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Objectives: This study aims to characterize the effect of medical therapy on headache and facial pain/pressure among patients with chronic rhinosinusitis (CRS)., Data Sources: CINAHL, PubMed, and Scopus., Methods: CINAHL, PubMed, and Scopus were searched from inception through April 10th, 2024, for English language articles reporting headache or facial pain/pressure outcomes in CRS patients. Inclusion was restricted to studies reporting results of the medical treatment of CRS in nonsurgical cohorts. Primary outcome measures included the sino-nasal outcome test (SNOT) and the visual analogue scale (VAS). Meta-analyses of continuous measures (mean), mean difference (Δ), and proportions (%) were conducted., Results: The initial search yielded 2429 unique articles. After a full-text review of 272 articles, 17 studies reporting outcomes for 2269 patients were included in the meta-analysis. The mean patient age was 48.6 years (range 18.0-86.0; 95% CI: 46.5 to 50.6), among which 55.4% (95% CI: 51.5 to 59.4) were male and 82.9% (95% CI: 68.8 to 93.4) had nasal polyposis. SNOT facial pain/pressure scores improved by 1.1 points (95% CI: -1.7 to -0.5; relative reduction 40.4%) with non-biologic therapies and 1.0 point (95% CI: -1.4 to -0.6; relative reduction 54.6%) with biologic therapies. On an 11-point scale, VAS headaches scores improved by 1.8 units (95% CI: -3.3 to -0.3; 42.1% relative reduction) in CRSwNP patients and 1.0 unit (95% CI: -1.7 to -0.3; 54.0% relative reduction) in CRSsNP patients., Conclusions: Our findings suggest medical therapy significantly reduces facial pain and pressure in the CRS population. Laryngoscope, 134:4458-4465, 2024., (© 2024 The American Laryngological, Rhinological and Otological Society, Inc.)

Although previous studies suggest that Piezo2 regulates chronic pain in the orofacial area, few studies have reported the direct evidence of Piezo2's involvement in inflammatory and neuropathic pain in the orofacial region. In this study, we used male Sprague Dawley rats to investigate the role of the Piezo2 pathway in the development of inflammatory and neuropathic pain. The present study used interleukin (IL)-1 β -induced pronociception as an inflammatory pain model. Subcutaneous injection of IL-1 β produced significant mechanical allodynia and thermal hyperalgesia. Subcutaneous injection of a Piezo2 inhibitor significantly blocked mechanical allodynia and thermal hyperalgesia induced by subcutaneously injected IL-1 β . Furthermore, the present study also used a neuropathic pain model caused by the misplacement of a dental implant, leading to notable mechanical allodynia as a consequence of inferior alveolar nerve injury. Western blot analysis revealed increased levels of Piezo2 in the trigeminal ganglion and the trigeminal subnucleus caudalis after inferior alveolar nerve injury. Furthermore, subcutaneous and intracisternal injections of a Piezo2 inhibitor blocked neuropathic mechanical allodynia. These results suggest that the Piezo2 pathway plays a critical role in the development of inflammatory and neuropathic pain in the orofacial area. Therefore, blocking the Piezo2 pathway could be the foundation for developing new therapeutic strategies to treat orofacial pain conditions., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2024 Min-Jeong Jo et al.)

Objectives: Persistent idiopathic dentoalveolar pain (PIDP) is a challenging clinical entity associated with both physical and emotional consequences. Currently, the management is symptom-based and includes both topical and/or systemic treatments. More recently, botulinum neurotoxin-A (BONT-A) has been suggested as a treatment option., Materials and Methods: We present a case series of 9 patients (5 female) with mean age 56 ± 15 diagnosed with PIDP. All patients reported prior experience with systemic drugs without a sufficient pain-relieving effect. BONT-A (BOTOX, Allergan) 100 U diluted with saline solution was used and the dose ranged from 20U to 50U distributed in 3 sites (intraoral and/or extraoral) per session. Patients underwent further injections (50U) monthly if pain severity measured using a Numerical Rating Scale (NRS 0-10) was still > 3 for 3 months. Pain severity and characteristics were recorded at baseline (T0), after 1 month (T1), 2 months (T2) and 3 months (T3)., Results: Mean pain intensity at baseline was NRS 6 (4-10). Latency before analgesic effect was at least 5-10 days after injection. Minor adverse effects were sickness and muscular hypotonia. Pain significantly reduced to NRS 4 (0-8) at T1, to NRS 2 (0-8) at T2 and to NRS 2 (NRS 0-8) at T3. Patients' functional variables (discomfort while chewing, talking, swallowing) were also recorded., Conclusions: BONT-A is widely used and although the exact mechanism of action remains unclear, it can be used effectively in reducing pain for a variety of conditions including PIDP., Clinical Relevance: Our results suggest that BONT-A seems to be an alternative therapeutic approach for patients with PIDP., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objectives: Acute and chronic orofacial pain are very common and remain a vexing health problem that has a negative effect on the quality of life. Serotonin (5-HydroxyTryptamine, 5-HT) is a kind of monoamine neurotransmitter that is involved in many physiological and pathological processes. However, its role in orofacial pain remains inconclusive. Therefore, this review aims to summarize the recent advances in understanding the effect exerted by 5-HT on the modulation of orofacial pain., Subjects and Methods: An extensive search was conducted on PubMed and Web of Science for pertinent studies focusing on the effects of 5-HT on the modulation of orofacial pain., Results: In this review, we concisely review how 5-HT mediates orofacial pain, how 5-HT is regulated and how we can translate these findings into clinical applications for the prevention and/or treatment of orofacial pain., Conclusions: 5-HT plays a key role in the modulation of orofacial pain, implying that 5-HT modulators may serve as effective treatment for orofacial pain. However, further research on the precise mechanisms underlying the modulation of orofacial pain is still warranted., (© 2024 Wiley Periodicals LLC.)

Background: Botulinum toxin type A (BTX-A), produced by the gram-positive anaerobic bacterium Clostridium botulinum, acts by cleaving synaptosome-associated protein-25 (SNAP-25), an essential component of the presynaptic neuronal membrane that is necessary for fusion with the membrane proteins of neurotransmitter-containing vesicles. Recent studies have highlighted the efficacy of BTX-A in treating chronic pain conditions, including lower back pain, chronic neck pain, neuropathic pain, and trigeminal neuralgia, particularly when patients are unresponsive to traditional painkillers. This review focuses on the analgesic effects of BTX-A in various chronic pain conditions, with a particular emphasis on the orofacial region., Highlight: This review focuses on the mechanisms by which BTX-A induces analgesia in patients with inflammatory and temporomandibular joint pain. This review also highlights the fact that BTX-A can effectively manage neuropathic pain and trigeminal neuralgia, which are difficult-to-treat chronic pain conditions. Herein, we present a comprehensive assessment of the central analgesic effects of BTX-A and a discussion of its various applications in clinical dental practice., Conclusion: BTX-A is an approved treatment option for various chronic pain conditions. Although there is evidence of axonal transport of BTX-A from peripheral to central endings in motor neurons, the precise mechanism underlying its pain-modulating effects remains unclear. This review discusses the evidence supporting the effectiveness of BTX-A in controlling chronic pain conditions in the orofacial region. BTX-A is a promising therapeutic agent for treating pain conditions that do not respond to conventional analgesics., Competing Interests: Declaration of competing interest The authors declare no conflict of interest., (Copyright © 2024 Japanese Association for Oral Biology. Published by Elsevier B.V. All rights reserved.)

