-Oriented Mobility Assessment is a clinical test used to evaluate gait and balance. The balance subscale includes 9 items and a total score ranging from 0 to 16. The gait subscale has 7 items, with a total score ranging from 0 to 12. A lower total POMA score (<15.5) corresponds to a greater risk of fall .The FIM is an 18-item ordinal scale that evaluates functional abilities in six areas—self-care, continence, mobility, transfers, communication, and cognition. For each item, it is possible to give a score ranging from 1 to 7 based on the level of independence . The total score will be a value between 18 and 126 and the cut-off for a poor outcome is considered 63 .The Fatigue Severity Scale is a 9-item questionnaire aiming to assess the severity of fatigue symptoms and their impact on daily functioning. Each question is scored from 1 (“completely disagree”) to 7 (“completely agree”). The total score is given by the mean score of the 9 items. A total score >36 suggests a high level of fatigue .In order to investigate the role of gender on symptoms and functional outcomes, we also analyzed any difference between male and female groups according to pain severity and interference.2) was reported, indicating a small (0.01), medium (0.06) or large (0.14) effect [2) was reported, indicating 0.00 < 0.01—negligible, 0.01 < 0.04—weak, 0.04 < 0.16—moderate, 0.16 < 0.36—relatively strong, 0.36 < 0.64—strong and 0.64 < 1.00—very strong effect [p < 0.05.Statistical analysis was carried out using the Statistical Package for the Social Sciences 25  software. Data for continuous variables are expressed as the means ± standard deviations or as the median (interquartile range (IQR)). Categorical data are reported in terms of counts (absolute numbers and percentage). Normality was checked through the Shapiro–Wilk test. We performed a multivariate logistic regression analysis to measure if pain severity and interference are influenced by disease duration (DD), FSS, FIM and POMA scores. We evaluated between-group differences for all the outcome measures. The independent-samples Mann–Whitney U test was used to compare POMA, FSS and FIM scores among the groups and for the sub-analysis on gender . Effect size (η) effect . Finallyg effect . We consA total of 45 DM1 patients  were recruited. In -p < 0.002);For the BPI-SI a–c, a st-p < 0.002) and for the FSS and the POMA, with a lower score in the male group with the BPI-II ≤ 4 compared to the female group with BPI-II ≥ 4 (p < 0.002).For the BPI-II d–f, a stFinally, dividing our sample into four groups based on gender and BPI sub-indexes:Neuromuscular disorders are characterized by several functioning impairments, including pain, although this symptom is often underdiagnosed and undertreated. In this scenario, we performed a cross-sectional study aiming to fill the gap about the knowledge on pain patterns in DM1 population in terms of intensity and functional implications, also focusing on gender differences.In our cohort, 80% of patients with DM1 reported musculoskeletal pain with low back region mostly involved (55.6%). This finding suggests that the prevalence of low back pain in our population is higher than that reported in age-matched individuals, who have a prevalence of low back pain ranging from 28% to 42% . These fMultidimensional scales such as the BPI, although complex to administer, seem to demonstrate good reliability and validity for many clinical situations. Moreover, the BPI is cross-cultural as it was validated in several languages, including Italian. However, the most used assessment tools for pain are the unidimensional scales  and the Visual Analogue Scale (VAS)). These tools, although easy to understand and quicker to administer, assign a single number to the pain experience and do not have psychometric properties that may discriminate among equivalent intervals in terms of scaling the intensity of pain (ceiling effect) . SolbakkAccording to pain distribution, our study confirms that the most involved anatomic region is the lower back (55.6%) ,10,11,12For pain interference in ADLs, our patients reported a low BPI-II in 26.66% of cases (score 1–3.9), and a high BPI-II (score 4–10) in 53.34% of cases. Miro et al. conducted a similar study using a modified version of the BPI-II, adapting the items to consider the unique characteristics of the study population [2 ≥ 0.1). This relationship between pain and fatigue has also been reported by previous studies on DM1 patients [As for fatigue, our participants reported a median FSS score of 43 (9–63), suggesting a moderate perceived fatigue. Moreover, fatigue seems to influence both pain severity and interference with ADLs and the FSS score was higher in individuals reporting a BPI-SI and -II ≥4, compared to those with lower scores (<4), with a large effect size . In our opinion, pain could adversely affect muscle function in DM1 patients, also resulting in the “reflex muscle inhibition” that might slow neuromuscular response, thus contributing to an increased risk of falls.The POMA is a mainstay in the evaluation of balance and gait in different populations and could be considered as a surrogate outcome for muscle function and fall risk assessment. In our study, we found an association between poor POMA scores and high BPI-II in the DM1 population, with a large effect size .These gender-related findings seem to have a biological basis, as demonstrated by a murine model describing the synergic role of Acid-Sensing Ion Channel Subunit 3  with testosterone to protect against muscle fatigue. Gender differences about fatigue onset might depend on both the presence of testosterone and the activation of the ASIC3 protein . ConsistOur study presents several limitations: (1) the cross-sectional design does not enable establishing a cause–effect relationship since the outcome and exposure are evaluated at the same time; (2) the sample of DM1 patients included is too small to draw strong conclusions, even if DM1 is a rare disease and this makes our population quite consistent; (3) the absence of a healthy control group does not permit establishing whether the observed events are specific for the disease; (4) the neuropathic component of pain was not addressed in our population, although peripheral neuropathy and conduction disturbance along the dorsal column–medial lemniscus pathway  was found in this condition. In the future, we will aim to address this issue in our cohort using the recently validated Italian version of the Leeds Assessment of Neuropathic Symptoms and Signs Scale and the Pain DETECT Questionnaire .DM1 is a rare disease with several clinical manifestations, including musculoskeletal pain as a common but underestimated finding. In our population, four out of five DM1 patients reported musculoskeletal pain, mostly in the lower back. In our cohort, our data suggest that pain perception in DM1 patients is gender related and has significant functional implications on clinical practice in terms of increased fatigue and poor balance and gait, despite no relevant difference in functional independence compared to male patients.In our opinion, pain assessment and treatment should be routinely addressed during the comprehensive management of people affected by DM1.


