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Background/purpose Burning mouth syndrome (BMS) is a chronic condition presenting as intraoral burning or dysesthesia, with a high preponderance in menopausal women. This study aimed to examine the association between somatosensory dysfunction and BMS in premenopausal, early postmenopausal, and late postmenopausal patients, using a standardized Quantitative Sensory Testing (QST) protocol, and to determine the predictive value of thermal or mechanical perception by QST for detecting BMS. Materials and methods An observational case–control study was performed with 36 female participants with BMS (12 premenopausal, 10 early postmenopausal, and 14 late postmenopausal) and 42 age- and sex-matched healthy volunteers (21 premenopausal, 10 early postmenopausal, and 11 late postmenopausal). Neurophysiological tests were used to evaluate somatosensory dysfunction at the tongue. Results Z-score in the late postmenopausal BMS group revealed a gain of function for the cold pain threshold and heat pain threshold (Z = 2.08 and 3.38, respectively). In the multiple regression analysis with the Visual Analog Scale as the dependent variable, the vibration detection threshold predicted the severity of burning mouth sensation in the premenopausal group. Conclusion Late postmenopausal patients with BMS showed an increased response of the tongue to noxious thermal stimuli. This supports the theory that changes in sex hormones may affect trigeminal somatosensory function, particularly during the late postmenopausal stage in patients with BMS.

Exercise is a known trigger of the inhibitory pain modulation system and its analgesic effect is termed exercise-induced hypoalgesia (EIH). Previous studies have demonstrated that rats with deficient analgesic response following exercise develop more significant hypersensitivity following nerve injury compared to rats with substantial analgesic response following exercise.A rat model of EIH as an indicator of the pain inhibitory system's efficiency was used to explore the association between EIH profiles and the effect of pharmacotherapy on rat's neuropathic pain.EIH profiles were assessed by evaluating paw responses to mechanical stimuli before and after exercise on a rotating rod. Rats with a reduction of ≤33% in responses were classified as low EIH and those with ≥67% as high EIH. Low and high EIH rats underwent sciatic nerve chronic constriction injury (CCI). Paw responses to mechanical stimuli were measured at baseline, following CCI, and after treatment with diclofenac, duloxetine or pregabalin. In a different group of low and high EIH rats, EIH was measured before and following treatment with the same medications.Low EIH rats developed more significant hypersensitivity following CCI. Duloxetine and pregabalin successfully reduced hypersensitivity, although significantly more so in low EIH rats. Diclofenac had limited effects, and only on low EIH rats. Four days of duloxetine administration transformed low EIH rats' profiles to high EIH.The findings of this study suggest that EIH profiles in rats can not only predict the development of hypersensitivity following injury but may also support targeted pharmacological treatment.Exercise is a known trigger of the inhibitory pain modulation. Rats with deficient analgesic response following exercise develop more significant hypersensitivity following nerve injury. Pain modulation profiles in rats can also support targeted pharmacological treatment; rats with deficient analgesic response following exercise benefit more from treatment with duloxetine and gabapentin. Treatment with duloxetine can improve pain modulation profile.

Aims To investigate the role of exercise-induced hypoalgesia (EIH) in the development of neuropathic pain (NP) following infraorbital nerve (ION) injury and to explore possible underlying mechanisms defining the differences between rats with high and low EIH. Methods EIH was evaluated by measuring the percentage of withdrawal responses to a series of 30 mechanical stimuli applied to the hind paw before and after 180 seconds of exercise on a rotating rod. The rats were assigned to low- and high-EIH groups based on reduction in the percent of withdrawal responses following exercise. NP was induced in high- and low-EIH rats via ION constriction injury. Rats were tested with graded nylon monofilaments to establish the withdrawal threshold. Increasingly stiff monofilaments were applied to the ION territory until there was a clear withdrawal by the rat. This was repeated a total of three times. A decreased withdrawal threshold indicates allodynia. Testing was performed at baseline and at 3, 10, and 17 days following the injury. On day 17 postinjury, IONs were harvested for the assessment of interleukin (IL)-6, IL-1β, and IL-10 levels. Samples from high-EIH and low-EIH surgically naive rats served as control for the cytokines study. In this second part of the study, the effects of cannabinoid 1 (CB1) and cannabinoid 2 (CB2) antagonists and naltrexone on EIH profiles and on the withdrawal thresholds to mechanical stimulation were measured. EIH and withdrawal thresholds in high- and low-EIH rats were measured before and after administration of antagonists. Results Low-EIH rats developed significantly more pronounced allodynia in the ION territory following injury compared to high-EIH rats. At 17 days postinjury, ION IL-1β levels were higher in low-EIH rats, and IL-10 levels were higher in high-EIH rats. CB1 antagonist blocked the analgesic effect induced by exercise in high- but not in low-EIH rats. The CB2 antagonist had no significant effect on high- or low-EIH rats. Naltrexone blocked the effects of EIH in both high- and low-EIH rats. Exercise induced a significant analgesic effect in high-EIH but not in low-EIH rats. CB1 or CB2 antagonist administration had no effect on pre-exercise responses to mechanical stimulation, while naltrexone administration resulted in significant allodynia in both low- and high-EIH rats. Conclusion This study demonstrated substantial differences between rats with high and low EIH. The results suggest that following ION injury, high-EIH rats may have a more prominent or activated endocannabinoids system and that their inflammatory response is moderated, with higher levels of IL-10 and lower levels of IL-1β.

This cross-sectional study compares prescribing patterns of opioid and nonopioid analgesics and patients’ dental pain outcomes before vs after implementation of an opioid reduction initiative at a single dental clinic.