Objectives: To conduct an equivalency randomized controlled trial comparing occlusal splint (OS) and botulinum toxin-A (BTX-A) on jaw muscle pain in probable sleep bruxism., Methods: Sixty patients (≥18 years, probable sleep bruxism, and jaw muscle pain) were randomly allocated into groups. The primary outcome was the reduction of jaw muscle pain, assessed using the Graded Chronic Pain Scale (GCPS, v2.0). Secondary outcomes included: parameters of jaw opening and mandibular mobility; distribution of muscle pain; Jaw Functional Limitation Scale-20 (JFLS-20), Oral Behaviors Checklist (OBC); and Oral Health Impact Profile-14 (OHIP-14). Only the evaluator was blinded. Multilevel mixed-effects regression models were used., Results: Fifty-nine patients (30 received OS and 29 BTX-A) were analyzed at baseline, 3 and 6 months follow-up. One patient dropped out after receiving the intervention. No differences between the interventions were observed concerning the GCPS (p = 0.627), although a significant reduction was observed at 3 (OR=13.26, 95%CI[6.61-26.59]) and 6 months (OR=12.36, 95%CI[4.93-30.98]), regardless of the treatment. BTX-A showed a lower score reduction on JFLS-20 than OS (OR=0.29, 95%CI[0.11-0.82]). BTX-A presented inferior results for the parameters: opening without pain(p = 0.045), unassisted maximum opening(p = 0.024), assisted maximum opening(p = 0.041), and protrusion(p = 0.016). An improvement in OHIP-14 scores was observed at 3 (IRR=1.08, CI95%[1.02-1.14]) and 6 months (IRR=1.10, CI95%[1.04-1.16]), regardless of the intervention. BTX-A participants(n = 23;79,3%) reported mild discomfort during chewing., Conclusion: OS and BTX-A can effectively decrease the GCPS scores, improve OHRQoL, and enhance functional outcomes in sleep bruxist patients with jaw muscle pain. OS demonstrated slight advantages in specific parameters., Clinical Significance: Both occlusal splints and botulinum toxin-A effectively reduce jaw muscle pain in bruxist patients, improving quality of life and mandibular function. Clinically, occlusal splints may offer additional benefits in specific functional parameters. (NCT03456154)., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Pain management is a primary goal after oral surgeries, but little is known about sex differences in the sensitivity to analgesics. This study aimed to compare the efficacy of three drugs with analgesic potential on heat and mechanical hyperalgesia, spontaneous pain and locomotion on male and female rats subjected to a model of orofacial postoperative pain. Male and female Wistar rats were submitted to intraoral incision or sham surgery, and on postoperative day 3, the effect of the ibuprofen (30 and 100 mg/kg), acetaminophen (100 and 300 mg/kg) and codeine (3 and 10 mg/kg) was assessed on responses to heat and mechanical facial stimulation, facial grooming, and locomotion. Ibuprofen reduced heat and mechanical hyperalgesia and grooming behavior in male and female rats in a non-sedative dose; acetaminophen dose-dependently reduced the mechanical hyperalgesia and abolished the heat hyperalgesia and the grooming behavior but caused sedation in both sexes; codeine dose-dependently reduced the mechanical hyperalgesia in male and female rats, and reduced the heat hyperalgesia, but females were less sensitive than males. It reduced spontaneous facial grooming in both sexes, but induced hyperlocomotion in females. Ibuprofen presented the most favorable profile, since it reduced over 50% heat and mechanical hyperalgesia in male and female rats, and significantly reduced spontaneous pain, without causing sedation or affecting locomotion. The identification of sex differences in the sensitivity and safety profile of frequently used analgesics can help guide the choice of more effective individualized therapies for pain control., Competing Interests: Declarations. Ethics approval: All procedures involving animals were approved by UFPR Ethics Committee (CEUA/BIO-UFPR #1464). Competing interests: The authors declare no competing interests., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

This is a nonclinical, controlled, and triple-blind study to investigate the effects of codeine-associated geraniol on the modulation of orofacial nociception and its potential central nervous system depressing effect in an animal model. The orofacial antinociceptive activity of geraniol in combination with codeine was assessed through the following tests: (i) formalin-induced pain, (ii) glutamate-induced pain, and (iii) capsaicin-induced pain. Six animals were equally distributed into six groups and received the following treatments, given intraperitoneally (i.p.) 30 minutes before the experiments: a) geraniol/codeine 50/30 mg/kg; b) geraniol/codeine 50/15 mg/kg; c) geraniol/codeine 50/7.5 mg/kg; d) geraniol 50 mg/kg; e) codeine 30 mg/kg (positive control); or f) 0.9% sodium chloride (negative control). We performed pain behavior analysis after the injection of formalin (20 µL, 20%), glutamate (20 µL, 25 µM), and capsaicin (20 µL, 2.5 µg) into the paranasal region. Rubbing time of the paranasal region by the hind or front paw was used as a parameter. In the neurogenic phase of the formalin test, the geraniol/codeine at 50/7.5 mg/kg was able to promote the maximum antinociceptive effect, reducing nociception by 71.9% (p < 0.0001). In the inflammatory phase of the formalin test, geraniol/codeine at 50/30 mg/kg significantly reduced orofacial nociception (p < 0.005). In the glutamate test, geraniol/codeine at 50/30 mg/kg reduced the rubbing time by 54.2% and reduced nociception in the capsaicin test by 66.7% (p < 0.005). Geraniol alone or in combination does not promote nonspecific depressing effects on the central nervous system. Based on our findings, we suggest the possible synergy between geraniol and codeine in the modulation of orofacial pain.

Introduction: The development of temporomandibular disorders specifically emphasizes the biochemical changes occurring in the synovial fluid at different stages of temporomandibular joint disease. Research has indicated that inflammation may be a primary reason behind the pain and dysfunction in temporomandibular joint diseases. Since its clearance several years ago, MESNA (sodium 2-mercaptoethanesulfonate) has been used in various formulations as a mucolytic drug in the respiratory domain. It operates by disrupting the disulfide bonds present between polypeptide chains within mucus. MESNA exhibits minimal tissue distribution, with the material being swiftly and thoroughly eliminated via the kidneys., Objectives: To assess the efficacy of injecting MESNA directly into the Temporomandibular Joint to treat internal derangement., Materials and Methods: A randomized clinical trial was conducted on sixty patients who exhibited non-responsiveness to conventional treatment and were diagnosed with TMJ anterior disc displacement with reduction. The patients were chosen from the outpatient clinic of the Oral and Maxillofacial Surgery Department at Tanta University Faculty of Dentistry. Two equal groups of patients were randomly assigned to each other. Group I (Mesna group) received intra-articular injection with MESNA solution. Group II (Standard group) received arthrocentesis with lactated ringer solution followed by injection of Hyaluronic Acid (HA). The data was gathered by functional examinations such as maximum interincisal opening (MIO) and clicking. A Visual Analogue Scale (VAS) assessed pain severity before and after treatments., Results: Both MESNA and HA showed significant improvement up to six months of the follow-up compared to preoperative status, as evidenced by better mouth opening, lateral excursion, lower clicking, and reduced pain score in patients with TMDs. MESNA showed significant improvement during follow-up compared to HA., Conclusion: Compared to HA, MESNA showed a more noticeable improvement during the follow-up period., (© 2024. The Author(s).)

Background and Objective: Temporomandibular disorders (TMDs) are a common pathology, associated with pain in the facial territory and with associated psychological disorders, such as anxiety and depression. The aim of this study was to evaluate the efficacy of antidepressants in the treatment of pain associated with TMD., Materials and Methods: Sixty four patients suffering from chronic orofacial pain, randomly distributed in 3 groups: control group treated with night splint, group treated with 10mg/day of citalopram and group treated with 25mg/day of amitriptyline. Pain intensity was assessed, randomly, by a single blinded evaluator, according to the VAS at baseline and after one, three, six and nine weeks., Results: All groups showed a reduction of pain throughout the period of time evaluated, however, the group treated with amitriptyline showed the best pain reduction results 3.3±1.5, 1.5±1.4 and 0.9±1.3 at 3, 6 and 9 weeks, respectively., Conclusions: Low doses of amitriptyline appear to be a good therapeutic option in patients with TMDs suffering from chronic orofacial pain., (Copyright © 2024 Elsevier España, S.L.U. All rights reserved.)

Objective: To evaluate the effects of low doses of botulinum toxin type A (BoNT-A) to control pain in patients with sleep bruxism (SB), awake bruxism (AB), and temporomandibular disorder (TMD) during 180 days., Methods: Overall sample of thirty-five patients with chronic pain related to TMD, SB, and AB received a single dose of 20 U of BoNT-A in masseter and temporalis muscles. The pain was assessed with a visual analog scale (VAS) before and after 15, 30, 60, 90, and 180 days of the application., Results: The three clinical conditions experienced decrease in pain after 15 days of treatment ( p < 0.0001); the maximum pain relief persisted for up to 90 days after BoNT-A application in patients with SB and AB and 15 days for patients with TMD., Conclusion: A low dose of BoNT-A may be effective for controlling chronic pain related to SB and AB, but TMD pain reduction was short-lived.