Monoclonal antibodies, such as PD-1 inhibitors, are increasingly used in various cancers. Acute low back pain as infusion-related reaction (IRR) to monoclonal antibodies is poorly described. We report a bicentric series of 10 cases of acute low back pain due to administration of monoclonal antibodies directed against PD-1/PD-L1 for skin cancer treatment in patients treated at University Hospital Heidelberg and University Medical Center Mainz (Germany). The management of IRR symptoms was immediate interruption of infusion and analgesia leading to quick improvement and complete symptom relief in all patients. Our findings suggest that the risk of developing low back pain as IRR is depending on the concentration of the administered drug. Low back pain as IRR can be managed by early interruption of infusion and by decreasing the infusion rate or concentration in following administrations. Monoclonal antibodies, such as programmed cell death protein 1 (PD-1) inhibitors, are among the main therapeutic agents for treating melanoma and other cancer entities. Their use can lead to long-term remission, but also risks generating adverse events including infusion-related reactions (IRRs) , howeverWe report a series of 10 cases of acute low back pain due to administration of monoclonal antibodies directed against PD-1/PD-L1 for skin cancer treatment Table 1.The median time from infusion start to the onset of low back pain was 25 minutes (15-60 minutes). Apart from acute low back pain in all patients  concomitant symptoms included abdominal pain (n = 2), pain radiating in the legs (n = 1) or the neck (n = 1). Pain sensation was described as pulsating, colic like, cramping and pressure. Routine laboratory assessment prior to therapy showed in none of the patients irregularities. Serum concentration of total IgE was in the normal range in 3 and slightly elevated in 2 patients . Abdominal ultrasound imaging performed in one patient (#3) showed no abnormalities. None of the patients showed either any remarkable comorbidities predisposing to low back pain or a history of acute low back pain in the past. The management of IRR symptoms was immediate interruption of infusion and analgesia leading to quick improvement and eventually within minutes complete symptom relief in all patients. No steroid treatment or antihistaminics were needed. In 5/10 patients infusions could be resumed with a slower flow rate without reoccurrence of symptoms. Few patients however developed a second (n = 5) or a third (n = 3) onset of equal IRR symptoms in subsequent drug administrations, in 3 cases  even despite a reduction of the flow rate. Half of the patients (n = 5) developed low back pain during the second administration of the antibody. One patient (#6) showed an IRR to the first administration of pembrolizumab after having reacted to nivolumab already before.The first case of acute low back pain as IRR to monoclonal PD-1/PD-L1 directed antibodies we observed at our department dates august 2017, whereas we did not observe a single case of infusion-related low back pain in the previous years. After consulting with our Department of Pharmacy we noticed that in the case of nivolumab, just one month before the first onset of infusion-related low back pain at our department, the concentration of the active substance has been increased by volume reduction of the carrier solution in the manufacturing process. In all cases the substance was dissolved in sodium chloride 0.9%. All administrations took place through an intravenous line containing a sterile in-line filter with a pore size of 0.2 µm. Concentrations before and after the shift were at all times within the eligible range and thus lege artis. Even after the increase, the concentrations were still far away from the maximum dose of 10 mg/ml, which is allowed according to the prescribing information of the drug. Despite being in the eligible range, the first cases of infusion-related low back pain in our department occurred not until the drug concentration had been increased. This suggests that the risk of developing low back pain as IRR is depending on the concentration of the administered drug. However, in none of the patients we did intentionally change concentration, flow rate or infusion volume just before the cycle during which the IRR occurred for the first time.The pathophysiology of IRRs is heterogenous. Immediate and nonimmediate hypersensitivity reactions (HSRs) to monoclonal antibodies have been described , among tOur aim was to report a series of patients with acute low back pain after administration of monoclonal antibodies specifically directed against PD-1/PD-L1. All cases (n=10) that we observed between the first appearance in 2017 and 2018 have been included in the study. Interestingly, our case series shows that symptoms appeared in patients having received different types of monoclonal antibodies directed against PD-1/PD-L1 and symptoms did not appear only after administration of a specific antibody like nivolumab. Nivolumab, pembrolizumab and avelumab are all antibodies targeting PD-1/PD-L1 pathway, which makes them somewhat comparable not only in mode of action but also in spectrum of side effects. Thus, although these drugs are different substances, they are from the same substance group. In contrast, we have not seen similar reactions after administration of e.g. the CTLA-4 antibody ipilimumab alone. However, the type of antibody is different also: Nivolumab and pembrolizumab are IgG4 antibodies, whereas ipilimumab and avelumab are IgG1 type. However, nivolumab was administered much more frequently than pembrolizumab or avelumab in the centers participating in the study at that time, which is probably the reason for having seen more symptoms in patients who received nivolumab than in patients who received pembrolizumab or avelumab.Similar cases of acute devastating low back pain have also been described during infusions of other agents such as amiodarone , 6. PetrSome publications discuss drug safety in the context of IRRs. Choi et al. report a patient with hepatocellular carcinoma successfully treated with pembrolizumab after experiencing an IRR with flushing, dyspnea and back pain to nivolumab . In our The cause of the side effect acute low back pain remains unclear. We assume, that the observed clinical manifestations do not fall within the category of typical immune reactions. Since dosage seems to be a crucial factor, we believe that decreasing the infusion rate or concentration presumably leads to less accumulation of intravascular cell aggregates in blood vessels and thereby prevents the development of ischemic pain sensations.In conclusion, acute low back pain as IRR to monoclonal antibodies is rare and the pathophysiology is not yet thoroughly understood. The risk of severe infusion induced pain possibly leading to therapy drop-out requires clinicians to pay attention to such symptoms in the course of intravenous drug administration. The onset of low back pain during or shortly after infusion, the acute progression and the severity of symptoms support the diagnosis of an IRR. Our series suggests that low back pain as IRR can be managed by early interruption of infusion and by decreasing the infusion rate or concentration in following administrations, while discontinuation of therapy is not strictly required in most cases.The original contributions presented in the study are included in the article/supplementary material. Further inquiries can be directed to the corresponding author.The studies involving humans were approved by the institutional review board of the Medical Faculty of the Heidelberg University Hospital . The studies were conducted in accordance with the local legislation and institutional requirements. Written informed consent for participation was not required from the participants or the participants’ legal guardians/next of kin in accordance with the national legislation and institutional requirements. Written informed consent was not obtained from the individual(s) for the publication of any potentially identifiable images or data included in this article because the ethical committee of the institutional review board of the Medical Faculty of the Heidelberg University Hospital had agreed to the retrospective analysis of routinely collected clinical data without prior informed consent of patients.PM and JH contributed to conception and design of the study. PM, JH and CL organized the database. PM, JH and TS participated in the final data analysis and interpretation. PM wrote the first draft of the manuscript with input from other authors. All authors contributed to manuscript revision, read, and approved the submitted version.


