Migraine and neuropathic pain (NP) are both painful, disabling, chronic conditions which exhibit some symptom similarities and are thus considered to share a common etiology. The calcitonin gene-related peptide (CGRP) has gained credit as a target for migraine management; nevertheless, the efficacy and the applicability of CGRP modifiers warrant the search for more effective therapeutic targets for pain management. This scoping review focuses on human studies of common pathogenic factors in migraine and NP, with reference to available preclinical evidence to explore potential novel therapeutic targets. CGRP inhibitors and monoclonal antibodies alleviate inflammation in the meninges; targeting transient receptor potential (TRP) ion channels may help prevent the release of nociceptive substances, and modifying the endocannabinoid system may open a path toward discovery of novel analgesics. There may exist a potential target in the tryptophan-kynurenine (KYN) metabolic system, which is closely linked to glutamate-induced hyperexcitability; alleviating neuroinflammation may complement a pain-relieving armamentarium, and modifying microglial excitation, which is observed in both conditions, may be a possible approach. Those are several potential analgesic targets which deserve to be explored in search of novel analgesics; however, much evidence remains missing. This review highlights the need for more studies on CGRP modifiers for subtypes, the discovery of TRP and endocannabinoid modulators, knowledge of the status of KYN metabolites, the consensus on cytokines and sampling, and biomarkers for microglial function, in search of innovative pain management methods for migraine and NP. Migraine and neuropathic pain (NP) are chronic pain syndromes with extensively studied pathogeneses. While their clinical manifestations strongly differ, their pathophysiologies have common roots. Cause-based treatment of these two devastating, painful neurological diseases is still unsatisfactory. Migraines are one of the frequent primary headache disorders with the typical clinical features of unilateral throbbing or pulsating and moderate to severe headaches with concomitant symptoms such as nausea, vomiting, photophobia, phonophobia, osmophobia, and allodynia. Its main subtypes are migraine without aura (M0) and with aura (MA). Episodic (EM) or chronic (CM) forms can be differentiated based on the number of migraine days per month . NP is aWe underline the difference between these two painful conditions as follows: the quality of the pain (throbbing in migraine and burning in NP), the associated symptoms of migraine  which are absent in NP, the action of triptans , and the effect of nonsteroidal anti-inflammatory drugs . These two different clinical entities meet via their common pathomechanisms, such as hyperexcitability and sensitization, which involve neuropeptides , transient receptor potential (TRP) ion channel alterations, the endocannabinoid system, the glutamatergic system, pro- and anti-inflammatory cytokines, and microglia activation ,14,15,16CGRP is a vasodilator neuropeptide that plays a crucial role in the pathomechanism of migraine. CGRP is well-documented in pain transmission in the somatosensory nervous system. The latest therapeutic innovation is based on human and fully humanized monoclonal antibodies (mAbs) targeting CGRP and CGRP receptors. Clinical trials in EM and CM patients revealed the high efficacy and safety of these pharmacons . ClinicaElements of the endocannabinoid system exert antinociceptive effects through the activation of cannabinoid receptors (CBR). Favorable preclinical results, which showed a decreased trafficking of pain transmission, were clinically confirmed in migraine patients. In the field of NP, only a few clinical studies are available . The gluThe key pro-inflammatory cytokines are interleukin (IL)-1, IL-2, IL-6, IL-17, IL-18 (previously interferon gamma), and tumor necrosis factor alpha (TNF)-alpha, while the anti-inflammatory ones are IL-4, IL-10, and IL-37. There are controversial results with cytokines in the field of migraine, while in NP, both pro- and anti-inflammatory cytokines are of significant importance ,23. MicrPreclinical research reveals valuable information on human diseases by employing in vitro and in vivo models ,26,27,28The first clinical data on the importance of the trigeminovascular system in the pathomechanism of migraine revealed that CGRP plasma concentration was elevated in the external jugular vein during a migraine attack  41]. La. La41]. The trigeminovascular system forms a bridge between the cerebral dura mater and the vasculature of the meninges, cortex, and of second-order nociceptive neurons of the trigeminocervical complex (TCC) ,49,50. OThe clinical sign of trigeminovascular activation and hyperexcitability is allodynia, which is pain due to an innoxious stimulus. Allodynia can have a cephalic or extracephalic localization . A doublA novel pharmacological innovation produced human and fully humanized mAbs against CGRP and CGRP receptors to prevent EM and CM. Eptinezumab, fremanezumab, and galcanezumab selectively bind to the CGRP itself as a ligand, while erenumab competitively and reversibly targets CGRP receptor components. All of the above-mentioned mAbs are highly effective and safe in the prophylaxis of both EM and CM ,61,62,63Human studies have found that nerve fibers in the spinal cord laminas I, III, and V had CGRP-like immunoreactivity, and that their receptors are widely distributed in the pain pathways of the nervous system ,65. ExpeIn skin biopsy samples of PHN patients, increased CGRP levels were found in keratinocytes  Table 1Table 1. TRP ion channels are non-selective cation channels and can be divided into six subfamilies: TRPV (vanilloid), TRPA (ankyrin), TRPM (melastatin), TRPC , TRPP (polycystin), and TRPML (mucolipin) ,70. PrecCapsaicin, as a potent and highly selective TRPV-1 receptor agonist, is a chemical compound isolated from chili pepper. A randomized controlled trial (RCT) using intranasal civamide (a synthetic stereoisomer of capsaicin) for M0 and MA patients during headache attacks revealed decreased pain severity at 2 h post-dose in 55.6% of patients, and 22.2% of patients were pain-free . A doublTRPM-8, a non-selective cation channel, can be activated by cold temperatures and menthol. A triple-blind RCT revealed that a 10% menthol solution applied to the forehead and the temporal skin areas was significantly superior to the placebo at providing 2 h long pain freedom .Umbellularia californica—‘headache tree’) are can trigger and worsen migraine attacks via TRPA-1 receptor agonism. Other agents, such as Tanacetum parthenium (feverfew) and Angelica sinensis  as desensitizing TRPA-1 receptor agonists, are migraine-preemptive factors. A well-known migraine trigger, glyceryl trinitrate (nitroglycerine-NTG) as a nitric oxide donor, is also a TRPA-1 receptor agonist ..76].A recent pilot study searching for predictors of migraine chronification investigated 1911A/G single nucleotide polymorphism (SNP) in the TRPV-1 gene in patients with EM and CM compared to healthy subjects. The results showed that genotype frequency distribution in EM was comparable with that in the controls, while it differed significantly in CM patients . AnotherNociceptors are special afferent sensory neurons which convey thermal, mechanical, and chemical stimuli. The members of the TRP family are densely expressed on nociceptors. Therefore, they have fundamental roles in nociception and NP transmission ,84,85,86Early phase clinical studies targeting thermo TRP channels for NP treatment, including an intranasal TRPV-1 receptor agonist in PHN (NCT01886313), a subcutaneous TRPV-1 receptor inhibitor (parentide) in non-specified NPs (EP002846-21), an oral TRPV-3 receptor antagonist for non-specified NPs (NCT01463397), and a TRPM-8 receptor agonist  for chemotherapy-induced peripheral neuropathy (NCT0185567) are under way . PublishCapsaicin, as a potent TRPV-1 receptor agonist, can decrease the intensity of pain either in migraine or NP via the modulation of the release of pain-related neuropeptides from nociceptors. In migraine, several agents targeting TRPA-1 and TRPV-1 receptors can trigger or preempt headache attacks. The high-concentration (8%) capsaicin patch is strongly recommended for the treatment of peripheral NPs such as PDN, PHN, and HIV-neuropathy ,89. EarlEndocannabinoids are endogenous cannabis-like substances. Chemically, they are characterized as small molecules, and they are derived from arachidonic acid. As neurotransmitters, endocannabinoids are part of the biological endocannabinoid system and act on CBRs: CBR type 1 (CBR-1) and CBR type 2 (CBR-2). Their main endogenous ligands are anandamide (N-Arachidonoylethanolamine) and 2-arachidonoylglycerol (2-AG). Moreover, the system involves enzymes that regulate the synthesis and degradation of the ligands. CBR-1 is located in the nervous system, mainly in the brain, while CBR-2 is found in the immune system ,90.1A, 5-HT2A receptors), the modulator of somatic pain transmission , meningeal vessel dilatation, and the activation of the TCC . A . A 94]. A comparative clinical trial demonstrated that levels of AMT and FAAH were significantly reduced in the platelets of CM patients compared to those in the platelets of EM patients and the control group, and this was observed for both sexes . A cliniA clinical trial was designed for migraineurs with medication overuse headaches before and after withdrawal treatment. The results demonstrated a marked facilitation of spinal cord pain processing  in migraineurs before withdrawal treatment when compared with controls. The significant acute reduction of FAAH activity in platelets was coupled with a reduction in the facilitation of pain processing after versus before withdrawal treatment . A cliniCNR1 (the gene of CBR-1) on headaches with migraine symptoms  only when using extreme trait combinations (0 symptoms versus 3 symptoms) . H. H118]. In EM M0 and MA patients, plasma levels of glutamic acid were lower during attacks, while CSF concentrations of glutamic acid were higher in the migraineurs than in the controls . IntericImaging studies in migraine patients have attempted to find a link between the glutamatergic system and specific brain regions. Altered excitatory neurotransmitter distribution in the anterior cingulate cortex and insula of migraineurs was observed by magnetic resonance imaging spectroscopy (MRI) . A meta-CACNA1A  gene disruption results in glutamate release from presynaptic nerve terminals. In FHM2 patients, the ATP1A2 gene (encoding the α2 subunit of Na+/K+ adenosine triphosphate (ATP)-ase pumps) is damaged and indirectly reduces the uptake of glutamate from the synaptic cleft in astrocytes. In FHM3, the SCNA1  gene lesion can reduce the firing of inhibitory interneurons and can increase glutamate levels in the synaptic cleft ..125].An exploratory pilot study involving female patients with NP-like syndromes, such as temporomandibular disorders myalgia and fibromyalgia, showed associations between the KYN/Trp ratio and pain intensity. In the temporomandibular disorder myalgia, a significant negative correlation between plasma Trp concentration and the worst pain intensity was observed, and a positive correlation between the KYN/Trp ratio and both the worst and average pain intensities were observed. Women suffering from fibromyalgia exhibited significantly lower plasma Trp levels than the controls did .In addition to neuropeptides, the pathomechanism of hyperexcitability and sensitization is an overactivated glutamate system both in migraine and NP. Alteration of the KYN system has been reported in these two painful clinical conditions. Metabolites of the KYN pathway might have future therapeutic potential for migraine and NP.In the late eighties and early nineties, clinical studies demonstrated that intravenously administered TNF produced headaches in patients with tumors ,146,147.The pro-inflammatory cytokines may have a role in inducing nausea and headaches during a migraine attack by increasing arachnoid acid production . SeveralA clinical trial analyzed IL-1beta, IL-6, and TNF-alpha in 24 h urine samples of female migraineurs during menstrual and non-menstrual migraine attacks and headache-free periods and compared them with those of non-headache controls. The mean IL-6 levels in the urine were higher in all three samples for migraineurs versus controls, while the IL-1beta levels showed no difference. The TNF-alpha values were very low in the menstrual migraineurs compared to those in the controls .Another clinical trial failed to demonstrate differences in the serum concentrations of TNF-alpha and IL-6 between patients with M0, patients with MA, and healthy controls; however, the soluble receptor TNF-RI tended to be lower . A cliniA prospective, case-control RCT of migraineurs concluded that the serum concentrations of TNF-alpha, IL-1beta, and IL-6 were significantly higher during migraine attacks compared to those in controls . In the An interesting study analyzing pro- and anti-inflammatory cytokine levels in the CSF revealed that IL-1 receptor antagonist levels were elevated in M0 and MA patients during attacks compared to those in controls. There were significant differences in the CSF levels of certain cytokines  between the migraine and episodic tension-type headache patients and the pain-free controls. The intrathecal pro-inflammatory monocyte chemoattractant protein-1 level was correlated with the IL-10 anti-inflammatory cytokine in MA patients .The analysis of genetic variations of cytokines has provided useful data regarding the neuroinflammation process of migraine. A genetic study showed significant differences in the TNF-alpha −308G/A and IL-1beta +3953C/T gene polymorphisms in migraineurs versus control subjects . A meta-A RCT of EM patients revealed downregulated IL-6 mRNA and decreased IL-6 serum concentrations . An inveThere is increasing evidence that cytokine expression is a contributor to NP . In the A clinical investigation of nerve biopsies in neuropathic patients with and without pain revealed upregulated TNF-alpha expression in human Schwann cells in the group with pain  186]. A. A186]. A prospective genetic study analyzing local (skin) and systemic (plasma) cytokine gene expression in patients suffering from small fiber sensory neuropathy revealed that the local gene expressions of IL-6 and IL-8 (chemokine) were significantly increased (5-fold), while an only mildly elevated gene expression of IL-2 and IL-10 was detected in the plasma (2-fold) .A cross-sectional study revealed that plasma TNF-alpha levels and immunoreactivity for TNF-alpha were higher in patients with severe pain, based on VAS in PDN patients, compared with controls . A prospA prospective study of patients with painful or painless peripheral neuropathy demonstrated that painful neuropathies are associated with increased pro-inflammatory IL-6 and anti-inflammatory IL-10 gene expression in the sural nerve .A clinical trial including patients with painful distal sensorimotor polyneuropathy (DSPN) from the German KORA F4 survey found positive associations between serum concentrations of IL-6 and painful DSPN, whereas no associations were observed with IL-18, TNF-alpha, and IL-1 receptor antagonists . A paralA genetic trial focused on patients with and without NP after peripheral nerve lesioning revealed that, in white blood cells, the gene expression of TNF-alpha was higher in patients with pain compared to those without pain. IL-1beta gene expression was higher in the patients with pain compared to the controls. IL-10 showed lower gene expression in the group with pain than in the control group, and IL-4 gene expression was not different between the control and painless patients .A pilot RCT of patients with peripheral NP due to PHN examined the mRNA expression of IL-6 in two study groups. In Group 1, patients with PHN-related NP received pregabalin monotherapy alone, while Group 2 patients were treated with a combination of pregabalin and cognitive behavioral therapy. The results showed that the patients in Group 2 had a significantly downregulated IL-6 mRNA expression compared to Group 1 .A recent meta-analysis focused on the association between pro-inflammatory  and anti-inflammatory (IL-10) cytokines as systemic inflammatory biomarkers in painful and painless diabetic neuropathy. It concluded that the serum levels of pro-inflammatory markers were increased, while those of the anti-inflammatory ones were lower in painful compared to painless diabetic polyneuropathy .In migraine, whether in ictal or interictal phases, the data regarding cytokines are inconsistent, but pro-inflammatory cytokines tend to be elevated in human clinical trials. InNP patients, the levels of pro-inflammatory cytokines have also been shown to be elevated compared to those of controls in the majority of clinical studies.The trigeminovascular system is the backbone of the most accepted hypothesis for migraine pathogenesis. The center of this system is the trigeminal ganglion, which involves pseudounipolar neurons and satellite glial cells. There are strong data that glial cells have a role in peripheral sensitization and neuroinflammation, which lead to migraine chronification and the development of autonomic symptoms during migraine attacks ,198.S100B is a calcium-binding protein in the cytoplasm of glial cells in the nervous system, and it is a sensitive marker for glial cell injury. Clinical studies have used it as a biomarker for the detection of glial involvement in the pathomechanism of EM and CM patients, ictally and interictally. Unfortunately, the results are inconsistent. In a clinical study which was performed during and after migraine attacks (2–4 days), the serum concentration of S100B was elevated  199]. A. A199]. In the case of peripheral nerve lesions , one of the main consequences is ATP release from the central terminals in the dorsal horn of the spinal cord. ATP acts on the microglia via purinergic P2 × 4 receptors and results in the release of brain-derived neurotrophic factor from the activated glial cells. This trophic factor stimulates second-order neurons via the activation of tyrosine kinase B receptors. The result of this process is the central sensitization of the second-order neurons, leading to the development of allodynia as a main clinical sensory sign of NP. It also leads to the overactivation of the third-order neurons in the thalamus ,209,210.An early PET study, using a sensitive in vivo marker of glial cell activation, demonstrated activated glial cells in the contralateral thalamus after limb amputation, which pointed to a long-term transsynaptic glial response in the central nervous system (CNS) following peripheral nerve injury  204]. A. A204]. Preclinical studies have confirmed that opioids could activate the microglia via the toll-like receptor 4 and the myeloid differentiation factor 2 receptor complex. The consequence was an activated mitogen-activated protein kinase (MAPK) system, which resulted in interleukin gene activation, leading to neuroinflammation ,214.Motor cortex stimulation is a potential therapeutic method for the relief of NP. In a clinical study, epidural strips were implanted over the motor cortex in central post-stroke NP patients and one trigeminal nerve injury NP patient. A comparison of postoperative PET with preoperative scans demonstrated significant decreases in a tracer, [(11)C] diprenorphine, binding to opioid receptors in different brain areas. Binding changes in the anterior middle cingulate cortex and periaqueductal gray matter were significantly correlated with pain relief . A brainThe inhibition of the activated microglia in NP might be a novel therapeutic target. A CNS glial modulator, propentofylline, administered orally, failed to decrease pain in PHN patients in a proof-of-concept clinical trial . Activated p38 MAPK in spinal microglia was detected in peripheral- nerve-injury-associated NP . A RCT oIn a prospective, open-label, pilot RCT of PDN patients, minocycline, a tetracycline antibiotic used as a microglial inhibitor, significantly improved Visual Analog Scale scores . In anotIn this scoping review, we have highlighted the available clinical data with reference to preclinical studies, starting from CGRP, which has recently gained credit as a target, focusing on the potential pathogenic players both in migraine and NP, and inspiring arguments and the direction of future research.Hyperexcitability with peripheral and central sensitization leading to allodynia is a common pathological feature in migraine and NP. One of the fundamental players in the pathogenesis of migraine and NP is CGRP. The clinical trials showed that CGRP mAbs reduce pain intensity in both conditions. Several CGRP antagonists and mAbs have been approved for the treatment of migraine, while more clinical studies are expected