Background: Chronic orofacial pain (COP) therapy is challenging, as current medical treatments are extremely lacking. Moutan Cortex (MC) is a traditional Chinese medicine herb widely used for chronic inflammatory diseases. However, the mechanism behind MC in COP therapy has not been well-established. The purpose of this study was to identify the active ingredients of MC and their specific underlying mechanisms in COP treatment., Methods: In this study, the main active ingredients and compound-target network of MC in COP therapy were identified through network pharmacology and bioinformatics analysis. Adult male Sprague-Dawley rats received oral mucosa lipopolysaccharide (LPS) injection to induce COP. Pain behaviors were evaluated by orofacial mechanical nociceptive assessment after intraganglionar injection. In vitro inflammatory cytokines in LPS-pretreated human periodontal ligament stem cells (hPDLSCs) and rat primary cultural trigeminal ganglion (TG) neurons were quantified by real-time quantitative polymerase chain reaction (RT-qPCR). Schrödinger software was used to verify the molecular docking of quercetin and critical targets. Whole-cell recording electrophysiology was used to evaluate the effect of quercetin on voltage-gated sodium (Na v ) channel in rat TG neurons., Results: The assembled compound-target network consisted of 4 compounds and 46 targets. As 1 of the active components of MC correlated with most related targets, quercetin alleviated mechanical allodynia in LPS-induced rat model of COP (mechanical allodynia threshold median [interquartile range (IQR) 0.5 hours after drug administration: vehicle 1.3 [0.6-2.0] g vs quercetin 7.0 [6.0-8.5] g, P = .002). Gene ontology (GO) enrichment and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis revealed that immune response and membrane functions play essential roles in MC-COP therapy. Five of the related targets were identified as core targets by protein-protein interaction analysis. Quercetin exerted an analgesic effect, possibly through blocking Na v channel in TG sensory neurons (peak current density median [IQR]: LPS -850.2 [-983.6 to -660.7] mV vs LPS + quercetin -589.6 [-711.0 to -147.8] mV, P = .006) while downregulating the expression level of proinflammatory cytokines-FOS (normalized messenger RNA [mRNA] level mean ± standard error of mean [SEM]: LPS [2. 22 ± 0.33] vs LPS + quercetin [1. 33 ± 0.14], P = .034) and TNF-α (normalized mRNA level mean ± SEM: LPS [8. 93 ± 0.78] vs LPS + quercetin [3. 77 ± 0.49], P < .0001)., Conclusions: Identifying Na v as the molecular target of quercetin clarifies the analgesic mechanism of MC, and provides ideas for the development of novel selective and efficient chronic pain relievers., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the International Anesthesia Research Society.)

Objective: Orofacial pain with high prevalence is one of the substantial human health issues. The importance of this matter became more apparent when it was revealed that orofacial pain, directly and indirectly, affects cognition performances. Currently, researchers have focused on investigating pharmaceutics to alleviate pain and ameliorate its subsequent cognitive impairments., Design: In this study, the rats were first treated with the central administration of methyl jasmonate (MeJA), which is an antioxidant and anti-inflammatory bio-compound. After 20 min, orofacial pain was induced in the rats by the injection of capsaicin in their dental pulp. Subsequently, the animals' pain behaviors were analyzed, and the effects of pain and MeJA treatments on rats learning and memory were evaluated/compared using the Morris water maze (MWM) test. In addition, the expression of tumor necrosis factor-α (TNF-α), IL-1β, BDNF, and COX-2 genes in the rats' hippocampus was evaluated using real-time polymerase chain reaction., Results: Experiencing orofacial pain resulted in a significant decline in the rats learning and memory. However, the central administration of 20 μg/rat of MeJA effectively mitigated these impairments. In the MWM, the performance of the MeJA-treated rats showed a two- to threefold improvement compared to the nontreated ones. Moreover, in the hippocampus of pain-induced rats, the expression of pro-inflammatory factors TNF-α, IL-1β, and COX-2 significantly increased, whereas the BDNF expression decreased. In contrast, MeJA downregulated the pro-inflammatory factors and upregulated the BDNF by more than 50%., Conclusions: These findings highlight the notable antinociceptive potential of MeJA and its ability to inhibit pain-induced learning and memory dysfunction through its anti-inflammatory effect., (© 2024 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: Botulinum toxin type A (BTX-A) is increasingly used to manage painful temporomandibular disorders (TMD). However, the effect of BTX-A on muscular TMD remains unclear., Objective: To assess the efficacy, safety and optimal dose of BTX-A for treating TMD., Methods: We conducted systematic literature searches in MEDLINE, Embase, Web of Science, ClinicalTrials.gov and Cochrane Library until March 2023. We extracted data from randomized controlled trials (RCTs) that evaluated the efficacy and safety of BTX-A in treating muscular TMD. We performed a meta-analysis using a random-effects model., Results: Fifteen RCTs involving 504 participants met the inclusion criteria. BTX-A was significantly more effective than placebo in reducing pain intensity, as measured on a 0-10 scale, at 1 month (MD [95% CI] = -1.92 [-2.87, -0.98], p < .0001) and 6 months (MD [95% CI] -2.08, [-3.19 to -0.98]; p = .0002). A higher dosage of BTX-A (60-100 U bilaterally) was associated with a greater reduction in pain at 6 months (MD [95% CI] = -2.98 [-3.52, -2.44]; p < .001). BTX-A also resulted in decreased masseter muscle intensity (μV) (MD [95% CI] = -44.43 [-71.33, -17.53]; p = .001) at 1 month and occlusal force (kg) at 3 months (MD [95% CI] = -30.29 [-48.22 to -12.37]; p = .0009). There was no significant difference in adverse events between BTX-A and placebo., Conclusions: BTX-A is a safe and effective treatment for reducing pain and improving temporomandibular muscle and joint function in muscular TMD patients. A bilateral dose of 60-100 U might be an optimal choice for treating muscular TMD pain., (© 2023 The Authors. Journal of Oral Rehabilitation published by John Wiley & Sons Ltd.)

Background: Flupentixol and melitracen are being investigated for their potential effectiveness in managing persistent idiopathic facial pain (PIFP), based on their mechanisms of action as dopamine receptor antagonists and noradrenaline/serotonin reuptake inhibitors, respectively. The efficacy and safety of flupentixol and melitracen (FM) tablets in treating PIFP were retrospectively analyzed at our hospital., Objectives: The aim of this study is to determine the effectiveness and safety of FM tablets in treating PIFP., Study Design: Retrospective unicentric cohort design., Setting: An academic university hospital., Methods: A retrospective analysis was conducted on a cohort comprising 128 patients with a definite diagnoses of PIFP who were treated with FM tablets (flupentixol 0.5 mg and melitracen 10 mg tablet, >= 4 tablets/d) from January 2022 through May 2023 at an academic university hospital. Baseline conditions were statistically described, and Numeric Rating Scale (NRS-11) scores of pain levels before and during treatment were collected. Pain relief rates were calculated. Differences in baseline characteristics between responsive and unresponsive patients were evaluated using statistical tests. Additionally, the side effects experienced during treatment were summarized., Results: Among the included 128 patients, 105 (82.0%) patients achieved pain relief (pain NRS-11 score reduction rate >= 50%). The median treatment onset time was 3 (1-7) days. NRS-11 scores of responsive patients at week 2, week 4, week 8, and week 12 were significantly lower than the baseline NRS-11 scores (P < 0.001), regardless of their Hamilton Depression Rating Scale score. Pain duration was the only factor that related to responsiveness (Wilcoxon rank sum test, P < 0.001; logistic regression, P = 0.001). No serious side effects that could affect patients' lives were observed during the first week of treatments., Limitations: Due to its retrospective nature, this study is limited by its lack of a randomized control. The lack of data on nonresponders who did not achieve significant pain relief hinders assessing overall change and the placebo effects'. Patients previously treated with antidepressants were excluded, making it hard to determine if FM tablets were a better treatment for PIFP. Additionally, the small sample size in a single center may be influenced by chance variation in pain relief., Conclusions: FM tablets showed its potential in the management of PIFP with considerable efficacy and safety. Early administration of FM tablets after a PIFP diagnosis may result in a high possibility of pain relief.