The objective of this study was to investigate the characteristics of emergencies and the requirement for emergency treatment after the suspension of orthodontic appointments. The attitude towards orthodontic treatment preference was evaluated as well, including receiving orthodontic treatment and the preference for orthodontic appliances.P < 0.05.An electronic questionnaire was distributed to the patients, including 4 sections: Section 1 – demographic and basic information; Section 2 – the characteristics of emergencies and emergency treatment requirements; Section 3 – the NRS-11 for pain and Manchester Orofacial Pain Disability Scale used to evaluate the intensity of orofacial pain and disability; and Section 4 – attitudes towards receiving orthodontic treatment and appliance preference. Descriptive statistics, Pearson’s chi-square test, Wilcoxon's rank-sum test and stepwise generalized linear model (GLM) were performed with significance set at P < 0.01) in the FA group (P < 0.05) and some emergencies in the FA (P < 0.05) suffered worse pain and disability. More FA participants preferred alternative appliances (P < 0.05) due to pain and disability (P < 0.05).Most participants’ (91.61%) follow-up appointments were suspended. The emergency rate and emergency treatment requirements were not different between the fixed appliance (FA) and clear aligner (CA) groups. Patients who reported emergencies (FA patients’ emergencies caused worse pain and disability when orthodontic appointments were suspended. Pain and disability were not the causes of emergency treatment requirements. The CA group seemed to show a tendency towards orthodontic appliance preference, which was an ideal modality to weather the epidemic, combined with telemedicine. Coronavirus disease 2019 (COVID-2019) was reported initially in Wuhan, Hubei Province, China, in December 2019 and swept all over the world. The World Health Organization declared COVID-2019 a global pandemic on March 13, 2020, meaning that the disease had worldwide influence by that time. The disease had been reported in more than 210 countries by May 21, 2020. Under the pressure of controlling the outbreak, many countries all over the world announced new policies to prevent it from further spreading [Another local epidemic occurred in Xian, Shan’xi Province, China, on December 9, 2021, which was derived from an imported case and influenced five provinces in China. There were 2050 cases reported in Xian, 2077 cases in Shan’xi and 2119 cases in all five provinces. With a series of anti-epidemic policies announced by the government, the number of cases stopped increasing after 41 days.During dental treatment, all participants, including patients, dentists and dental assistants, are exposed to aerosols of blood and saliva . AdditioBetween orthodontic visits, orthodontic patients might suffer from adverse events, such as pain, discomfort, exposed ends of wires, brackets/bands coming off and loose aligners –8. UnforThe main appliances used to treat malocclusion are fixed appliances (FAs) and clear aligners (CAs). The incidence of mucosal injury and orthodontic appliance detachment in FA patients is much higher than that in CA patients. When compared with FA patients, CA patients did not require strict monthly follow-up visits, their chair-time was shorter, and their bonding requirements were lower . At the Therefore, the objective of this study was to investigate the characteristics of emergencies and the requirements for emergency treatment after the suspension of orthodontic appointments. The attitude towards orthodontic treatment preference was evaluated as well, including receiving orthodontic treatment and orthodontic appliance preference.This cross-sectional study was designed to examine orthodontic patients suffering under a 2-month lockdown in Xi’an.The inclusion criteria of participants were as follows: (1) patients accepting orthodontic treatment in the public hospital; (2) having the ability to understand Mandarin Chinese online; (3) providing informed consent for the use of the questionnaire and the recording of data; (4) finishing all of the items on the questionnaire within the given time; and (5) aged 7 and older. All experimental protocols were established according to the ethical guidelines of the Helsinki Declaration and approved by the ethics committee . Informed consent was obtained from individuals before they participated in the survey.All the FA patients were asked to follow up by appointment monthly before the epidemic outbreak. As soon as CA progress began, every CA patient was guided to wear aligners 22 h a day, exchange aligners every 14 days and use aligner chew.www.wjx.cn with 43 items. In the process of designing it, many professors and scholars majoring in epidemiology and orthodontics gave advice, and many studies were consulted [We designed an anonymous online questionnaire consisting of 4 sections in Mandarin Chinese via onsulted , 12–16.Section 1 gathered demographic and epidemic-related basic information, such as sex, age, education level, hospital location, orthodontic application, time since the last appointment, reasons for postponing, and contact between dentists and patients, with 14 items.Section 2 had 20 items that investigated the orthodontic problems and emergencies reported by patients during the lockdown, such as “debonded bracket” and “attachment drop”. The methods that they undertook to resolve emergencies and the intention to receive emergency treatment in public hospitals were also assessed.Two mature scales were used to investigate orofacial pain and disability in Section 3: (1) the Numerical Rating Scale (NRS-11) of pain  is a segSection 4 focused on the participants’ attitudes about receiving orthodontic treatment and their orthodontic appliance preferences after the two-month lockdown experience.The Cronbach’s alpha of this questionnaire was 0.937, which showed high reliability. KMO and Bartlett’s test were used to test the validity, and the KMO value was 0.959, which showed high validity of the study data.Twelve orthodontists from the orthodontic department were invited to participate in the project. The distribution and collection of the questionnaire were available online from January 24 to January 28. To reduce recall bias and increase authenticity, we distributed the questionnaires immediately after lifting the lockdown and collected them in four days.P < 0.05. All analyses were performed using IBM SPSS Statistics software .We used the mean, median, range and interquartile range in descriptive statistics. NRS-11 and MOPDS scores were recorded to evaluate pain and disability. Pearson’s chi-square test was used to compare the