for CGRP intervention in NP. Regarding the clinical studies of CGRP, many data remain unavailable, including data on interictal M0, MA, CM, and central NP. Hopefully, more clinical studies will reveal the consequences of CGRP modulator administration to clarify its efficacy in those subtypes of pain disorders ,225,226.Migraine and NP share a common pathogenic mechanism with endocannabinoids through the trigeminovascular and pain transmission systems. Potential analgesic lead compounds may be distributed among the cannabinoid system’s receptors and enzymes, such as CBR antagonists and FAAH and MAGL modulators. Clinical studies of peripheral NP on the endocannabinoid remain to be released, and more studies in other subtypes may help ascertain the potential of the system as a target ,91,92,93Inflammation plays a certain role in both conditions. Preclinical data support the significant involvement of both pro- and anti-inflammatory cytokines . GeneralOverviewing the common potential pathogenic factors in the pathogenesis of migraine and NP in search of novel targets for pain management, the following issues have emerged and may play a role in validating whether the targets we have proposed could remain as main topics of research: the efficacy of CGRP remains uncharted in many subtypes; a better understanding of TRPs in the pathogenesis and research on more TRP modulators remain prerequisites; identifying the key players in the endocannabinoids system and the discovery of more modulators may help research in this field to proceed a step forward; more studies on the status of KYN metabolites in reference to glutamate levels may reveal their potential; a consensus is expected regarding cytokines and sampling to monitor inflammatory status and to zero in on a target; the discovery of more biomarkers and imaging techniques to monitor the status of glial function remains a target .The authors acknowledge the limitations of this review, which include the fact that it has not covered other potential targets and that it has not referred to emerging analgesics that are under extensive research. Matrix metalloproteinases (MMPs) are extracellular matrix metalloproteinases that are implicated in various diseases including migraine and NP. MMPs may play a role in the disintegration of the blood-brain barrier, leading to increased neuronal excitability and thus migraine attacks. Preclinical studies have reported that increased levels of MMPs induce pain-like symptoms, suggesting that MMPs may participate in the pathogenesis of NP and thus could be a potential target for NP. Drug repurposing has helped to identify a cosmetic product as an antimigraine agent. Onabotulinum toxin A (Botox) is a potent neurotoxin that is widely applied in cosmetic procedures. Botox is approved by the FDA for the prophylactic treatment of CM and has been extensively investigated for the potential treatment of NP. The exact mechanisms by which Botox relieves CM and NP remains unknown ,240. FurThis scoping review has recapitulated human data on the pathological components that play a role in the pathogenesis of both migraine and NP with reference to preclinical findings. The data successfully support the hypothesis that migraine and NP have shared pathomechanisms involved in CGRP, TRP ion channels, endocannabinoids, Trp-KYN metabolism, neuroinflammation, and microglial malfunction, clarifying the unchartered areas which are to be explored, reinforcing the need for a better understanding of the mechanisms of those participating components, and inspiring the discovery of more modulators that may provide more options for future research. This line of research, buttressed by preclinical studies, paves an exploratory path forward to help identify new biomarker profiles, develop novel therapeutic agents, and thus build a personalized treatment plan for migraine as well as NP.


Introduction: Non-autoimmune sacroiliac joint pain contributes to nearly a quarter of low back pain patients. Non-surgical management fails to satisfy patients. A new minimally invasive technique for sacroiliac stabilization has been introduced, defying the traditional rules of fusion. The results outside explanatory trials and in day-to-day practice have not been reported. Materials and methods: This case series includes 20 patients diagnosed with chronic sacroiliac pain resistant to conservative management for at least 6 months. The diagnosis was confirmed with a positive sacroiliac injection. Patients underwent stabilization using the iFuse® implant. Patients were followed up for a minimum of one year. The primary outcome was the functional outcomes, assessed using VAS, ODI, and SF36. Secondary procedure rates, complication rates, and radiological assessments of fusion were collected as secondary outcomes. Results: At one year, the mean VAS score improved from 81.25 ± 10.7 SD preoperatively to 52.5 ± 26.8, p-value 0.0013. The mean ODI improved from 54.8 ± 11.21 SD preoperatively to 41.315 ± 15.34, P value = 0.0079. The mean PCS and MCS of SF36 improved by 17 and 20 points, respectively. Only 55% of patients achieved the MCID for the VAS score. 35% of the cohort had secondary procedures. Discussion: Minimally invasive sacroiliac fusion resulted in an improvement in mean functional scores with a wide dispersion. Patients not achieving MCID are patients with either a malpositioned implant, an associated lumbar pathology, or an inaccurate diagnosis. Our results are underwhelming compared to similar work but are still better than conservative cohorts in comparative studies. Conclusion: Minimally invasive sacroiliac fusion can be used successfully in select patients. Attention to diagnosis and surgical technique can improve the reproducibility of results. Low back pain (LBP) is the leading worldwide cause of years lost to disability . The sacConservative management is the first line of treatment. It is not effective in the long run , 5, failFusion is the surgical procedure of choice in resistant cases. Minimally invasive (MI) SIJ fusion has been shown to have lower operative blood loss, hospital stay, surgical time, and better pain relief compared to open SIJ fusion , 9. ThisA meta-analysis evaluating the quality of evidence in fourteen publications on a commercially available system rated the available evidence as poor . ShamrocTo our knowledge, the results of this procedure achieved within the national health services (NHS) settings have not been reported, and the question of whether the published results are reproducible outside explanatory trials is yet to be answered.The primary aim of the study is to report on functional outcomes following MI SIJ fusion, adding to the available literature. Secondary outcomes include complication rate, secondary procedure rate, and a radiological assessment of fusion would highlight challenges with diagnosis, surgical technique, and follow-up.We reviewed the treatment outcomes of 20 consecutive patients treated at a single NHS trust and a local private hospital between January 2019 and March 2021. The mean follow-up was 19.9 ± 3.4 standard deviation (SD) months with a minimum follow-up of 14 months.Patients were referred with chronic low back pain resistant to conservative management for at least six months. The mean age at the time of surgery was 49.6 ± 14.5 SD years. Fifteen patients (75%) were females. Seven patients (35%) had previous lumbar surgery, six patients (30%) had a history of hip pathology or replacement, and two patients (10%) previously had a contralateral SIJ fusion .Patients were diagnosed as either dynamic sacroiliac dysfunction or degenerative sacroiliitis using history, physical examination, and a positive SI block. The main symptom was pain localizing to SIJ using the Fortin finger test . An examWhen symptoms, examination, and imaging pointed towards the SIJ, patients were sent for a diagnostic computed tomography (CT) guided SI injection. A 50% reduction in visual analog score (VAS) right after the procedure was considered the threshold to confirm the SIJ as the primary pain generator .® implant  [Conservative management was maximized, which included personalized physiotherapy, multiple SI injections, and radiofrequency ablation. Patients with a VAS score of more than 50, an oswestry disability index (ODI) of more than 30, and a positive response to injection failing conservative management were offered MI SI fusion using the iFusenia USA) .® is a triangular-shaped titanium implant with a porous plasma spray coating. It relies on interference fit for initial stability and has a large surface area to promote bone ingrowth to create bony bridges across the SI joint [The iFuseSI joint .The procedures were performed by three consultants with expertise in sacroiliac screw placement. Under a general anesthetic with the patient in a supine position on a radiolucent table, a 3 cm lateral skin incision superimposed on the lateral sacral projection is performed. This is followed by a blunt division of gluteal fascia and muscles to reach the outer table of the ilium. Three guide wires were inserted under image guidance in the inlet, outlet, and lateral view corridor across the sacroiliac joint at the level of the S1 body, S1 foramen, and S2 body, respectively. The first wire is placed using a freehand technique as described for iliosacral screw placement . SubsequThe pain was assessed using VAS, functional outcome using ODI, and quality of life using short form 36 (SF36) , 18. TheComplications and secondary procedures were recorded up until the final follow-up. Radiological assessment using a pelvis AP X-ray obtained at 1 year and a CT scan when clinically indicated .T-tests. p-Values less than 0.05 were considered statistically significant.Data were coded and entered using graph pad prism version 9. Data were summarized using mean and standard deviation (SD) and using frequency (count) and relative frequency (percentage) for categorical data. Comparisons between quantitative variables were made using the paired student p-value of 0.0013. The mean ODI improved from 54.8 ± 11.21 SD preoperatively to 41.315 ± 15.34, p-Value = 0.0079. However, only eleven patients (55%) and 10 patients (50%) achieved the MCID for VAS and ODI, respectively.An overall improvement in pain and functional outcome was observed. The VAS score improved from a mean of 81.25 ± 10.7 preoperatively to 52.5 ± 26.8 at one year, The quality of life assessed by SF36 improved at 1 year. The mean physical component section (PCS) of SF36 improved from 28.9 preoperatively to 45.6, and the mean mental component section (MCS) changed from 35.3 to 55.85 at one year.A complication requiring a secondary procedure occurred in two patients (10%). Both patients developed radicular pain due to a breaching implant. One patient had an implant removal, and the other had a selective nerve root block .An overall secondary procedure rate of 35% was observed. In addition to the aforementioned two patients, five patients (25%) presented with recurrent low back pain; one patient required an L4–L5 fusion, 3 required a facet injection, and one needed a secondary sacroiliac injection.We found it difficult to confirm fusion on X-rays at the one-year mark; however, absence of significant displacement, implant breaches, or loosening was considered a radiological success (75% of patients) . Three p® system with a minimum follow of 14 months. A statistically significant improvement in pain and functional outcomes was achieved, with only 55% and 50% achieving MCID using VAS and ODI, respectively. A 10% complication rate and a 35% secondary procedures rate were noted during the follow-up.The sacroiliac joint is a well-recognized cause of low back pain . SurgicaThe study limitation is the small sample size and the lack of a comparative group. To our knowledge, this is the first study to report its outcomes achieved in day-to-day practice within the NHS setting with no conflict of interest.