It has been demonstrated that the nucleus accumbens (NAc) plays an important role in modulation of nociception due to its extensive connections with different regions of the brain. In addition, this nucleus receives histaminergic projections from tuberomammillary nucleus. Considering the role of the central histaminergic system in nociception, the effect of histamine and its H 2 and H 3 receptors agonist and antagonist microinjections into the NAc on orofacial formalin nociception was investigated. In male Wistar rats, using stereotaxic surgery, two guide cannulas were bilaterally implanted into the right and left sides of the NAc. Diluted formalin solution (1.5%, 50 µl) injection into the vibrissa pad led to orofacial nociception. Immediately after injection, face rubbing was observed at 3-min blocks for 45 min. Orofacial formalin nociception was characterized by a biphasic nociceptive response (first phase: 0-3 min and second phase: 15-33 min). Microinjections of histamine (0.5 and 1 μg/site), dimaprit (1 μg/site, H 2 receptor agonist) and thioperamide (2 μg/site, H 3 receptor antagonist) attenuated both phases of formalin orofacial nociception. Prior microinjection of famotidine (2 μg/site) inhibited the antinociceptive effects of dimaprit (1 μg/site). Furthermore, comicroinjection of thioperamide (2 μg/site) and immepip (1 μg/site) prevented thioperamide (2 μg/site)-induced antinociception. Naloxone (2 μg/site) also prevented histamine, dimaprit- and thioperamide-induced antinociception. The results of this study demonstrate that at the level of the NAc, histamine and its H 2 and H 3 receptors are probably involved in the modulation of orofacial nociception with an opioid system-dependent mechanism., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

Background: The efficacy of botulinum toxin for management of myofascial pain disorder (MPD) remains controversial., Purpose: The purpose was to determine if the use of onabotulinumtoxinA (onabotA) in patients with MPD reduces pain, improves function, or enhances quality of life (QoL)., Study Design, Setting, and Sample: This is a multicenter, prospective, randomized, double-blinded, placebo-controlled clinical trial. Subjects with orofacial pain were screened for MPD as defined by the Diagnostic Criteria for Temporomandibular Disorders., Predictor Variable: The primary predictor variable was MPD treatment with random assignment to onabotA or placebo (saline)., Main Outcome Variable: The primary outcome variable was pain before treatment (T0) and at 1 month (T1) using a visual analog scale. Secondary outcome variables included pain at 2 months (T2) and 3 months (T3), maximal incisal opening (MIO), jaw function (jaw functional limitation scale), and QoL (Short Form 36) measured at T0, T1, T2, and T3., Covariates: Covariates included subject demographics, prior treatments, and temporomandibular joint signs/symptoms., Analyses: Descriptive and bivariate statistics included χ 2 test, Fisher's exact test, or t-test., Results: Seventy five subjects with a mean age of 37 (±11) and 35 (±12) years in the onabotA and placebo groups, respectively (P = .6). Females represented 32 (86%) and 29 (76%), respectively (P = .3). Mean visual analog scale pain score in the onabotA group was 58 (±15), 39 (±24), 38 (±23), and 38 (±20) at T0, T1, T2, and T3, respectively; and the placebo group was 54 (±14), 40 (±23), 34 (±20), and 36 (±22) at T0, T1, T2, and T3, respectively. There was no statistically significant difference in pain between groups at any time point (P = .36). There was no statistically significant difference between groups in MIO (P = .124), jaw function (P = .236), or QoL domains (P > .05) at any time point. Within-group improvement in pain was seen in both groups (P < .005). Within-group improvement in jaw function was seen in the onabotA (P = .007) and placebo (P = .005) groups. There was no within-group improvement in MIO or QoL with either group (P > .05)., Conclusions: OnabotA and saline (placebo) injections both decrease pain and improve jaw function in subjects with MPD., (Copyright © 2023 American Association of Oral and Maxillofacial Surgeons. Published by Elsevier Inc. All rights reserved.)

Carbamazepine (CBZ) represents the first-line treatment for trigeminal neuralgia, a condition of facial pain that affects mainly women. The chronic constriction of the infraorbital nerve (CCI-ION) is a widely used model to study this condition, but most studies do not include females. Thus, this study aimed to characterize sensory and affective changes in female rats after CCI-ION and compare the effect of CBZ in both sexes. Mechanical allodynia was assessed 15 days after CCI-ION surgery in rats treated with CBZ (10 and 30 mg/kg, i.p.) or vehicle, together with the open-field test. Independent groups were tested on the Conditioned Place Preference (CPP) paradigm and ultrasonic vocalization (USV) analysis. Blood samples were collected for dosage of the main CBZ metabolite. CBZ at 30 mg/kg impaired locomotion of CCI-ION male and sham and CCI-ION female rats and resulted in significantly higher plasma concentrations of 10-11-EPX-CBZ in the latter. Only male CCI-ION rats showed increased facial grooming which was significantly reduced by CBZ at 10 mg/kg. CBZ at 10 mg/kg significantly reduced mechanical allodynia and induced CPP only in female CCI-ION rats. Also, female CCI-ION showed reduced emission of appetitive USV but did not show anxiety-like behavior. In conclusion, male and female CCI-ION rats presented differences in the expression of the affective-motivational pain component and CBZ was more effective in females than males. Further studies using both sexes in trigeminal neuropathic pain models are warranted for a better understanding of potential differences in the pathophysiological mechanisms and efficacy of pharmacological treatments., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Descending control of nociception (DCN), a measure of efficiency of descending pain inhibition, can be assessed in animals by the combined application of test and conditioning noxious stimuli. Evidence from pre-clinical and clinical studies indicates that this mechanism of pain control may differ between sexes and might be impaired in many chronic pain states. However, little is known about sex differences in DCN efficiency in models of acute and chronic orofacial pain. Herein, we first evaluated DCN responses in male and female rats by the applying formalin into the upper lip or capsaicin into the forepaw as the conditioning stimulus, followed by mechanical stimulation (Randall-Selitto) of the hind paw as the test stimulus. The same protocol (i.e., capsaicin in the forepaw followed by mechanical stimulation of the hind paw) was evaluated in male and female rats on day 3 after intraoral incision and on day 15 and 30 after chronic constriction injury of the infraorbital nerve (CCI-ION). Additionally, we assessed the effect of the kappa opioid receptor (KOR) antagonist Norbinaltorphimine (nor-BNI) on DCN responses of female nerve-injured rats. This study shows that naïve female rats exhibit less efficient DCN compared to males. Postoperative pain did not alter DCN responses in female and male rats, but CCI-ION induced loss of DCN responses in females but not in males. Systemic pretreatment with nor-BNI prevented the loss of DCN induced by CCI-ION in female rats. The results reveal sex differences in DCN responses and female-specific impairment of DCN following chronic orofacial pain. Moreover, the findings suggest that, at least for females, blocking KOR could be a promising therapeutic approach to prevent maladaptive changes in chronic orofacial pain., Competing Interests: Declaration of Competing Interest The authors have no conflict of interest to declare., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Objective: Botulinum toxin type A (BoNT-A) provides lasting pain relief in patients with craniofacial pain conditions but the mechanisms of its antinociceptive activity remain unclear. Preclinical research revealed toxin axonal transport to the central afferent terminals, but it is unknown if its central effects involve transsynaptic traffic to the higher-order synapses. To answer this, we examined the contribution of central BoNT-A transcytosis to its action in experimental orofacial pain., Material and Methods: Male Wistar rats, 3-4 months old, were injected with BoNT-A (7 U/kg) unilaterally into the vibrissal pad. To investigate the possible contribution of toxin's transcytosis, BoNT-A-neutralizing antiserum (5 IU) was applied intracisternally. Antinocicepive BoNT-A action was assessed by duration of nocifensive behaviors and c-Fos activation in the trigeminal nucleus caudalis (TNC) following bilateral or unilateral formalin (2.5%) application into the vibrissal pad. Additionally, cleaved synaptosomal-associated protein of 25 kDa (cl-SNAP-25) immunoreactivity was analyzed in the bilateral TNC., Results: Unilaterally injected BoNT-A reduced the nocifensive behaviors and bilateral c-Fos activation induced by formalin, which was accompanied by the toxin's enzymatic activity on both sides of the TNC. BoNT-A antinociceptive or enzymatic activities were prevented by the specific neutralizing antitoxin. BoNT-A contralateral action occurred independently from ipsilateral side nociception or contralateral trigeminal nerve-mediated axonal traffic., Conclusion: Herein, we demonstrate that antinociceptive action of pericranially administered BoNT-A involves transsynaptic transport to second order synapses and contralateral trigeminal nociceptive nuclei. These results reveal more complex central toxin activity, necessary to explain its clinical effectiveness in the trigeminal region-related pain states., Competing Interests: Declaration of competing interest The authors declare no conflicts of interest., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Background: Temporomandibular disorders (TMD) are manifested by soreness in the jaw joint area and jaw muscles, clicks or creaks when opening or closing the mouth. All these symptoms can be disabling and occur during chewing and when the patient yawns or speaks. Several classes of drugs are used to treat symptoms. This review aims to assess which drug suits the different signs., Methods: Pubmed, Web of Science and Lilacs were systematically searched until 01/02/2023. Clinical trials were selected that dealt with drugs used in temporomandibular dysfunction RESULTS: Out of 830 papers, eight studies were included. The Meta-Analysis with Continuous Outcomes with Pre-Calculated Effect Sizes resulted in the rejection that there is intergroup variability (p.0.74)., Conclusions: Treatment of orofacial pain is still a significant challenge for dentistry. We can conclude that there is no drug of first choice in the treatment of temporomandibular pain. However, the clinician must distinguish the type of pain and the aetioloic cause of the pain so that the patient can be treated and managed pharmacologically., (© 2024. The Author(s).)