differences in emergencies and the preferences for orthodontic treatment in the two groups (FA and CA). Wilcoxon’s rank-sum test was used to compare the differences in NRS-11 and MOPDS scores between different groups for skewed distribution data. Then, stepwise regression was used in the generalized linear model (GLM) to investigate the relationship between discomfort (pain and disability) and various factors when controlling for potential confounders. The level of statistical significance was set at A total of 200 online questionnaires were distributed to the patients accepting orthodontic treatment, and 154 valid questionnaires were collected. The mean age was 21.54 years old (SD 7.07). Eighty-one (52.6%) participants were younger than 23. A total of 110 (71.43%) were female, and 144 (93.5%) accepted treatment in Xian. Only 12 (8.39%) accepted orthodontic treatment within 1 month, and 52 (36.36%) had not visited for more than 2 months. A total of 104 (79.39%) stopped treatment for fear of the spread of COVID-2019. A total of 83 (58.04%) communicated with their dentists, the majority of participants (92.77%) used mobile phone apps (WeChat), and none of them used telemedicine  patients reported emergency treatment, and 12 (33.3%) of them wanted emergency treatment. The most common trouble reported was “Debonded brackets” (50%), and the others are presented in Fig. For the CA patients, 16 29.63%) reported emergency treatment, and 7 (43.75%) of them required emergency treatment. The most common emergency was “attachment drop” (50%), and the others are shown in sequence in Fig. 9.63% repIn response to emergencies, most patients contacted their dentists during the lockdown, and none of them used telemedicine. The response to emergencies between the two appliances was not significantly different and the details of response in the two groups were showed in Fig. The hierarchical Comparison of the emergencies in the two orthodontic types was showed in Table 2 = 4.129, P < 0.05) (Table Nineteen (13.29%) expressed a negative attitude when asked whether they would accept orthodontic treatment assuming that treatment had not yet started. The willingness to accept orthodontic treatment between the two groups was not significantly different Table . ThirteeP < 0.01) and the FA patients  had worse pain (Table P < 0.01) in multivariable analysis (Table The median pain intensity on the NRS-1 1 was 2 (range: 1–9). No significant differences were found between the different sexes in the intensity of pain or different lengths of postponements. Participants who reported emergencies  in Table P < 0.05) when controlling for other factors, such as “orthodontic pain” and “poking wires” (Table P < 0.05) had lower pain in Table P < 0.001), “attachment drop” (P < 0.01), and “ran out of aligners” (P < 0.01) had lower pain scores, while those reporting “orthodontic pain” (P < 0.001) had higher scores  and “ulcer”  groups had higher pain scores in the rank-sum test  had higher pain scores, and the participants preferred CA over FA   Table .Table 10P < 0.01) in the FA group; those reporting “aligner cannot be in position” (P < 0.05) and “attachment drop” (P < 0.05) suffered less disability, and those reporting “orthodontic pain” (P < 0.001) reported higher disability scores in the clear aligners group (Tables The median disability score was 2 (range 0–25). The most common physical disabilities were “I cannot eat hard foods” (53.14%) and “I take longer to finish my meals” (44.06%), and the highest scores in psychosocial disabilities were for “I have had to take time off work” 23.08%) and “I find it difficult to talk for long periods of time” (21.75%), followed by “I am irritable, angry, and easily frustrated” (21.68%). Similar characteristics were found in most results on the MOPDS and NRS-11 for pain. However, in the GLM, patients reporting “poking wires” reported worse disability (% and “I p Tables .P < 0.001) with the Equation y = 1.753  x + 0.084.There was a significant association in the linear regression model between the intensity of pain and disability score  has been rampant all over the world since 2019. Therefore, many countries have been influenced by the virus, and the pandemic led to a huge burden on medical resources. During dental procedures, respiratory droplets and close contact are regarded as the main transmission routes for the virus , 4. In mP > 0.05). Most participants’ (91.41%) normal follow-up appointments were suspended for the lockdown, and some of them (36.3%) could not visit for more than two months. Although the interval was prolonged, the negative effects on pain and disability did not appear for that the suspension of appointments was short.In our study, female patients accounted for 71.43% of all participants because they tended to accept orthodontics treatment , 20. SimP > 0.05). Worse pain was caused by “ulcers” (19.44%) and “poking wires/sharp ligature ties” (44.44%) in the FA group. When controlling for other confounding factors, ulcers might be the main cause of pain. In contrast, “poking wires/sharp ligature ties” were the main causes of orofacial disability, and ulcers did not affect oral activities, such as eating and speaking [P < 0.05) and MOPDS (P < 0.05) scores. More comfort should be given to FA patients when the appointments were suspended for long time, and “ulcers” and “poking wires/sharp ligature ties” would be the major concern.FA patients had equal opportunity for suffering emergency compared with CA patients (speaking . ParticiP < 0.005) and disability (P < 0.005) scores in patients who reported emergency were significantly higher, but the patients who required emergency treatment did not suffer worse pain and disability. Eight-one FA patients’ (91.01%) routine appointments were suspended and their orthodontic progresses were interrupted. Sixteen CA patients (29.10%) reported emergency like “attachment drop”, “ran out of aligners” and “aligner cannot be in position”, which might reduce the efficiency of aligners and prolong the treatment course [The requirement for emergency treatment between the two appliances showed no differences. The pain , assuming that the participants had not yet started orthodontic procedures. Although orofacial pain and disability influenced the attitude of accepting orthodontic treatment, the difference in participants’ discomfort between the FA and CA groups was so fine that the willingness to accept orthodontic treatment was similar between the two groups.With the experience of suspending orthodontic appointments during the pandemic, the willingness to accept orthodontic treatment (86.71%) was reduced for pain and disability (P < 0.05), and participants in the FA group