® system for MI SIJ fusion is the most widely published method. There are two randomized controlled trials [The iFused trials , 6, one d trials , three rd trials –9, and 4d trials , 22, 23 This study’s diagnostic algorithm mirrors published studies . All theAs the procedure is relatively new, it is unclear in the literature what the threshold is to offer fusion. In this study, conservative management was exhausted before offering surgery as a salvage procedure. A threshold of a VAS score of 50 and an ODI of 30 was used based on the work of Polly et al. In his trial, 84.4% of the conservative cohort failed conservative treatment and went on to undergo fusion after 6 months. This could serve as an estimate of how often fusion is required in cases crossing the threshold [This study’s patient’s preoperative data are well matched to published studies with regard to age, sex, BMI, and functional status  and 3. A® Minimally Invasive Arthrodesis (iMIA) trials [The mean improvement in functional scores and percentage of patients achieving MCID in this study is lower than the available literature . This ca) trials , 6.® implant design adds to the stability of fixation but decreases the margin of error during its insertion. Its cross-section is formed of an equilateral triangle, with each limb measuring 11.35 mm. This is substantially bigger than the biggest sacroiliac trauma screw at 8.0 mm. In this study, 10% of patients had an implant breech requiring a secondary procedure compared to 6% in the Rudolf et al. case series [The iFusee series . Denglere series . Polly ee series , 21, 22.The difficulty in instrumentation is further complicated by the sacral morphology. The dysmorphic sacrum bony corridor is more inclined superiorly in the frontal plane and anteriorly in the axial plane  Figure . In thisDifferentiation of SIJ pain from lumbosacral pathology proved challenging and can be a cause for secondary procedures. In this study, four patients (20%) represented after fusion with the pain believed to be from lumbosacral pathology. This is not unique to our study, Sachs et al. reported that 20% of his cohort represented facet joint pain . It is dThe lack of an imaging modality to confirm the diagnosis adds to the difficulty with standard cross-sectional studies being of limited utility . Cusi etRadiological evaluation of fusion proved to be difficult on X-ray and CT scans. This has been echoed by Dengler et al.  and DuhoThere is no consensus on the depth of implant insertion. Dengler et al. found no correlation between the length of implants and clinical results . Duhon eNo revisions were performed for the suspected failure of the fusion at the time of final follow-up. Duhon et al. reported 4 revisions for the suboptimal placement of implants . Polly eOur study sample size, heterogenicity of population, lack of comparative and high rate of complications did not allow for analysis of predictors of success. Dengler et al. performed a large meta analysis on two randomized controlled trials and a large multicentric prospective case series. The study reported better outcomes in nonsmokers, non-opioid users, older age groups, and longer pain duration .Surgeons performing these procedures should be aware of the challenges with diagnosing the pathology and the challenges with safe implant positioning. Further work is needed to determine the utility of SPECT/CT in the primary diagnosis. Familiarity with instrumentation, surgical planning using cross-sectional imaging, and the use of 3d navigation could help increase the safety profile of the procedure.In conclusion, the diagnosis and treatment of SI pain remains a difficult topic. Our results have shown that fusing SI joints is a difficult operation performed often in patients with chronic pain symptoms. However, all patients improved after SIJ fusion, some more so than others. There was a significant secondary procedure rate. We believe that most patients who did poorly fell into one of three groups, wrong diagnosis, a complication, or another condition that resulted in a poor outcome, such as failed back syndrome. Further work is needed to help identify patients who will have the best results from this surgery.MHA certifies that he has no financial conflict of interest. WA certifies that he has no financial conflict of interest. SAK certifies that he has no financial conflict of interest. KFMA certifies that he has no financial conflict of interest. MAC certifies that he has no financial conflict of interest. JG certifies that he has no financial conflict of interest. PMS certifies that he has no financial conflict of interest.The research did not receive any specific funding.Ethical approval was not required.Written informed consent was obtained from all patients for the procedure, and oral consent for the collection of functional scores and use of their data.MHA data collection, writing up of original draft, and analysis. WA writing up, editing, and analysis. SAK reviewing and editing. KFMA supervision and conceptualization. MAC clinical contribution. JG clinical contribution. PMS conceptualization, supervision, clinical contribution, reviewing, and editing.


The multivariable Cox proportional hazards regression models showed that patients who received USFNB achieved meaningful pain relief 2.37-fold faster (hazard ratio (HR) = 2.37, 95% confidence intervals (CI) = 1.73–3.24, p < 0.001). Conclusions: In geriatric patients with hip fractures, a lidocaine-based single-shot USFNB can significantly reduce opioid consumption and provide more rapid and effective pain reduction.Background and Objectives: Systemic analgesics, including opioids, are commonly used for acute pain control in traumatic hip fracture patients in the emergency department (ED). However, their use is associated with high rates of adverse reactions in the geriatric population. As such, the aim of this study was to investigate the impact of lidocaine-based single-shot ultrasound-guided femoral nerve block (USFNB) on the standard care for acute pain management in geriatric patients with traumatic hip fracture in the ED. Methods: This retrospective, single-center, observational study included adult patients aged ≥60 years presenting with acute traumatic hip fracture in the ED between 1 January 2017 and 31 December 2020. The primary outcome measure was the difference in the amount of opioid use, in terms of morphine milligram equivalents (MME), between lidocaine-based single-shot USFNB and standard care groups. The obtained data were evaluated through a time-to-event analysis (time to meaningful pain relief), a time course analysis, and a multivariable analysis. Results: Overall, 607 adult patients  were included in the study. The patients in the USFNB group required 80% less MME than those in the standard care group (0.52 ± 1.47 vs. 2.57 ± 2.53,  Hip fracture is one of the most common causes of emergent anesthesia and surgery in the elderly . In a naAcute pain management in the geriatric population with hip fracture is challenging, and contraindications and comorbidities may lead to delayed recovery ,7. The uTo deviate from the prevailing opioid-driven mindset, it is important to identify alternative analgesic agents. Regional nerve blockade for the early analgesic management of elderly patients with hip fracture has become important in the last decade . As an eCurrently, evidence suggests that femoral nerve block yields superior outcomes to standard care; however, previous studies have used small samples or obtained temporally limited measures of meaningful pain relief yielded by femoral nerve block and opioids in elderly patients with hip fractures ,15,16,17To address these gaps in the literature, the current study aimed to investigate whether lidocaine-based single-shot USFNB reduces acute pain in elderly patients with hip fracture in the emergency department (ED). The primary outcome measure was the difference in opioid consumption between patients who received USFNB and those who were managed with conventional analgesics under the emergency physician’s discretion, a mode of treatment known as standard care.This retrospective, single-center, observational study was conducted at an academic medical center with an ED. This ED manages approximately 41,000 annual visits, including approximately 20,000 visits by patients aged ≥60 years. The study protocol for the health record review was approved by the Institutional Review Board of Dalin Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Taiwan (No. 10903015). The study was structured according to recommendations detailed in the “Methods of Medical Record Review Studies in Emergency Medicine Research” .Elderly patients aged ≥60 years presenting in the ED with a diagnosis of traumatic hip fracture between 1 January 2017 and 31 December 2020, were included. We excluded patients who were aged <60 years, were non-communicative, were non-consenting, lacked follow-up within our health system or did not undergo hospitalization, had an allergy to opioids or local anesthetics, required