This study aimed to evaluate the effects of inhibitors of the fractalkine pathway in hyperalgesia in inflammatory and neuropathic orofacial pain in male rats and the morphological changes in microglia and satellite glial cells (SGCs). Rats were submitted to zymosan-induced arthritis of the temporomandibular joint or infraorbital nerve constriction, and treated intrathecally with a P 2 X 7 antagonist, a cathepsin S inhibitor or a p-38 mitogen-activated protein kinase (MAPK) inhibitor. Mechanical hyperalgesia was evaluated 4 and 6 h following arthritis induction or 7 and 14 days following nerve ligation. The expression of the receptor CX 3 CR 1 , phospho-p-38 MAPK, ionized calcium-binding adapter molecule-1 (Iba-1), and glutamine synthetase and the morphological changes in microglia and SGCs were evaluated by confocal microscopy. In both inflammatory and neuropathic models, untreated animals presented a higher expression of CX 3 CR 1 and developed hyperalgesia and up-regulation of phospho-p-38 MAPK, which was prevented by all drugs (p < .05). The number of microglial processes endpoints and the total branch length were lower in the untreated animals, but the overall immunolabeling of Iba-1 was altered only in neuropathic rats (p < .05). The mean area of SGCs per neuron was significantly altered only in the inflammatory model (p < .05). All morphological alterations were reverted by modulating the fractalkine pathway (p < .05). In conclusion, the blockage of the fractalkine pathway seemed to be a possible therapeutic strategy for inflammatory and neuropathic orofacial pain, reducing mechanical hyperalgesia by impairing the phosphorylation of p-38 MAPK and reverting morphological alterations in microglia and SGCs., (© 2023 Wiley Periodicals LLC.)

Oral ulcerative mucositis (OUM) induces severe pain, leading to a low quality of life. Linalool odor exposure has recently been reported to suppress inflammatory pain in the hind paws. However, the analgesic effect of linalool odor on orofacial pain remains unclear. In this study, we examined the mechanism underlying the analgesic effect of linalool odor on oral pain caused by OUM using nocifensive behavioral and immunohistochemical analyses in rats. OUM was developed by treating the labial fornix region of the inferior incisors with acetic acid. Linalool at 1% was exposed for 5 min at 30 min before nocifensive behavioral measurements. OUM induced spontaneous pain and mechanical allodynia, which were suppressed by the linalool odor. Mechanical allodynia in the hind paw following the injection of complete Freund's adjuvant was also suppressed by linalool odor. Application of lidocaine to the olfactory bulb attenuated the inhibition of spontaneous pain and hyperactivation of trigeminal spinal nucleus caudalis neurons in OUM model rats. Linalool odor exposure-induced neuronal activation in the locus coeruleus (LC) of OUM model rats was decreased by lidocaine application to the olfactory bulb. The decrease in neuronal activation in the LC was attenuated by the administration of orexin 1 receptor (OX-1) antagonist to the LC. These results suggest that linalool odor stimulation through the olfactory pathway activates LC neurons via OX-1 signaling, leading to the suppression of OUM-induced oral pain., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

It is important for Oral and Maxillofacial Surgeons to be familiar with the various neuropathic facial pain disorders and their appropriate treatments. Neuropathic pain can be characterized by the nature of the pain experienced by patients; episodic or continuous. Episodic neuropathic pain disorders include trigeminal neuralgia and glossopharyngeal neuralgia. Continuous neuropathic pain disorders compromise of disorders such as idiopathic trigeminal neuralgia, postherpetic neuralgia, central post-stroke pain, and complex regional pain syndrome. Various forms of pharmacologic management exist for these neuropathic pain disorders., (Copyright © 2023 Elsevier Inc. All rights reserved.)

Cerebral venous thrombosis is a rare condition, with identified and described risk factors mainly associated with prothrombotic states, with a wide variety of symptomatology based on the site affected, the most common being intracranial hypertensive syndrome, focal or encephalopathy. Cortical veins of the superficial system are among the least frequently affected veins. The following describes a case of painful facial symptoms progressing to a focal syndrome associated with a history of chronic oral contraceptive use, with thrombosis of vein of Trolard detected and successfully treated with oral anticoagulants., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

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 ( p < 0.001) in both groups to 3.1 ± 2.3 (type 1 TN) and 3.5 ± 2.3 (type 2 TN) at the 1-month follow-up and to 3.2 ± 2.5 (type 1 TN) and 3.6 ± 2.5 (type 2 TN) at the 3-month follow-up. 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 (r 0.8, p < 0.001)., 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: Ketamine has garnered increased interest for its promising applications in chronic pain treatment, particularly in cases where conventional therapies have proven insufficient. Nevertheless, despite its potential advantages, ketamine remains classified as a third-line medication for pain management. While there are well-documented reactions to ketamine such as hypertension and tachycardia, not much is known about its relationship to cortisol. In this case report, we explicate the administration of ketamine in a patient presenting with atypical facial pain, examining its multifaceted effects on cortisol levels and concurrent pain management., Case Presentation: A patient with a history of Cushing's disease underwent multiple resections of a pituitary tumor. Afterwards, the patient began experiencing a burning-like pain on the left side of the face. The discomfort was initially treated with a variety of neuromodulatory and anti-inflammatory medications, which caused intolerable side effects and were not effective for pain. As a final recourse, we initiated a regimen of oral compounded ketamine at 5-10 mg three times daily as needed. The patient exhibited marked amelioration in their pain symptoms; however, there was an elevation in their baseline cortisol. In view of the potential risk of inducing Cushing's syndrome, the administration of daily ketamine was discontinued., Conclusion: While ketamine is primarily known to control pain through the antagonization of N-methyl-D-aspartate receptors, its effects on cortisol may also contribute to its analgesic properties. Physicians should be aware of the potential for these interactions, particularly when treating patients with a predisposition to hormonal imbalances., Competing Interests: Competing interests: None declared., (© American Society of Regional Anesthesia & Pain Medicine 2023. No commercial re-use. See rights and permissions. Published by BMJ.)