who preferred CA suffered more pain (P < 0.05) and disability (P < 0.01). Therefore, it would seem that the FA group tended to select alternative orthodontic appliances (CA). The worse pain and disability caused the change in FA participants’ appliance preferences. Additionally, Xiong X [The preference for appliances in the FA and CA participants was different. A significant change was observed in the FA participants’ appliance preferences compared with the CA group ( Xiong X  reported Xiong X –29. Tele Xiong X .This study had some limitations. The sample size was determined by the small range of the COVID-19 epidemic in a city. The lockdown was soon lifted so that the suspension of appointments was for only 2 months. The questionnaire survey that we designed might inevitably have incurred recall bias.When suspending orthodontic appointments, emergencies in FA patients caused worse pain and disability. More comfort should be given to FA patients when the appointments were suspended for long time.Pain and disability were not the causes of emergency treatment requirements. Guiding patients in resolving emergencies by themselves and caring about the mental issues that arise due to suspending orthodontic treatment might be beneficial, as well as avoiding unnecessary orthodontic emergency treatment. Also, CA combined with delivery seems to be a solution of keeping orthodontic progress when visits are suspended.The CA seemed to show a tendency towards being orthodontic appliance preference after the experience of suspending orthodontic appointments during the pandemic, and it was an ideal modality to weather the epidemic and reduce the spread of virus, combined with telemedicine.


There was no difference between the two groups (p 0.345). The baseline paroxysm frequencies (number per week) were 86.7 ± 69.3 and 88.9 ± 62.2 for the type 1 and type 2 TN groups, respectively; they were significantly reduced in both groups at the 1-month and 3-month follow-ups without significant differences between the two groups (p 0.902). The Pain Facial Pain Scale improved at the 1-month follow-up, and no significant differences were found between the two groups. There was a strong correlation between background pain and paroxysm pain intensity . Conclusions: Botulinum toxin type A effectively reduced the pain, paroxysm frequency, and PFPS scores of type 1 and type 2 trigeminal neuralgia patients without statistically significant differences. Facial asymmetry was the only adverse event.Background: Botulinum toxin type A is an effective treatment for trigeminal neuralgia. Moreover, its efficacy in type 2 trigeminal neuralgia and comparative studies between type 1 and type 2 trigeminal neuralgia (TN) still need to be improved. Methods: We treated 40 TN patients with onabotulinumtoxinA; 18 had type 1 TN, and 22 had type 2 TN. We compared the baseline pain score with the Visual Analogue Scale (VAS) and paroxysm frequency (number per week) at the baseline with those obtained at 1-month and 3-month follow-ups. Nonetheless, we compared the baseline Penn Facial Pain Scale with the scores obtained at the 1-month follow-up. Results: BoNT/A effectively reduced pain intensity and frequency at the 1-month and 3-month follow-ups. Moreover, the type 1 TN and type 2 TN groups had baseline pain scores of 7.8 ± 1.65 and 8.4 ± 1.1, respectively. Pain significantly improved ( Theal nerve ,5,6,7. Tal nerve ,9. Idiopal nerve ,11. In Mal nerve ,13; howeal nerve ,15. Demyal nerve ,17,18,19al nerve . Clinicaal nerve ,22,23,24al nerve ,26,27. Cal nerve . Other mal nerve . Refractal nerve ,33,34,35al nerve . The rolal nerve . Althougal nerve . Interesal nerve ,40,41 anal nerve ,43. Noneal nerve . The litForty TN patients were treated with BoNT/A; the mean age was 63.4 ± 18.4 years old, and 67.5% were female. Eighteen had type 1 TN, whereas twenty-two had type 2 TN. The mean disease duration was 5.8 ± 4.6 years; the type 2 TN group had a longer duration of the disease and a greater mean age than the type 1 TN group. Seventeen out of forty patients (42.5%) were on CBZ or OXC, and 42.5% were on gabapentinoids. The left side was involved in 47.5% of cases. Twenty-two patients had idiopathic etiologies, and the remaining eighteen patients had a classical form of TN; no cases of secondary TN were present in our sample. Twenty-two and eighteen patients had only one or two branches involved, respectively. The mean BoNT/A doses were 29.7 ± 11.4 U and 29.3 ± 11.1 U for the type 1 and type 2 TN groups, respectively. See 1.3,48.8 = 128.3, p < 0.001) and paroxysm frequency , as shown in 1.3,47.5 = 123.5, p < 0.001). Both groups had their paroxysm frequencies (number of episodes per week) significantly reduced  at the 1-month and 3-month follow-ups  and paroxysm frequency . The graphical representations of the data are shown in p < 0.001).All the TN patients improved in their VAS (Fp 0.944). The overall mean duration was 3.5 ± 1.5 months; the maximum duration of BoNT/A was up to 6 months. The PFPS total scores and every item of this scale improved significantly in both groups (see Seven patients out of forty (17.5%) were pain-free at the 1-month follow-up; four had type 1 TN, and three had type 2 TN. Six patients were pain-free at the 3-month follow-up . The treatment was effective (>50% pain reduction) for 25 patients (62.5%) at the 1-month follow-up; among them, 11 patients had type 1 TN (27.5%) and 14 had type 2 TN (35%). At the 3-month follow-up, the treatment was considered effective for 24 patients (60%); 13 had type 2 TN (32.5%), and 11 had type 1 TN (27.5%). The mean durations of BoNT/A were 3.4 ± 1.4 and 3.5 ± 1.5 months in the type 1 and type 2 groups, respectively; there was no statistical difference between the two groups . In addition, idiopathic vs. classical etiology  did not predict the outcome. In fact, as shown in 1.3,46.6 = 121.5, p < 0.001) and frequency , without significant differences .The presence of type 2 TN did not predict a more favorable or less favorable response (<50% VAS reduction) to the treatment with BoNT/A ; the PFPS score  improved from 88.3 ± 18.8 to 29.3 ± 23.6 (p < 0.001). The total PFPS score of the non-responder group (<50% VAS reduction) also improved from 115.6 ± 41.0 to 67.6 ± 42.6 (p <0.001); the PFPS score, only considering the interference with daily facial activities score, improved from 87.6 ± 37.0 to 50.3 ± 36.5 (p < 0.001). We compared the mean PFPS score reductions  of the responder and non-responder groups, and the difference was not significant .At the 1-month follow-up, the responder group (>50% VAS reduction) improved in total PFPS score from 116.0 ± 18.7 to 37.1 ± 29.6 (p < 0.001), as shown in p 0.555), disease duration , or age . The correlation between background and paroxysm pain at the 3-month evaluation remained statistically significant . There was also a significant correlation between the mean paroxysm pain and background pain reduction . The mean paroxysm pain reduction (VAS) positively correlated with the mean PFPS score  reduction ; the mean paroxysm pain reduction (VAS) also positively correlated with the PGIC , as shown in Interestingly, there was a strong correlation between the baseline paroxysm pain intensity and the baseline background pain intensity of type 2 TN patients . This adverse event was reported to be mild to moderate, lasting 2–3 weeks to 1–2 months. There were no other adverse events reported. p 0.047) on the univariate logistic regression; however, multivariate logistic regression was not performed.Type 2 TN is more frequent in women and is more frequently associated with sensory abnormalities than type 1 TN ,46. ContIn our study, BoNT/A treatment was effective overall (>50% pain reduction) for 62.5% and 60% of patients at the 1-month and 3-month follow-ups, respectively; these data are in line with the current literature . MoreoveOur study has some limitations. The first one is the relatively small sample and the short follow-up. Since this was a single-center study, there could be a bias in patient selection, implying that the sample may not represent the entire TN population. Botulinum toxin type A is an effective and safe treatment for TN patients; the only adverse event was facial asymmetry. Type 1 and type 2 TN had similar responses to the treatment with BoNT/A in pain intensity, paroxysm frequency, and PFPS, without statistically significant differences. Larger studies are needed to confirm our results.This is an open-label, single-center, longitudinal study. Forty patients >18 years old were recruited from our tertiary headache outpatient clinic from January 2018 to August 2022 . The patients fulfilled the criteria for trigeminal neuralgia, and the presence of type 1 (ICHD-3 13.1.1.1.1 or 13.1.1.3.1) and type 2 (ICHD-3 13.1.1.1.2 or 13.1.1.3.2) TN was assessed according to ICHD-3 [This study was conducted following the Declaration of Helsinki and approved by the Institutional Review Board of the University of Udine . All patients gave written consent for the treatment with BoNT/A and for their clinical data to be used for research purposes.®) was reconstituted with 1 mL of sterile sodium chloride at 0.9% to achieve a dilution of 100 U/mL. The injections were performed with a 30-gauge 0.3 × 8 mm needle. A total of 5–2.5 U was injected intradermally or subcutaneously in the region of pain (“follow the pain” approach) and along the course of the trigeminal branches involved. For the treatment of the V1 branch, we injected 2.5–5 U above the eyebrow, in the mid-frontal and upper-frontal regions of the affected side  to form a rectangle; the supraorbital or supratrochlear exit zones were treated with 5 U if there was a trigger point. For the V2 and the V3 branches, the treatment was performed following the course of the nerves; we injected 5–2.5 U per site with a total of 5–6 points per side, separated by 1.5–2.5 cm. We applied a higher dose (5 U) in the terminal branches’ trigger point regions and exit sites.A 100 U vial of onabotulinumtoxinA  is a multidimensional scale used to evaluate facial pain severity  and pain interference with daily facial activities (14 items). The patient gives a score from 0 to 10 for every item, and the total score is calculated from the sum of each item ; obtainiThe study’s primary endpoint was to assess the efficacy of BoNT/A based on the pain intensity and paroxysm frequency during the follow-up. The treatment was effective when pain intensity (VAS) improved >50% at 1-month and 3-month follow-ups. The secondary endpoint compared the responses in type 1 and type 2 TN based on the frequency of paroxysms (number per week), pain intensity (VAS), and PFPS. The tertiary endpoint compared the responses in classical and idiopathic TN based on pain intensity (VAS) and frequency of paroxysms (number per week).t-test, when the data distribution was normal, or a Mann–Whitney test, when the data distribution was not normal, was used to compare continuous variables. A chi-square test was used to compare categorical variables. A Shapiro–Wilk test was used to assess the normal distribution of data. We calculated the power of the study with G*power 3.1 ; we set an effect size of 0.25, an α-error of 0.05, two groups, three measurements, forty subjects, and a correlation among repeated measures of 0.5. The preplanned power of the study was 0.9. Comparison between groups was performed with a t-test or Mann–Whitney test as appropriate for the PFPS. A paired t-test, when the data had a normal distribution, or a Wilcoxon test, when the distribution was not normal, was used to compare the PFPS and background pain data at the baseline and 1-month and 3-month follow-ups, respectively. Repeated measures ANOVA was used to investigate the changes in pain intensity (VAS) and paroxysm frequency (number per week) at the baseline and 1-month and 3-month follow-ups. Because Mauchly’s test of sphericity was significant, we used the Greenhouse–Geisser correction. Repeated measures ANOVA was also used to compare the differences in mean scores for the type 1 and type 2 TN groups. A Bonferroni post hoc test was used to compare the means at different follow-up times. For the analysis of the predictive factors for response (>50% pain reduction at three months), we conducted a univariate logistic regression analysis considering the type of TN (type 1 and type 2) and the etiology ; the odds ratio (OR), the 95% confidence interval (CI), and the level of significance (p) are presented. Repeated measures ANOVA was used to investigate the changes in pain intensity and paroxysm frequency in idiopathic and classical TN at the baseline and at 1-month and 3-month follow-ups. Correlation analysis was performed with Spearman’s test. All analyses used Stata/SE  for Mac OS. All 2-tailed statistical significance levels were set at p < 0.05. The descriptive analysis of the sample was performed using mean ± SD for continuous variables and percentages for categorical variables. A