management for ≥2 fractures within one visit, were diagnosed with avascular necrosis or hip infection, or had hemodynamic instability.The variables and outcome were defined using the International Classification of Disease, 9th Revision, as well as codes, associated treatments, radiologist reports, and orthopedist consultation lists. Data were collected by an investigator from an electronic health record database using a standardized case record form. A second investigator collected data for 10% of a random selection of the total patient cohort. Both investigators were blind to the hypothesis. We calculated the ĸ-value for inter-observer reliability.USFNB was performed by emergency physicians (EPs) trained in emergency medicine, certified by the regional anesthesia training board. The EPs administered each USFNB when providers were available. The patients were divided into two groups by convenience non-probability sampling: the USFNB group and the standard care group. ® 21G × 70 mm) at the level of the inguinal area, lateral to the femoral artery, under real-time ultrasound guidance. Upon identification of the femoral nerve, the needle was inserted in-plane in a lateral to medial orientation, and the provider injected lidocaine once the needle tip was adjacent to the nerve . We used 20 mL of 1% lidocaine for nerve block because this drug has a short onset time, which is adequate to relieve pain before surgical intervention [USFNB was performed using a hypodermic needle  administered over all ED visits during the study period. The treatment response was recorded according to the ED policy, i.e., pain intensity was assessed using the 11-point Numerical Rating Scale (NRS) at baseline; immediately after the analgesic treatment at 15, 30, 60, and 120 min after the dose was administered; every 2 h thereafter until discharge from the ED; and at the time of transfer from the ED and arrival at the orthopedic ward before surgery. They were also investigated through analysis of pain intensity difference (PID). PID represents the difference in NRS scores between any observation time and the baseline . Time-toThe primary outcome measure was the difference in opioid consumption between the USFNB and standard care groups. The secondary outcomes included changes in the duration of ED stay, the duration of hospital stay, and the occurrence of complications. Complications were defined as vascular puncture (hematoma), permanent nerve injury, local anesthetic systemic toxicity, or any other adverse event. The obtained data were evaluated for multiple effectiveness aspects of USFNB compared with those of standard care.t-test was performed to determine the continuous variables. A p-value of <0.05 was considered statistically significant. Multivariable linear regression analysis was performed to analyze the outcome measures, including MME, duration of ED stay, and duration of hospital stay, with adjustments made for covariables including age, sex, body mass index (BMI), Charlson Comorbidity Index (CCI), initial pain score, chronic arthritis, chronic opioid use, and fracture type.Patient characteristics and outcome measures are reported as means, standard deviations (SDs), 95% confidence intervals (CIs), and percentages, as appropriate. The Chi-squared test or Fisher’s exact test was performed to determine the categorical variables, and Student’s Since PID was measured as an unequally spaced time series, we used a continuous autoregressive time series model, AR (1), to model the dependencies between timepoints within each patient’s PID trajectory. An additional patient-specific random intercept was also added to reflect the variation in initial pain level between patients. The mean trajectory of PID was modeled with restricted cubic splines to allow for the non-linear relation between PID and time . The difThe time to onset of meaningful pain relief within 6 h after the dose initiation was determined using time-to-event analysis. A Kaplan–Meier plot was used to illustrate the time to meaningful pain relief, and a log-rank test was performed to compare the curves between the groups. A Cox proportional hazards regression model was used to compute the HRs and corresponding 95% Cis for achieving meaningful pain relief; multivariable Cox proportional hazards regression analysis was performed with adjustments made for covariables including age, sex, BMI, CCI, initial pain score, chronic arthritis, chronic opioid use, and fracture type. The time-to-event data were right censored when a patient’s event time (time to meaningful pain relief) was not observed, and the observation was imputed to have occurred later than the time when the last known value was recorded. For example, if a patient withdrew from the study 6 h after intervention without meaningful pain relief, then the event time was censored at 6 h. We excluded variables with >25% of the data missing or a cell count of ≤5. When the outcome data were missing, the appropriate statistical data imputation techniques were used to ensure the completion of the data set. All statistical analyses were conducted using STATA version 15.1  and R Statistical Software .The data collected from 607 patients were included in the final analysis  . In the p = 0.013). Overall, there was no significant difference between the two groups in age, sex, BMI, fracture type, and CCI.The baseline characteristics are presented in p < 0.001; p = 0.203) and hospital stay , after adjusting for age, sex, BMI, CCI score, initial pain score, chronic arthritis, chronic opioid use, and fracture type  and multivariable Cox proportional hazards regression models .To compare the analgesic efficacy of lidocaine-based single-shot USFNB with that of standard care in elderly patients with acute hip fracture, the data of 607 patients were analyzed using time-to-event analysis (time to meaningful pain relief) and pain trajectory. Meaningful pain relief was experienced by 71% and 67% of patients in the USFNB and standard care groups in 6 h, respectively. Time-to-event analysis of the outcomes showed that the median time to meaningful pain relief was significantly shorter in the USFNB group (96 min) than in the standard care group (185 min). Kaplan–Meier analysis showed that the difference in meaningful pain relief between the USFNB and standard care groups was statistically significant . Patients who received USFNB for preoperative analgesia in the ED experienced 2.37-fold faster meaningful pain relief than those who received standard care . USFNB recipients also revealed a trend of lower reported pain scores than those who received standard care within 6 h, but this result was not statistically significant  and does not prolong the duration of ED stay (p = 0.203) or hospital stay (p = 0.199).The American Geriatrics Society recommends reducing opioid use in geriatric patients with trauma . Howeverp < 0.001). In the ED, timely pain control is an important component of optimal pain management. Given its short onset time and short duration of action, regional anesthesia with short-acting regimens, such as lidocaine, is considered to help achieve good pain reduction . A shortp = 0.013). The study by Olsen et al. demonstrated that patients with a higher initial pain score require greater pain reduction to reach a minimum clinically important difference than those with a lower initial pain score [In this retrospective study, patients in the USFNB group reported a higher initial pain score than those in the standard care group . Furthermore, our results appeared robust with time-to-event analysis performed with a 3-point decrease  or a 5-point decrease . Pain measurement is most strongly associated with a patient-determined indicator of clinical importance. A cut-off point of PID ≥ 4 provided higher specificity to define meaningful pain relief . ThroughThe mechanism of fast pain reduction with the use of peripheral nerve blocks is based on the hypothesis that peripheral nerve blocks inhibit the propagation of impulses in nerve terminals to inhibit the perception of pain by the cerebral cortex. Local anesthetics can temporarily block the transmission of pain. Theoretically, by providing a site-specific afferent neural block, peripheral nerve blocks should offer timely pain control compared with general anesthesia . In periDespite these promising findings, there are several limitations. First, based on availability and willingness to participate, the non-probability convenience sampling method was used to select participants for this study, which caused a discrepancy between the patients who received USFNB and those who received standard care. The association between the intervention and the results may have been influenced by the challenges in identifying and controlling all the confounding factors, including the pain score recording at different time points in each group, dosage and route of opioid administration, and differences in treating EPs. This analysis allowed for control of only the most common measurable confounders; however, unknown factors, such as the increasing intention to decrease opioid use, may also have contributed to the decrease in MME, and this aspect is difficult to measure. Second, this study retains a potential risk of self-selection bias that should be considered when analyzing and interpreting the obtained data. Because this was a retrospective observational study, the patients included in the study could select their own treatment. Third, although all the treating EPs were instructed to manage pain according to the WHO analgesic ladder, our retrospective observational study is limited because of a potential risk in the use of variable analgesics caused by the EPs’ personal experience and preference, which can influence the analysis and interpretation of the data. Lastly, the study was completed at an urban level 1 trauma center, and the patients who visit this center may not be representative of all EDs. Since there are more opioid needs at higher level trauma centers, the results should be similar or better in other EDs .This retrospective, single-center cohort study indicated that the use of lidocaine-based single-shot USFNB is a fast-acting, non-opioid analgesic alternative that provides prolonged analgesic effects. It can be used to effectively reduce pain while minimizing opioid requirements to control acute pain in geriatric patients with traumatic hip fracture in the ED. Further large, randomized studies are warranted to confirm our observations.