Purpose: The present study investigates the efficacy of Photobiomodulation (PBM) and Vitamin B Complex (VBC) to relieve pain, both in separately and combined (PBM and VBC)., Methods: Rats with chronic constriction injury of the right infraorbital nerve (CCI-IoN) or Sham surgery were used. PBM was administered at a wavelength of 904 nm and energy density of 6.23 J/cm 2 and VBC (containing B1, B6 and B12) subcutaneously, both separately and combined. Behavioral tests were performed to assess mechanical and thermal hypersensitivity before and after CCI and after PBM, VBC, or PBM + VBC. The expression of inflammatory proteins in the trigeminal ganglion and the immunohistochemical alterations of Periaqueductal Gray (PAG) astrocytes and microglia were examined following CCI and treatments., Results: All testeds treatments reversed the painful behavior. The decrease in pain was accompanied by a decrease of Glial Fibrillary Acidic Protein (GFAP), a specific astrocytic marker, and Ionized calcium-binding adaptor molecule 1 (Iba-1), a marker of microglia, and decreased expression of Transient Receptor Potential Vanilloid 1 (TRPV1), Substance P, and Calcitonin Gene-Related Peptide (CGRP) induced by CCI-IoN in PAG and Trigeminal ganglion. Furthermore, both treatments showed a higher expression of Cannabinoid-type 1 (CB1) receptor in the trigeminal ganglion compared to CCI-IoN rats. Our results show that no difference was observed between groups., Conclusion: We showed that PBM or VBC regulates neuroinflammation and reduces inflammatory protein expression. However, the combination of PBM and VBC did not enhance the effectiveness of both therapies alone., (© 2023. The Author(s), under exclusive licence to European Photochemistry Association, European Society for Photobiology.)

Background: The aim of this paper is to provide a systematic review of the literature regarding the clinical use of botulinum toxin (BTX) to treat various orofacial neuropathic pain disorders (NP)., Methods: A comprehensive literature search was conducted using Medline, Web of Science, and the Cochrane Library databases. Only randomized clinical trials (RCT) published between 2003 and the end of June 2023, investigating the use of BTX to treat NP, were selected. PICO guidelines were used to select and tabulate the articles., Results: A total of 6 RCTs were selected. Five articles used BTX injections to treat classical trigeminal neuralgia, and one to treat post-herpetic neuralgia. A total of 795 patients received BTX injections. The selected studies utilised different doses and methods of injections and doses. All the selected studies concluded superiority of BTX injections over placebo for reducing pain levels, and 5 out 6 of them highlighted an improvement in the patient's quality of life. Most of the studies reported transient and mild side effects., Conclusion: There is evidence of the efficacy of BTX injections in orofacial pain management. However, improved study protocols are required to provide direction for the clinical use of BTX to treat various orofacial neuropathic pain disorders.

Orofacial pain is a category of complex disorders, including musculoskeletal, neuropathic and neurovascular disorders, that greatly affect the quality of life of the patient. These disorders are within the fields of dentistry and medicine and management can be challenging, requiring a referral to an orofacial pain specialist, essential for adequate evaluation, diagnosis, and care. Management is specific to the diagnosis and a treatment plan is developed with diverse pharmacological and non-pharmacological modalities. The pharmacological management of orofacial pain encompasses a vast array of medication classes and approaches. This includes anti-inflammatory drugs, muscle relaxants, anticonvulsants, antidepressants, and anesthetics. In addition, as adjunct therapy, different injections can be integrated into the management plan depending on the diagnosis and needs. These include trigger point injections, temporomandibular joint (TMJ) injections, and neurotoxin injections with botulinum toxin and nerve blocks. Multidisciplinary management is key for optimal care. New and safer therapeutic targets exclusively for the management of orofacial pain disorders are needed to offer better care for this patient population., (© 2023. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Orofacial pain represents a multidisciplinary biomedical challenge involving basic and clinical research for which no satisfactory solution has been found. In this regard, trigeminal pain is described as one of the worst pains perceived, leaving the patient with no hope for the future. The aim of this review is to evaluate the latest discoveries on the involvement of neurotrophins in orofacial nociception, describing their role and expression in peripheral tissues, trigeminal ganglion, and trigeminal nucleus considering their double nature as "supporters" of the nervous system and as "promoters" of nociceptive transmission. In order to scan recent literature (last ten years), three independent researchers referred to databases PubMed, Embase, Google Scholar, Scopus, and Web of Science to find original research articles and clinical trials. The researchers selected 33 papers: 29 original research articles and 4 clinical trials. The results obtained by the screening of the selected articles show an interesting trend, in which the precise modulation of neurotrophin signaling could switch neurotrophins from being a "promoter" of pain to their beneficial neurotrophic role of supporting the nerves in their recovery, especially when a structural alteration is present, as in neuropathic pain. In conclusion, neurotrophins could be interesting targets for orofacial pain modulation but more studies are necessary to clarify their role for future application in clinical practice.

Orofacial pain has significant psychological and physiological effects. Citral (3,7-dimethyl-2,6-octadienal) is the main component of Cymbopogon citratus (DC) Stapf, an herb with analgesic properties. Although citral has been considered a potent analgesic, its putative effects on orofacial pain are still unknown., Objective: The objective of this study is to test the hypothesis that citral modulates orofacial pain using two experimental models: formalin-induced hyperalgesia in the vibrissae area and during persistent temporomandibular hypernociception using Complete Freund's Adjuvant - CFA test., Methods: For the formalin test, citral (100 and 300 mg/kg, oral gavage) or its vehicle (Tween 80, 1 %) were given 1 h before the formalin injection subcutaneously (sc) into the vibrissae area. For the CFA model, we analyzed the prophylactic (100 mg/kg of citral by oral gavage, 1 h before CFA injection) and the chronic therapeutic (citral treatment 1-hour post-CFA injection and daily post-CFA injection) effect of citral or its vehicle in animals treated with CFA for 8 days., Results: Citral caused a decrease in formalin-induced local inflammation and the time spent performing nociceptive behavior in a dose-dependent fashion. Similarly, prophylactic and therapeutic citral treatment decreased the CFA-induced persistent mechanical hypernociception in the temporomandibular area., Conclusion: Our data strengthen the notion that citral plays a powerful antinociceptive role by decreasing orofacial hypernociception in formalin and CFA models., Competing Interests: Declaration of Competing Interest The authors have not disclosed any conflicts of interest., (Copyright © 2023 Elsevier Ltd. All rights reserved.)

Objective: To investigate the efficacy and safety of injecting onabotulinum toxin A (BTA) towards the sphenopalatine ganglion (SPG) using the MultiGuide® in patients with persistent idiopathic facial pain (PIFP)., Methods: This cross-over, exploratory study compared the injection of 25 units BTA versus placebo in patients who met modified ICDH-3 criteria for PIFP. Daily pain diaries were registered for a 4-week baseline, a 12-week follow-up after each injection, and an 8-week conceptual washout period in between. The primary efficacy endpoint was the change from baseline to weeks 5-8 in average pain intensity using a numeric rating scale. Adverse events were recorded., Results: Of 30 patients who were randomized to treatment, 29 were evaluable. In weeks 5-8, there was no statistically significant difference in average pain intensity between BTA versus placebo (0.00; 95% CI = -0.57 to 0.57) ( P =  0.996). Following both BTA and placebo injections, five participants reported at least a 30% reduction in average pain during weeks 5-8 ( P  = 1.000). No serious adverse events were reported. Post-hoc analyses indicated a possible carry-over effect., Conclusions: Injection of BTA toward the SPG with the MultiGuide® did not appear to provide a reduction in pain reduction at 5-8 weeks, although this finding may be influenced by a carry-over effect. The injection appears to otherwise be safe and well-tolerated in patients with PIFP. Trial Registration: The study protocol is registered in ClinicalTrial.gov (NCT03462290) and EUDRACT (number: 2017-002518-30).

Despite advancements in dental pain management, one of the most common reasons for emergency dental care is orofacial pain. Our study aimed to determine the effects of non-psychoactive Cannabis constituents in the treatment of dental pain and related inflammation. We tested the therapeutic potential of two non-psychoactive Cannabis constituents, cannabidiol (CBD) and β-caryophyllene (β-CP), in a rodent model of orofacial pain associated with pulp exposure. Sham or left mandibular molar pulp exposures were performed on Sprague Dawley rats treated with either vehicle, the phytocannabinoid CBD (5 mg/kg i.p.) or the sesquiterpene β-CP (30 mg/kg i.p.) administered 1 h pre-exposure and on days 1, 3, 7, and 10 post-exposure. Orofacial mechanical allodynia was evaluated at baseline and post-pulp exposure. Trigeminal ganglia were harvested for histological evaluation at day 15. Pulp exposure was associated with significant orofacial sensitivity and neuroinflammation in the ipsilateral orofacial region and trigeminal ganglion. β-CP but not CBD produced a significant reduction in orofacial sensitivity. β-CP also significantly reduced the expression of the inflammatory markers AIF and CCL2, while CBD only decreased AIF expression. These data represent the first preclinical evidence that non-psychoactive cannabinoid-based pharmacotherapy may provide a therapeutic benefit for the treatment of orofacial pain associated with pulp exposure.