To identify the processes of cancer-related pain relief and exacerbation faced by outpatients in an acute care hospital and to examine the support needed for outpatient pain control.We conducted semi-structured, in-depth interviews with patients from the outpatient department of Showa University Northern Yokohama Hospital in Kanagawa Prefecture, Japan. Participants were recruited by purposive sampling. From the recorded data, verbatim transcripts were made and used as textual data for analysis by consistent comparative method.Between April 2018 and April 2022, interviews were conducted with 30 participants. Analysis of the verbatim transcripts generated 13 categories from 27 concepts. Category relationships were examined, and a conceptual framework was developed. Outpatients went from being in a state of hesitation towards consultation with medical professionals to receiving individual consistent follow-ups by medical professionals in the hospital and community pharmacies, which led to patient teleconsultations when their physical condition changed, leading to an improvement of pain.The process of relief and exacerbation of cancer-related pain experienced by outpatients in the acute care hospital reveals that the provision of consistent follow-up through remote or in-person interviews has an important role to play in pain management, as it helps to build relationships between patients and medical professionals. Alternatively, when outpatients exhibited endurance, their pain worsened, and they fell into a negative cycle of poor pain control. To meet the needs of all patients, different levels of palliative care have recently been proposed: primary, secondary, and tertiary . PalliatAn increasing number of outpatients have undergone cancer drug treatment in recent years . It is eWe conducted a qualitative semi-structured, in-depth interviews with patients from the outpatient department of Showa University Northern Yokohama Hospital in Kanagawa Prefecture, Japan. An interview guide was developed with the consensus of hospital and community pharmacists Table . The stuThe first author (MH), a female hospital pharmacist trained by a specialist, conducted the interviews. Age (date of birth), gender, primary disease, chemotherapy, and medications were collected from the medical records of the consenting study participants. Eastern Cooperative Oncology Group (ECOG) Performance Status were recorded by the researcher, as determined during the interviews. Field notes were made for each survey, describing the participants and their situation at the time of the survey.*Based on the agreement between hospital pharmacists and community pharmacists.Participants were recruited by purposive sampling. Selection criteria were: outpatients with advanced cancer, who had been administered medical narcotics for cancer pain control at Showa University Northern Yokohama Hospital; patients aged 20–80 years at the time of consent; and patients who provided written informed consent to participate in the study. Exclusion criteria were patients with a Numerical Rating Scale pain scale score ≥ 3 at rest to avoid interviewing patients in severe pain, patients who were judged ineligible by the doctor in charge, and patients who were unable to communicate in Japanese. The study was approved by the research ethics committee of Showa University Northern Yokohama Hospital . The purpose of the study and protection of personal privacy were explained to the participants and written informed consent.From the recorded data, verbatim transcripts were created and used as textual data for analysis by constant comparative analysis , 13, an Between April 2018 and April 2022, interviews were conducted with participants who met the eligibility criteria. We recruited 32 people, two of whom did not participate further due to not knowing what to say. Theoretical saturation was considered to have been reached when 30 interviews were conducted .The average duration of the interviews was approximately 39 min. We conducted interviews at Hospital room(n = 11), Outpatient chemotherapy room(n = 10), Lounge(n = 7), Waiting roomn = 2). There were five participants in their forties, eight in their fifties, seven in their sixties, and 10 in their seventies or older. Primary diseases of participants included gastrointestinal cancer (n = 5), lung cancer (n = 15), breast cancer (n = 3), urological cancer (n = 4), and other (n = 3). In addition, 22 participants were undergoing chemotherapy and eight were receiving best supportive care (BSC) , concept (indicated in bold), and narrative . Outpatients with cancer-related pain control had unexpressed pain due to difficulties in communicating pain, an example of which was: “But I think it’s difficult to communicate. Because pain can be different to the person who thinks it’s painful” (Patient A). Patients also experienced resistance to narcotics from the fear of drug addiction and experiencing the painful adverse event of narcotics: “That is to forcibly stop the pain, isn’t it? So, in that sense, I think it is not good for us, so we tried to endure as much as we could, but…” (Patient B). In addition, participants had various concerns about medication, such as anxiety about side effects, difficulty in rescue opioid timing, and hard-to-obtain narcotics: “I used to take very few medicines, but now I take seven or eight in the morning, five or six at lunchtime, nine at night, and one at night. I’m getting used to it, but when I’m living a normal life, I’m not sure if it’s safe to take that many pills. I have a fear that I might get something from the combination” (Patient C). However, outpatients experienced hesitation towards consultations due to difficulty in the consultation atmosphere, consideration for the medical professionals, and exhaustion due to waiting times in hospitals and community pharmacies: “Generally, when I talk to the pharmacist, I only talk to the pharmacist when I ask for my medication, and they are just going through the motions, giving me the medication, and telling me what the medication is. They don’t know much more about me than that.” (Patient D).We constructed a storyline using each participant’s category . However, due to untreated pain and exacerbation of pain, participants had persistent pain in their daily lives: “Well, I had problems with the medication not working; and, as a result, I think it was because the dose was too low; and, as I said before, I was a patient person, so they didn’t prescribe much medicine. So, when the medication ran out, it was really hard, and I did nothing but fainting in agony.” (Patient A). Furthermore, outpatients had anguish over pain due to mental anguish, pessimism about pain, and anxiety about the future, leading to a negative spiral of pain control: “So, I’ve already given up halfway, or rather, to the pain, towards the pain, just the pain, just saying, it’s pain here. I don’t think I’m holding back, I think I’m just enduring the pain, the pain that’s right in front of me right now” (Patient F).Outpatients had Pain beyond endurance made emergency hospitalization necessary: “Generally, if I go there, in my case, they say, ‘Oh, you’re going to be hospitalized.’ But that one step is a bit. If they told me to go home again, I felt like I’d gone all the way there and now I have to go home again with all this pain” (Patient G). On the other hand, there were approaches by medical professionals such as the presence of medical professionals who always care and remote follow-up suggestions to outpatients: “When I was getting my medication, the community pharmacist asked me if he could call me at home. And I said, ‘Please.’ So, they set a date for me to contact them and that’s when I got the call” (Patient H).consistent follow-up, outpatients felt multidisciplinary support, remote follow-up reassurance, and multidisciplinary information sharing: “I thought, ‘The fact that they are calling me means that they are worried about me, and I need to do something to respond to them, like keeping a diary or something, instead of being so careless’” (Patient I).In Consistent follow-up led to teleconsultations, where outpatients received consults at home from medical professionals: “Well, he gave me his mobile phone number, the number to call at midnight, and I left him a message, and the next day he called me on my mobile phone. He said he was sorry he couldn’t reply immediately. I didn’t expect such a quick response. I just needed you to listen to what I had to say” (Patient J).encourage them to consult a doctor and they were subsequently examined by a doctor through urgent hospital visits: “I called them just to ask about that, whether I should go to the hospital or not. I was told to go to the hospital and was admitted immediately. So, I knew I needed to ask for advice” (Patient K). Outpatients experienced improvement of pain due to the appropriate use of drugs: “Honesty, well, it doesn’t go that far. It’s not that I don’t feel a little bit of some pain relief. There, you know, mentally, it’s a little bit easier than it was two weeks ago” (Patient L).When patients were not sure whether they should go to hospital, they had a medical professional The process of relief and exacerbation of cancer-related pain experienced by outpatients in the acute care hospital reveals that the provision of consistent follow-up has an important role to play in pain management, as it helps to build relationships between patients and medical professionals. Outpatients progress from a state of hesitation towards consultation to consistent follow-up owing to the medical professionals’ approach in the hospital or community pharmacy, and when their physical condition changes, patients receive consultations telephonically, leading to improved pain management. Alternatively, when outpatients exhibited endurance, their pain worsened, and they fell into a negative cycle of poor pain control. The patient was then in a vicious circle of untreated pain, pessimism regarding the future, and further psychological anguish over pain. Patients endured at home until they reached the limit of their endurance, and then followed the process of emergency hospitalization.The changes in outpatient behaviour identified in this study can be interpreted using social cognitive theory (SCT). SCT states that human behaviour is always dynamic due to the interaction of three factors: person, environment, and behaviour . We suggBased on SCT , the patEarly provision of palliative care reduces unnecessary hospital admissions and use of health services . On the Those patients who received consistent follow-up were able to improve pain without having to wait for the endurance limit through teleconsultation when their pain worsened. Palliative care for outpatients in acute care hospitals is positioned as secondary palliative care, where cancer specialists provide pain management alongside cancer treatment. None of the participants-attending physicians in this study specialized in palliative care. The approach by medical professionals and subsequent consistent follow-up by doctors, nurses, and hospital and community pharmacists who do not specialize in palliative care may function as a type of patient education and contribute to improving patient pain. A systematic review of randomized controlled trials on pain management found that patient education resulted in a statistically significant reduction in pain intensity . PatientOur findings suggest that the relationship established between medical professionals and patients through consistent follow-up has an important role in pain management, as it succeeds in eliciting active consultation from patients. However, consistent follow-up of outpatients by medical professionals through remote or in-person interviews is an initiative that has been implemented in hospitals and community pharmacies for some patients with pain control problems, and there is no mechanism to calculate a medical service fee. Consistent follow-up by medical professionals through the telephone or PC should be implemented for all patients with pain management as part of the palliative care service for outpatients. Furthermore, if community pharmacists conduct consistent follow-up, the subsequent sharing of information to the hospital is important. Previous studies have shown the importance of team involvement in palliative care for cancer patients from an early stage . The comThe study recruited subjects from only one acute hospital, which may differ from other hospitals and community pharmacy initiatives. The unique circumstances of this study need to be carefully considered before they can be applied to the palliative care of outpatients with cancer in other settings. Sampling was done by purposive sampling and at least one patient was recruited from all departments treating cancer to prevent bias in patient opinion, but selection bias due to patient physical condition considerations and the fact that the investigator was a hospital pharmacist meant that critical opinions may not have been adequately elicited. However, the processes of cancer-related pain relief and exacerbation faced by outpatients in an acute care hospital in the context of secondary palliative care, as identified in this study, focus on the psychological aspects of outpatients. Therefore, we believe that it can be applied in other regions as well.The process of relief and exacerbation of cancer-related pain experienced by outpatients in the acute care hospital reveals that the provision of consistent follow-up through remote or in-person interviews has an important role to play in pain management, as it helps to build relationships between patients and medical professionals. Alternatively, when outpatients exhibited endurance, their pain worsened, and they fell into a negative cycle of poor pain control.