In order to improve the treatment effect of supracondylar fracture of the humerus, the application value of elbow press combined with Zhongtong Ling paste in postoperative swelling and pain in children with supracondylar fracture of the humerus is analyzed. 82 children with humeral condylar fracture undergoing surgery in our hospital from March 2019 to May 2020 are selected and divided into the control group and research group according to the symptoms of soreness. The VAS score is used to observe and compare the pain degree before intervention (T1), 1 month after intervention (T2), and 3 months after intervention (T3).The Kaplan–Meier survival curve is obtained to observe the recurrence rate of swelling and pain in the two groups. Besides, the satisfaction scale designed by our hospital is employed to evaluate parents' satisfaction with the treatment. The application of Zhongtong Ling ointment combined with elbow compression can effectively improve the curative effect, improve children's pain, and promote rehabilitation in the treatment of postoperative swelling and pain of supracondylar fracture of the humerus in children. Supracondylar fracture of the humerus refers to the fracture above the medial and lateral condyles of the distal humerus. Humeral supracondylar fractures are mostly caused by indirect violence, and most of them occur in sports injuries, life injuries, and traffic accidents . AccordiThe rest of the paper is organized as follows: After operation for the supracondylar fracture of the humerus in children, swelling of limbs may occur due to inflammatory reaction, abnormal local microcirculation, and exudation . In addiTraditional Chinese medicine believes that after a fracture, due to broken bones and tendons, the meridians are damaged, blood overflows outside the veins, and bad blood stays inside, which is blood stasis . BecauseExercise therapy was an important technology in massage. It was a massage treatment method characterized by doctor-patient cooperation and the combination of movement and rest . Under tn = 41): age range 2–13 years, mean (7.02 ± 1.31) years, and the ratio of female to male patients 17 : 24 and the study group (n = 41): age range 3–12 years, mean (6.89 ± 1.56) years, and the female to male ratio 18 : 23. The basic data of children are compared, and the difference is very small (P > 0.05), reaching the comparative study standard, see 82 children with a humeral condylar fracture undergoing surgery in our hospital from March 2019 to May 2020 are enrolled in this study. The children are divided into the reference group  The child is in the sitting position or supine position, and the doctor is on the affected side. (2) The rolling method, kneading method, dipping method, or one-finger Zen method are applied 3∼5 times on the radial side of the forearm. (3) We take the radial side of the forearm 3∼5 times and click Quchi, Shou Sanli, Chize, and Shaohai acupoint. (4) We click Yangxi and Zhouliao acupoints. (5) We click the Jianzhen acupoint upward, lift the twist Waiguan acupoint, and click the tennis elbow point . (6) This line is about 2 cm long in the radial side of Chize acupoint, and the doctor used this line as a method of kneading.Next, the local pressing method is adopted as follows: (1) Elbow flexion and extension pressing method: Child sitting position. The doctor is located on the affected side, with the thumb of one hand pressing the curved cistern and pain point of the elbow on the affected side, and the other hand holding the wrist of the affected side to make the elbow joint flex and extend passively for 3∼5 times. (2) The elbow rotation toggle method is applied. The doctor is located on the affected side, with one hand holding the curved cistern of the elbow on the affected side or the point of pain in the three limbs of the hand, and the other hand holding the wrist on the affected side to make the elbow joint rotate passively inside and outside for 3∼5 times so that the child can tolerate it.The observation indicators are as follows: (1) Rehabilitation effect. The postoperative swelling recovery of children in two groups is evaluated. (2) Effectiveness. The degree of swelling symptom relief is 30–70%. (3) Significant effect. The degree of swelling symptom relief is 71–95%. (4) Recovered rate. Swelling symptoms relieved to over 95% or completely subdued swelling.This scale is mainly used to assess the pain degree of children. The specific operation is to draw a straight line with a length of 10 cm on the paper, with a header marked with 0 points, representing no pain. The other header is 10 points, representing extreme pain, and the patient is asked to make a mark on the straight line according to self-feeling, representing the pain at this time. A score of less than or equal to 3 indicates mild pain that can be tolerated. A 4∼ score of six indicates that pain has affected sleep but is still tolerable. A score of 7 or more indicates that pain is unbearable and affects daily life.The scale is self-made by the hospital and is scored 4, 3, 2, 1, and 0, respectively, according to very satisfactory, satisfactory, general, unsatisfactory, and very unsatisfactory. The main contents include recovery speed, pain degree, the influence of daily living ability, and self-reported feelings of children.t is used for the test within the group; variance comparison is used between groups. Repeated measures analysis of variance (ANOVA) is used for multiple time points within the group, and the spherical test is performed. For counting data, the percentage is used for descriptive statistical analysis, and the x2 test is used. All the above data showed significant differences at P < 0.05.SPSS 25.0 statistical software is used for data analysis. If the measurement data are subject to normal distribution and homogeneity of variance after a normal test, they are expressed by mean + standard deviation, and the matched sample P < 0.05), as shown in Compared with the reference group, the overall response rate of children in the study group is higher, and the difference is statistically significant (P > 0.05). There is a significant difference in VAS scores between the two groups (P < 0.05), as shown in ∗” and “#” represent the comparison of the result with T1 and T2, respectively. The symbol “a,” “b,” and “c,” respectively, indicate that if the letters in the group are common, P > 0.05.There is no significant difference in the degree of pain between the two groups before treatment , as shown in The Kaplan–Meier survival curve showed that the recurrence rate of four children in the study group is significantly smaller than that in the reference group (11 cases), accounting for 9.8% and 26.8%. The difference between the two groups is statistically significant (P < 0.05), as shown in The results showed that the mean scores of the parents' satisfaction with the treatment regimen in the study group are significantly higher than those in the reference group , 1 month after intervention (T2), and 3 months after intervention (T3). The children with postoperative swelling and pain of the supracondylar fracture of the humerus are treated by routine Zhuantong Ling application, and at the same time, elbow massage is carried out according to the moving method, which could alleviate postoperative pain of children, promote rehabilitation, and is worthy of clinical practice.


Deficient endogenous pain modulation has been implicated in the development and exacerbation of chronic orofacial pain. To date, relatively little is known regarding the function of the endogenous pain modulation in patients with burning mouth syndrome (BMS). This case–control study investigated endogenous pain modulation in women with BMS.Conditioned pain modulation (CPM) was assessed upon temporal summation (TSP) of thermal pain. Forty female subjects, 20 BMS patients and 20 age-matched control subjects, were included in a 2 session-protocol. Mechanical and thermal pain thresholds were measured on the forearm and hand. TSP was obtained using repetitive laser-evoked thermal stimuli applied on the non-dominant hand, at an intensity yielding to moderate pain. During TSP, CPM was produced by immersing the contralateral foot in a water bath at painful cold (8 °C) temperature. In control conditions, the foot was immersed in a water bath at not painful (30 °C) temperature.BMS was not associated with any impairment in thermal as well as mechanical extracephalic pain thresholds. TSP and CPM efficacy were similar in BMS patients and control subjects. However, BMS patients exhibited enhanced extracephalic heat hyperalgesia.This study reveals that there is no impairment of endogenous pain inhibition mechanisms in BMS patients, but rather an increase in pain facilitation. The patThis is a case–control study conducted in the Clinical Investigation Centre of Clermont-Ferrand University Hospital (France). The study conformed to the STROBE guidelines for case–control studies. The study was performed after approval was obtained from the referent Ethics Committee “CCP Sud-Est VI”. Standard written informed consent was obtained from all participants, according to the 1964 declaration of Helsinki. The study was registered as N°2010-A00403-36.The sample size calculation was based on pilot data obtained in eight healthy subjects from the Clermont-Ferrand center, in which CPM decreased the test heat pain by 2.6 ± 1.8. Expecting that the CPM in BMS patients would be decreased compared to controls as it is the case in fibromyalgia patients , the samThe patients were recruited from the Clermont-Ferrand Hospital Orofacial Pain Clinic. Identification of the patients was carried out taking into account the inclusion/exclusion criteria reported below.BMS group: females patient over 40 year-old; daily presence of localized burning sensation in the oral mucosa during all or part of the day lasting for longer than 3 months; no paroxysm and not following any unilateral nerve trajectory; no clinical oral mucosal alterations; pain intensity ≥ 3 on a Visual Analogue Scale (VAS).For all participants: subjects must have given their written consent.BMS group: report of pain and/or burning in the mouth of known origin ; recent change in current medication. Unknown local or systemic pathologies