Resolvin D5 (RvD5) is a specialized pro-resolving lipid mediator with potent anti-inflammatory and analgesic properties. Orofacial pain conditions, especially those that are chronic, present clinical challenges in terms of pharmacological management. Thus, new therapeutic options are clearly warranted. Herein, we investigated the antinociceptive effect of RvD5 in the chronic constriction injury of the infraorbital nerve (CCI-ION) model and in the orofacial formalin test in female and male Wistar rats. Our results indicated that repeated subarachnoid medullary injections of RvD5 at 10 ng resulted in a significant reduction of heat and mechanical hyperalgesia induced by the CCI-ION in male and female rats, but males were more sensitive to RvD5 effects. In addition, after CCI-ION, interleukin-6 (IL-6) level was increased in the trigeminal nucleus caudalis of male, but not female rats, which was reduced by RvD5 repeated treatment. No changes in the levels of IL-1β were found. Minocycline blocked the effect of RvD5 in male rats but failed to affect RvD5 antinociceptive effect in females. Moreover, a single medullary injection of RvD5 caused a significant reduction of formalin-induced facial grooming, in phases I and II of the test, but only in male rats. This study demonstrated for the first time the analgesic effect of RvD5 in trigeminal pain models, and corroborated previous evidence of sex dichotomy, with a greater effect in males. This article presents a translational potential of RvD5 for targeted therapies aiming at the control of acute and chronic trigeminal pain, but further studies are needed to elucidate its sex-related mechanisms. PERSPECTIVE: This study demonstrated that RvD5 may provide the benefits for trigeminal neuropathic pain treatment in male and female rats, but its effect on inflammatory orofacial pain seems to be restricted only to males. Also, it provided the evidence for sex dichotomy in the mechanisms related to the antinociceptive effect of RvD5., (Copyright © 2022 United States Association for the Study of Pain, Inc. Published by Elsevier Inc. All rights reserved.)

Botulinum toxin type A (BTA) is applied in muscle hyperactivity disorders and injected into affected muscles, producing deep and persistent muscle relaxation. Several multidisciplinary groups investigated the treatment of temporomandibular disorders for several years, and there is currently some data on the beneficial effects of BTA in specific cases of chronic masticatory myalgia. Percutaneous needle electrolysis (PNE), which applies a low-intensity galvanic current to promote tissue regeneration, has been shown to be effective in reducing pain and improving masticatory function. The purpose of this study was to investigate the efficacy and safety of BTA and to assess whether its application in patients with localized masticatory myalgia can significantly reduce pain and improve function compared to a group treated with PNE. Fifty-two patients with long-term refractory masticatory myalgia were randomly assigned to two groups. The BTA group ( n = 26) received a bilateral botulinum toxin injection and the PNE group ( n = 26) received percutaneous electrolysis. The dose of BTA injected was 100 units distributed among the main primary masticatory muscles, and PNE was administered at 0.5 mA/3 s/3 consecutive times in a single session. Patient assessments were performed prior to treatment and one, two, and three months after treatment. The results revealed good therapeutic response in both groups. In the long term, both BTA and PNE showed high efficacy and safety in reducing pain and improving muscle function for the treatment of chronic masticatory myalgia. This improvement was sustained over a three-month period in both groups. Therefore, the use of BTA and PNE could be considered a valid and safe therapeutic alternative among the available options to treat refractory and localized masticatory myalgia when a better therapeutic response is expected as it demonstrated high efficacy.

Auriculotemporal neuralgia is a rare pain disorder in which anesthetic nerve blockade is usually effective but not always resolutive. Botulinum toxin type A has proven to be effective in treating neuropathic pain, and patients with auriculotemporal neuralgia could also benefit from this treatment. We described nine patients with auriculotemporal neuralgia treated with botulinum toxin type A in the territory of auriculotemporal nerve innervation. We compared the basal NRS and Penn facial pain scale scores with those obtained 1 month after BoNT/A injections. Both Penn facial pain scale (96.67 ± 24.61 vs. 45.11 ± 36.70, p 0.004; mean reduction 52.57 ± 36.50) and NRS scores (8.11 ± 1.27 vs. 4.22 ± 2.95, p 0.009; mean reduction 3.89 ± 2.52) improved significantly at one month after treatment. The mean duration of the effect of BoNT/A on pain was 95.00 ± 53.03 days and no adverse effects were reported.

Introduction: Chronic pain can trigger both physical and mental health complications. During the COVID-19 pandemic, patients with chronic diseases have had reduced access to some medications., Objective: To determine the pharmacological management of patients with chronic pain and its continuity during the COVID-19 pandemic., Methods: This was a retrospective longitudinal study of the continuity of analgesic use in patients with chronic pain between September 1, 2019 and February 28, 2021 based on a drug dispensing database. Survival analysis was performed until the discontinuation of chronic analgesics., Results: A total of 12,701 patients who were being treated for chronic pain were identified. Their median age was 70.3 years, and 74.4% were women. The pain of rheumatological origin was the most frequent etiology (46.1%); the most used medications were nonopioid analgesics (78.9%), pain modulators (24.8%) and opioid analgesics (23.3%). A total of 76.1% of the patients experienced interruptions in their management during the study period. The median time to the first interruption of treatment was 5.0 months (95% CI: 4.8-5.2). Those who were treated for oncological pain experienced a greater number of interruptions in their management., Conclusions: The pharmacological management of patients with chronic pain is heterogeneous, and this real-world study showed that a high proportion of patients experienced an interruption of pain management during the 12 months following the onset of the COVID-19 pandemic., (© 2022 World Institute of Pain.)

Mast cell degranulation impacts the development of pain and inflammation during tissue injury. We investigated the antinociceptive effect of a combination of cromoglycate and magnesium in the orofacial model of pain and the histological profile of the effect of magnesium in orofacial pain. In male Wistar rats, formalin (1.5%, 100 µL) was injected subcutaneously into the right upper lip of rats after cromoglycate and/or magnesium. Pain was measured as the total time spent on pain-related behavior. Toluidine blue staining was used to visualize mast cells under the light microscope. In the formalin test, in phase 1, magnesium antagonized the antinociceptive effect of cromoglycate, while in phase 2, it potentiated or inhibited its effect. Magnesium significantly reduced mast cell degranulation in the acute phase by about 23% and in the second phase by about 40%. Pearson's coefficient did not show a significant correlation between mast cell degranulation and pain under treatment with magnesium. The cromoglycate-magnesium sulfate combination may prevent the development of inflammatory orofacial pain. The effect of a combination of cromoglycate-magnesium sulfate depends on the nature of the pain and the individual effects of the drugs. Magnesium reduced orofacial inflammation in the periphery, and this effect did not significantly contribute to its analgesic effect.

Temporomandibular disorders (TMDs) occur frequently within the general population and are the most common non-dental cause of orofacial pain. Temporomandibular joint osteoarthritis (TMJ OA) is a degenerative joint disease (DJD). There have been several different methods of treatment of TMJ OA listed, including pharmacotherapy among others. Due to its anti-aging, antioxidative, bacteriostatic, anti-inflammatory, immuno-stimulating, pro-anabolic and anti-catabolic properties, oral glucosamine seems to be a potentially very effective agent in the treatment of TMJ OA. The aim of this review was to critically assess the efficacy of oral glucosamine in the treatment of TMJ OA on the basis of the literature. PubMed and Scopus databases were analyzed with the keywords: (temporomandibular joints) AND ((disorders) OR (osteoarthritis)) AND (treatment) AND (glucosamine). After the screening of 50 results, eight studies have been included in this review. Oral glucosamine is one of the symptomatic slow-acting drugs for osteoarthritis. There is not enough scientific evidence to unambiguously confirm the clinical effectiveness of glucosamine supplements in the treatment of TMJ OA on the basis of the literature. The most important aspect affecting the clinical efficacy of oral glucosamine in the treatment of TMJ OA was the total administration time. Administration of oral glucosamine for a longer period of time, i.e., 3 months, led to a significant reduction in TMJ pain and a significant increase in maximum mouth opening. It also resulted in long-term anti-inflammatory effects within the TMJs. Further long-term, randomized, double-blind studies, with a unified methodology, ought to be performed to draw the general recommendations for the use of oral glucosamine in the treatment of TMJ OA.

Treatment of chronic orofacial pain remains a major therapeutic challenge despite available medications. Melanocortins have been implicated in pathologic pain. Intrathecal administration of MC4R antagonists has been shown to alleviate neuropathic pain (NP) in male rats. However, intrathecal delivery is very invasive and requires surgeon's intervention. Intra-nasal rout offers a non-invasive drug delivery method that can be self-administered making it very attractive clinically. In this study, we investigated the effects of intra-nasally delivered MC4R antagonist (HS014) on trigeminal neuropathic pain (TNP) in male and female rats. We also measured the MC4R protein levels in the trigeminal ganglia (TG) and infraorbital nerve (ION) of rats. We used ION chronic constriction injury (ION-CCI) to induce TNP in rats. We used von Frey and pinprick assays to measure the development of hypersensitivity in the face following ION-CCI. At 22 days post-ION-CCI, we delivered HS014 intra-nasally to measure its effects on TNP in rats. We used enzyme linked immunosorbent assay to measure MC4R protein levels in the TG and ION. ION-CCI resulted in a significant increase of MC4R protein levels in the ipsilateral TG and ION of male and female rats. Intra-nasal delivered HS014 resulted in a significant reduction of ION-CCI induced hypersensitivity in male and female rats. These results demonstrate that intranasal delivery of MC4R antagonist alleviated TNP in male and female rats and suggest that such treatment could be beneficial therapeutically for individuals with chronic NP., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 Elsevier B.V. All rights reserved.)

Attention-deficit/hyperactivity disorder (ADHD) has been reported to be associated with primary chronic pain syndromes, such as fibromyalgia, migraine, and chronic low back pain. Although idiopathic orofacial pain (IOP) is classified as burning mouth syndrome or persistent idiopathic facial or dentoalveolar pain and as a primary chronic pain, the association between IOP and ADHD has not been investigated. This retrospective cohort study investigated the severity of ADHD symptoms measured using the ADHD scale and the effects of treatment using ADHD drugs and the dopamine system stabilizer aripiprazole. The participants were 25 consecutive patients with refractory IOP referred to a psychiatrist and diagnosed with coexisting ADHD according to the Diagnostic and Statistical Manual of Mental Disorders-5. The ADHD scale scores were higher in patients with intractable IOP than those in the general population. Pharmacotherapy used in this study led to clinically significant improvements in pain, anxiety/depression, and pain catastrophizing. Intractable IOP and ADHD were shown to be associated. In the future, screening and pharmacotherapy for ADHD should be considered in the treatment of intractable IOP., (© 2023. The Author(s).)

Background: Nociceptive and inflammatory orofacial pain is highly prevalent in the population, which justifies the search for safer analgesics. There is increasing evidence of the analgesic and anxiolytic potential of Lavandula angustifolia essential oil (LAV EO), which may represent, when administered through inhalation, may represent a safer alternative for pain treatment., Objective: to evaluate whether LAV EO has antinociceptive effect in the formalin test, and anti-hyperalgesic and anxiolytic-like effects in rats subjected to a model of orofacial postoperative pain., Methodology: Female Wistar rats were exposed to LAV EO (5%) by inhalation for 30 minutes. After exposure, animals were injected with formalin (2.5%, 50 μL) or saline into the hind paw or upper lip and the number of flinches or facial grooming time, respectively, were evaluated. Likewise, on day 3 after intraoral mucosa incision, the animals were exposed to LAV EO and facial mechanical, and heat hyperalgesia were assessed. The influence of LAV EO inhalation on anxiety-like behavior was assessed in operated rats by testing them on the open field (OF) and elevated plus maze (EPM)., Results: LAV EO reduced the phase II of the paw formalin test and both phases of the orofacial formalin test. On day three post-incision, LAV EO reduced heat and mechanical hyperalgesia, from 30 minutes up to three hours, and reduced the anxiety-like behavior in operated rats without causing locomotor deficit., Conclusion: LAV EO inhalation results in antinociceptive and anxiolytic-like effects in orofacial pain models, which encourages further studies on LAV EO indications and effectiveness on orofacial pain conditions.

Painmanagement after oral surgeries is essential to enhance recovery, reduce negative outcomes and improve the experience of the patient. Naltrexone (NTX) is a non-selective opioid receptor antagonist that has been shown to modulate neuro-inflammation when employed in low to ultra-low doses. In addition, ultra-low dose naltrexone (ULDN) has been shown to potentiate opioids' analgesia and to have opioid-sparing effects. Herein it was investigated the effect of ULDN in a model of postoperative orofacial pain in rats, and it was tested the hypothesis that blockade of TLR4-signalling pathway contributes to its antinociceptive effect. Systemic NTX reduced heat hyperalgesia in female rats and heat and mechanical hyperalgesia in male rats after incision surgery. Combined treatment with NTX and morphine, both at ineffective doses, resulted in a significant reduction of heat hyperalgesia in male rats. NTX injection at the incision site failed to change heat hyperalgesia, but injection at the trigeminal ganglion (TG) or subnucleus caudalis (Sp5C) caused a significant reduction in heat hyperalgesia. At these sites, blockade of TLR4 impeded NTX effect. Lipopolysaccharide (LPS) injection in the intraoral mucosa resulted in facial heat hyperalgesia an increase in IL-1β levels in the TG, which were reduced by systemic NTX. Stimulation of macrophages with LPS resulted in increase of nitric oxide, IL-1β and CXCL-2 levels which were reduced by NTX. Altogether, these results provide evidence for an antinociceptive effect of ULDN in postoperative orofacial pain and suggest that blockade of TLR4 and downstream signaling pathway contribute to its effect., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Background & Objectives: Intranasal midazolam-fentanyl is commonly used as pre-medication in paediatric patients, but there is a risk of respiratory depression with this combination. Dexmedetomidine is a drug that preserves respiratory function. The objective of this study was to compare the efficacy of intranasal midazolam-fentanyl and dexmedetomidine-fentanyl in paediatric patients undergoing elective surgeries., Methods: Hundred children in the age group of 3-8 yr of American Society of Anaesthesiologists physical status grade 1 were randomized into two groups- group A received intranasal midazolam (0.2 mg/kg)-fentanyl (2 μg/kg) and group B received intranasal dexmedetomidine (1 μg/kg)-fentanyl (2 μg/kg) 20 min before induction of general anaesthesia. Heart rate and SpO 2 were monitored. Sedation score, parental separation and response to intravenous cannulation were seen after 20 min. Children were monitored for 2 h for post-operative analgesia by Oucher's Facial Pain Scale., Results: Sedation scores were satisfactory in both groups, although children in group A were more sedated than in group B. Parental separation and response to intravenous cannulation were comparable in both the groups. The two groups were also haemodynamically comparable intraoperatively. Post-operative heart rate was also comparable at all-time intervals in both the groups except for heart rate at 100 and 120 min which were more in group A. Group A experienced more post-operative pain as assessed by Oucher's Facial Pain Scale as compared to group B. Children receiving intranasal dexmedetomidine-fentanyl had better post-operative analgesia as compared to those who received intranasal midazolam-fentanyl., Interpretation & Conclusions: Both intranasal midazolam with fentanyl and intranasal dexmedetomidine with fentanyl provided satisfactory sedation. Both groups were comparable in separation reaction and response to intravenous cannulation with better post-operative analgesia in children receiving intranasal dexmedetomidine-fentanyl.

The management of orofacial pain to alleviate the quality of life of affected patients is becoming increasingly challenging for scientific research and healthcare professionals. From this perspective, in addition to conventional therapies, new alternatives are being sought, increasingly looking at the use of both natural and synthetic products. Cannabis sativa L. represents an interesting source of bioactive compounds, including non-psychoactive cannabinoids, flavonoids, and terpenes, many of which are effective in improving pain intensity. Here, we aim to analyze the possible mechanisms of action of the bioactive natural and synthetic hemp-derived compounds responsible for the modulatory effects on pain-related pathways. The ability of these compounds to act on multiple mechanisms through a synergistic effect, reducing both the release of inflammatory mediators and regulating the response of the endocannabinoid system, makes them interesting agents for alternative formulations to be used in orofacial pain.