were ruled out thanks to the medical history and blood sampling looking for iron deficiencies, vitamins, diabetes or thyroid dysfunction.e.g. fibromyalgia, chronic low back pain, chronic pelvic pain, tension headache, migraine, irritable bowel syndrome, temporomandibular disorder); progressive cardiovascular disease; subject not cooperating or unable to speak or read French fluently, or to understand a pain scale; major cognitive or incapacitating disorder.For all participants: taking one of the following antidepressants: venlafaxine, duloxetine, tricyclic antidepressants or bupropion; current medication with neuroleptics; co-morbidity with another ongoing chronic pain  short form, the State-Trait Anxiety Inventory (STAI) and the Pain Catastrophizing Scale (PCS).The burning pain intensity in the past week was rated using both the 0–10 cm visual analogue scale (VAS) and the 4-point--verbal rating scale (VRS).Explorations were conducted in quiet conditions and at constant temperature (23 °C). For measurement of mechanical pain thresholds (MPTs), punctuate stimuli were applied on the forearm using an electronic algometer . The strain gauge was connected to a plastic sterile cone , the tip of which was applied perpendicularly to the studied skin area. The punctate pressure was gradually increased with a constant slope under visual control of the pressure value up to the detection of MPT. Threshold was defined as the lowest pressure that produced a sensation of pain. The results of three separate consecutive measurements at different points in the testing area were averaged to establish the MPT value. The applied pressure could not exceed 500 g, which was the default threshold if pain was not elicited at this level.–1, respectively for pain and tolerance threshold measurement. The patient pushed a stop-button when the threshold was reached and there was an interval of five seconds between repeated thermal stimuli. The whole procedure was repeated five times and the average of five thresholds was taken. In pre-experimental explanations given to patients, particular emphasis was placed on the concept of pain threshold as opposed to tolerance threshold, in order to avoid bias due to patient fear. Immediate pain intensity was scored by the patient on a 0–10 cm visual analogue scale (VAS).Measurement of heat pain and tolerance thresholds were performed using a thermotester  on the skin of the non-dominant forearm. The dimensions of the skin thermode were 25 × 50 mm. The baseline temperature was set at 32 °C, the maximum temperature was 52 °C and the temperature change rate was set at 0.5 and 1.0 °C.s2 at the dorsal aspect of the hand. Cutaneous heat stimuli were applied in incremental intensities in steps of 0.25 J, starting at a minimum of 0.75 J and reaching a maximum of 2 J. After determination of the pain threshold, the laser energy that was able to produce a pain intensity between 3–6 on 0–10 VAS was determined (~ 10 min before CPM assessment). On the one hand, such intensity was needed to elicit sufficient pain to observe a CPM effect, but, on the other hand, not too strong, for ethical reasons. Thereafter, the stimulation at this same intensity was applied repeatedly (from 1st to 45th) every 40 s for 30 min. Thus, each patient received a series of 45 stimulations applied at constant intensity. Subjects were asked to score pain on a 0–10 VAS scale after each block of stimulation. The laser beam was moved (~ 1 cm) between each block to avoid skin lesions.To explore the subjects’ individual CPM potency, the temporal summation of pain (TSP) evoked by a stimulation of the back of the non-dominant hand by a YAP laser stimulator  was used as test stimulus. A stimulator with optic-fiber guidance was placed on a skin area of about 6 cmth and 20th min of the experiment. In control experiments that were performed on a different day in the same subjects, the water bath temperature was neutral (30 °C). In all cases, water was constantly re-circulated to prevent laminar warming around the immersed foot. All subjects were asked to rate the cold pain on a 0–10 VAS scale immediately at the end of immersion. The order CPM vs. control experiments was assigned randomly.The conditioning stimulus consisted in the immersion of the contralateral foot into a water bath at noxious cold temperature (8 °C), between the 10The responses for each block in each condition were plotted over time. The first 15 responses were used to study the unconditioned responses (1st to 15th), the next 15 ones (16th to 30th) to study CPM and the 15 last ones (31st to 45th) to study the post-effects of CPM.Statistics were computed with STATA V12 . Results were expressed as mean ± standard deviation or median (interquartile range) and as frequencies (percentage). Groups were compared using Chi square test (or Fisher’s exact test when appropriate) for categorical data, and using Student t-test  test depending on data distribution for continuous data. Normality was assessed graphically and using Shapiro–Wilk's test. Relationships between the pain intensity and BDI, STAI, and PCS scores were assessed by Pearson’s correlation coefficient . Intra-groups comparisons of pain at discrete time points were performed using Students paired t-test.P value < 5% was considered statistically significant.Pain perception was analyzed using linear mixed models with random subject intercept. Groups, time and foot water immersion were tested as fixed effects. Those methods were developed for temporal subdivision  in order to test: 1) the session effect, 2) the effect of the repeated painful stimulation, 3) the water immersion effect and the post-water immersion effect. Those analyzes were repeated intra and inter-groups. Moreover, for the 1) and 2) we adjusted for the mean pain of the 15 first blocks (= baseline adjustment). All tests were two-sided and a The control participants were age- and gender-matched with the BMS patients. The clinical characteristics of the BMS patients are displayed in Table th block of stimulation in control subjects , from 26.7 ± 2.7 to 46.5 ± 4.8, as well as in BMS patients , from 38.1 ± 2.6 to 51.7 ± 3.1. Moreover, while the magnitude of TSP – as calculated by the difference between the last and the first pain rating – did not differ between BMS patients and control subjects , the sum of pain intensities between the 1st and the 15th block of stimuli was greater in BMS patients than control subjects , while there was no difference in TSP.Following repetitive laser-mediated thermal stimuli, pain intensity progressively increased in both groups, showing TSP Fig.  Pain int2 = 0.02, df = 1, p = 0.893), as well as BMS patients . We also tested whether STAI scores (which are higher in BMS patients than in control subjects) might affect the group effect, by assessing the group x STAI interaction. We found no significant interaction .As BMS patients exhibited higher STAI scores than control subjects, we tested whether the severities of anxiety, on the one hand, and pain (between the 1st and 15th block of stimuli), on the other hand, are correlated. There was no correlation between STAI scores and pain intensities in the control subjects (chist-15th stimulations), during  and after  immersing the contralateral foot into a water bath at painful cold (8 °C) temperature. Second, we also compared the intensity of laser stimulation-evoked pain during  and after  application of the painful conditioning stimulation  with those during and after application of a non-painful conditioning stimulation (water at 30 °C).In the present study, we performed two analyses. First, we assessed the intensity of pain evoked by the laser stimulation before  and after  the application of the painful conditioning stimulation on the contralateral foot  and after  the application of the painful conditioning stimulation of the contralateral foot.In control subjects, laser-evoked pain was depressed during  and after  the application of the painful conditioning stimulation on the contralateral foot  and after  the conditioning stimulation. However, there was no group effect (patients vs. controls) on the CPM, either during  or after  the conditioning stimulation.In BMS patients, laser-evoked pain was also depressed during  stimuli delivered at a remote body location , 8. DysfTSP, when assessed in response to repetitive laser-evoked thermal stimuli , was simDespite normal TSP, BMS patients showed greater extracephalic heat hyperalgesia than control subjects. An enhanced heat hyperalgesia seems common in patients with chronic, either cephalic , 21 or eAlthough we cannot exclude the possibility that the enhanced heat hyperalgesia in BMS patients results from peripheral mechanisms, several observations rather suggest a central contribution. First, neither heat pain thresholds nor MPTs were reduced in the BMS group, showing that thermal and mechanical nociceptors were not sensitized. Second, that That hyperalgesia was observed in a healthy area (hand), remotely located from the painful site (mouth), suggests that it is a secondary hyperalgesia. There is ample evidence for secondary hyperalgesia resulting, at least in part, from a facilitation of nociceptive transmission – i.e. central sensitization – within the dorsal horn . FinallyPrevalence of psychological disorders, anxiety especially, is high in BMS patients, but its role in the pathogenesis of BMS remains unclear (1). Psychological assessment using the STAI reported significantly higher scores in the BMS patients compared with control subjects. However, no correlation between STAI score and pain ratings could be found. Previous studies, too, saw no association between pain ratings and psychological factors in BMS patients , 28. TakWe are aware of the limitations that apply to the present study. First, our sample was limited to females and our results thus cannot be generalized to males. Second, we studied a peri-menopausal population in which CPM effect is known to weaken with age . Third, This study reveals that BMS patients’ sensory profile is characterized by enhanced extracephalic heat hyperalgesia, without alterations in CPM. Altogether, the results suggest that an increase in endogenous pain facilitation and no impairment in inhibition underlies BMS in women.


We conducted a retrospective study on IOL at term, on singleton pregnancies from 2019 to 2021, in a university hospital. The study included 195 patients, comprising 144 compliant protocols. Pain was statistically more frequent in the non-compliance group , and when a midwife was unavailable . A multivariable analysis found factors of good response  to be an indication for PROM , and gestational age at induction , independently of BMI, initial Bishop score, and parity. Patients with pain who were able to follow the protocol delivered 9 h earlier than patients with pain who interrupted the protocol and 16 h earlier than patients who experienced no pain. We identified two key elements that favored compliance: (i) providing the next tablet in advance; and (ii) offering patients early epidural analgesia when in pain in order to continue the protocol and go into labor promptly.We set out to identify factors of non-compliance with a protocol for the oral administration of misoprostol 25 µg (Angusta Among the cervical ripening techniques used during induction of labor (IOL), intravaginal dinoprostone was used in 90% of cases , according to the statistical distribution. The rate of compliant administration was presented with a 95% confidence interval (95% CI). Comparisons between independent groups  were made using the chi-squared test or Fisher’s exact test for categorical variables, and a Student’s In all, 195 consecutive patients were recruited for the study over two years. Of these, 141 were nulliparous and 54 were multiparous .p < 0.001). There was no difference between the nulliparous and multiparous patients in terms of gestational age, BMI, or initial Bishop score at the beginning of induction. Regarding the indications for IOL, nulliparous patients were induced in 43.3% of cases for PROM, in 19.1% of cases for post-term, and in 19.1% of cases for gestational diabetes. In the multiparous group, 29.6% of the patients were induced for gestational diabetes or fetal macrosomia, and 25.9% were induced for PROM , and more intense . In 4.6% of cases, a midwife being time-constrained was reported, leading to delayed administration in eight cases and compliant administration in one case (tablet administration before 3 h) (p < 0.001). The occurrence of a rupture of membranes (ROM) during the protocol was not associated with the compliant administration (p = 0.36). The use of nalbuphine was significantly more frequent in the delayed administration group.Of the 195 patients included, 144 had compliant administration of the tablets . Patient’s age, BMI or parity were not significantly associated with compliant administration, and neither were the initial Bishop score, gestational age at induction, or the number of tablets taken . Pain wap = 0.34). The time between taking the first misoprostol tablet and the beginning of labor was significantly shorter in the group with compliant administration . The results were similar for the time between taking the first misoprostol tablet and the active labor phase . The time from IOL to delivery differed between the two groups and was shorter in the group with compliant administration (p = 0.004) (There was no significant difference for going into labor before five tablets between patients who had compliant administration and those with delayed administration (= 0.004) .p < 0.001). In particular, the indication for PROM was higher in the group with good response (68.2% vs. 19.3%). Gestational age was higher in patients with PROM who took fewer than six tablets (p = 0.009). Pain during the protocol and pain intensity were significantly associated with good response to the protocol. Having a more advanced Bishop score at the IOL was found to be a factor indicating good response to the protocol (p = 0.03) (A good response to the protocol was achieved in 86 patients (44.1%), who went into labor before the administration of six tablets, i.e., the median number of tablets. Age, BMI, parity, gestational age at induction, and the occurrence of ROM during the treatment were not associated with the response to this protocol. The indication for IOL emerged as a factor influencing the protocol response ( = 0.03) .p < 0.001), as was the gestational age at induction . However, being nulliparous emerged as a factor of poor response to the protocol   .p < 0.001). Furthermore, having no pain and compliant administration vs. having pain and delayed administration lengthened the time of IOL until childbirth by about 16 h. Complying with the protocol while in pain was a factor of good response . We looked at the different indications for cesarean section, whether due to a failure of induction , stagnation at 3 cm (7.3%), and whether at the beginning of labor , or during the active phase of labor . In the group with compliant administration, there were as many cesarean sections for failure of induction as during the active phase of labor (34.5%). However, in the group with delayed administration, there was no cesarean for failure of induction, and more than half of the cesareans were during the active phase of labor (58.3%)  .The maternal and neonatal variables did not differ between compliant and delayed administration groups .This observational study found evidence that compliance with a protocol for IOL in a tertiary maternity unit was possible. Pain was the first non-compliance factor for our protocol. We know that misoprostol is used to induce uterine contractions, and that in many studies it is even responsible for uterine hyperstimulation when taken vaginally compared to orally . In our The delayed administration of tablets by midwives also proved to be a factor of non-compliance with our protocol. It led to the protocol being modified during our study, when patients were progressively empowered to take their own tablets. Pain assessment and medication schedules were filled in by the patients themselves. For example, in Denmark, IOL has been performed in low-risk pregnancies at home since 2016, and delivery is achieved within 48 h for 70.1% of women . It mighp = 0.004). In the literature, there is still a lack of data to establish a clear protocol with a precise dose and frequency of administration [Median time to delivery was significantly shorter in the group with compliant administration  providing the next tablet in advance , and (ii) offering patients early epidural analgesia when they are in pain, and so continuing the protocol to go into labor promptly. Oral misoprostol appears more effective for patients with PROM after 39 weeks.


Labor represents the most common reason for hospitalization, and most patients will use some form of pain management during their labor. While some studies have suggested that virtual reality (VR) may be an effective option for managing pain, more study is necessary to understand the patient experience of VR. The aim of this study is to characterize the effect of VR on patient perceptions of coping in labor and their descriptions of the VR experience.A nested prospective, descriptive study within a randomized controlled trial of VR in laboring patients. We included nulliparous, term patients, having contractions at least every 5 min, a pain score on the Wong-Baker pain scale of 4–7, and who had been randomized to receive the 30 min virtual reality intervention in the trial. Subjects completed a childbirth self-efficacy inventory prior to the intervention. After the intervention, they completed a modified childbirth self-efficacy inventory related to VR and underwent a structured interview. Self-efficacy scores were compared using t-tests and qualitative, thematic analysis was performed using Dedoose.Twenty-one subjects received the VR intervention. Twenty subjects completed the post-intervention survey and structured interview; one declined due to discomfort. Subjects noted a significant increase in perceived degree to which VR could improve their self-efficacy in managing pain during labor. Thematic analysis revealed that subjects described the VR experience as allowing them to connect with their breathing, feeling more relaxed, and being distracted from pain. In total, 70% believed VR reduced their pain, 60% felt it reduced their anxiety, and 100% would recommend VR availability for laboring patients.VR can improve patient self-efficacy for managing pain in labor. Future studies should focus on the content of the visualizations, optimized user experience and design, and effectiveness with ongoing exposure to VR content in labor. Labor represents the most common reason for hospitalization in the United States, exceeding the next two diagnoses combined . Labor iVirtual reality (VR) therapy describes the use of a headset with a close-proximity stereoscopic screen to deliver images and videos which create an immersive experience intended to yield a response for the viewer. VR is believed to rely on a combination of distraction, time acceleration, and alterations to gate control of pain signals to reduce perception of nociceptive stimuli and pain . It has The objective of this qualitative study is to characterize the effect of VR on patient perceptions of coping in labor and their descriptions of the VR experience.We conducted a prospective, descriptive study within an open-label randomized controlled trial to assess the effect of VR on pain management for pregnant persons in labor. Prior to initiating the trial, it was approved by the Cedars-Sinai Medical Center Institutional Review Board (Pro00050082) and the protocol registered with clinicaltrials.gov (NCT03437031). Enrollment began in March 2018 and completed in February 2019.The details of the randomized controlled trial have been described in detail elsewhere . In brieSubjects were identified, screened, and consent was obtained. All subjects also completed a Childbirth Self Efficacy Inventory prior to the intervention . The Chi: “when you think about your experience participating in the Virtual Reality study, what is the first thing that comes to your mind”; “how did participating in this study make you feel?”; “what was your favorite part about watching the experiences?”; “what about your least favorite part?”; “did you have any concerns while you were watching the experiences? If so, what were they?”; “do you have any thoughts on how the device can be improved?”  with formal training in qualitative methods using the Dedoose software package. The transcripts were carefully read multiple times to enable total immersion in the discussions. Throughout the reading, sentences and paragraphs were highlighted and coded. Hence, key labels were inductively identified in the unstructured data. After sorting, combining, and refining the generated codes and labels, a set of inductive themes and subthemes were defined and justified with verbatim quotes. Of note, thematic saturation was achieved after completing 15 interviews. Similar instances were found in the data after the 15p < 0.05 was used as threshold for statistical significance.Analysis of differences in the pre and post intervention self-efficacy scores was performed using two-tailed t-tests, assuming unequal variances. Statistical tests were performed using SPSS Statistics® version 24; Twenty-one subjects received the VR intervention; nineteen were allocated to the control (no intervention) arm. The baseline mean CBSEI scores for the VR group were 105.1. The mean self-efficacy scores in the original Lowe trial were 103.1; this score corresponds to average self-efficacy (p < 0.001). The qualitative interviews show that the use of VR was perceived as calming, relaxing, and distracting from pain. According to the patients, the use of VR helped them “connect with the breathing”, “relax”, and “focus on something else” while laboring .Our next steps will be to further analyze the effect of VR on continuous maternal and fetal indicators, specifically maternal heart rate variability and fetal heart rate changes, as well as to evaluate impact on analgesic and anesthetic use. Ultimately, our goal is to optimize a pregnancy-specific experience and make continuous use of the headset available at the bedside during a patient's labor. In doing so, we anticipate being able to demonstrate ongoing effectiveness and potential benefits to reducing analgesic and anesthetic use.