ObjectiveTo evaluate long-term changes in pain management strategies and assess the outcomes of opioids and non-opioid combination analgesics after dental extractions.MethodsThis is a cross-sectional study of patients who received dental extractions and analgesic prescriptions in a large dental urgent care center in two 12-month periods: January 2012 to December 2012 (Year-2012) and March 2021 to February 2022 (Year-2022). Data extracted from electronic records include type of dental extractions, analgesics prescribed, and follow-up visits. The primary outcome was failure rate measured by the proportions of patients who returned to the clinic for management of pain after receiving dental extractions and analgesic prescriptions.ResultsA total of 3,357 patients in Year-2012 and 3,785 patients in Year-2022 received analgesic prescriptions in conjunction with dental extractions. Combination analgesics were significantly higher in Year-2022 (62.5%) than in Year-2012 (34.9%) (RR=1.79, 95% CI 1.70-1.89. pConclusions and RelevanceThis study showed a paradigm shift from opioids and single medication analgesics to non-opioids and combination analgesics with ibuprofen, acetaminophen and gabapentin as components in prescribing for pain after dental extractions, which presents an opportunity to minimize or eliminate our reliance on opioids for dental pain.

To investigate the predictive power of depression and anxiety for conditioned pain modulation (CPM) and to examine the relationships of CPM at 40°C and CPM at 47°C with age, disease-related pain, pain duration, and psychosocial factors in burning mouth syndrome (BMS).A total of 22 patients with BMS and 22 healthy female controls participated in this study. Temporal summation was used as the test stimulus for CPM, and subsequent exposure either to a nonpainful (40°C) or a painful (47°C) Peltier thermode was used as the conditioning stimulus. CPM was calculated as the difference in pain perception following the conditioning stimulus. Psychosocial factors were examined using the Profile of Mood States (POMS) and the State-Trait Anxiety Inventory (STAI).State anxiety and tension-anxiety scores were significantly higher for patients with BMS than for control participants. Multiple regression analyses showed that CPM47°C was affected by vigor, fatigue, confusion, and trait anxiety (adjusted RIncreases in trait anxiety reduced the CPM effect. These findings suggest that CPM impairments and increases in trait anxiety are involved in the development of BMS.

Painful traumatic trigeminal neuropathy (PTTN) may occur following major craniofacial or oral trauma, or may be subsequent to relatively minor dental interventions. Following injury, pain may originate from a peripheral nerve, a ganglion, or from the central nervous system. In this review, we focus on molecular mechanisms of pain resulting from injury to the peripheral branch of the trigeminal nerve. This syndrome has been termed painful traumatic trigeminal neuropathy (PTTN) by the International Headache Society and replaces previous terms including atypical odontalgia, deafferentation pain, traumatic neuropathy and phantom toothache. We emphasize the scientific evidence supporting the events purported to lead to PTTN by reviewing the pathophysiology of PTTN based on relevant animal models. Additionally, we briefly overview clinical correlates and pathophysiological manifestations of PTTN.

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.

Trauma or injury to the dentition and supporting tissues is associated with pain and discomfort, as expected, that may present immediately, shortly afterwards, or within a few days. Pain is an essential response to injury because it allows the organism to develop avoidance behavior to potential threats and helps the organism to avoid usage of the injured organ during the healing process. Not only does external trauma induce pain, but also essential invasive dental procedures such as extractions, dental implant insertions, root canal treatments, and oral surgeries are accompanied by similar post-surgical (post-traumatic) pain. The pain intensity after trauma varies and does not always correlate with the extent of injury. Trauma to the orofacial region or the teeth may also indirectly affect and induce pain in other orofacial structures such as the masticatory muscles, the temporomandibular joint, and even the cervical spine. In most cases, the pain will resolve as soon as healing of the affected tissue occurs or after dental and routine palliative treatment. In a limited number of cases, the pain persists beyond healing and evolves into a chronic pain state. Chronic pain in the orofacial region presents diagnostic and management challenges. Misdiagnosis or delayed diagnosis of the oral chronic pain condition may lead to unnecessary dental treatment. This article will discuss diagnosis and treatment for acute and chronic pain as well as potential mechanisms involved in the undesirable transition from acute to chronic pain.

BACKGROUND: Genetic variation in the catechol-O-methyltransferase (COMT) gene is associated with sensitivity to both acute experimental pain and chronic pain conditions. Four single nucleotide polymorphisms (SNPs) have traditionally been used to infer three common haplotypes designated as low, average and high pain sensitivity and are reported to affect both COMT enzymatic activity and pain sensitivity. One mechanism that may partly explain individual differences in sensitivity to pain is conditioned pain modulation (CPM). We hypothesized that variation in CPM may have a genetic basis. METHODS: We evaluated CPM in 77 healthy pain-free Caucasian subjects by applying repeated mechanical stimuli to the dominant forearm using 26-g von Frey filament as the test stimulus with immersion of the non-dominant hand in hot water as the conditioning stimulus. We assayed COMT SNP genotypes by the TaqMan method using DNA extracted from saliva. RESULTS: SNP rs4680 (val(158)met) was not associated with individual differences in CPM. However, CPM was associated with COMT low pain sensitivity haplotypes under an additive model (p = 0.004) and the effect was independent of gender. CONCLUSIONS: We show that, although four SNPs are used to infer COMT haplotypes, the low pain sensitivity haplotype is determined by SNP rs6269 (located in the 5′ regulatory region of COMT), suggesting that inherited variation in gene expression may underlie individual differences in pain modulation. Analysis of 13 global populations revealed that the COMT low pain sensitivity haplotype varies in frequency from 13% to 44% and showed that two SNPs are sufficient to distinguish all COMT haplotypes in most populations.

It is important for dental care professionals to reliably assess carbon dioxide (CO2) levels and ventilation rates in their offices in the era of frequent infectious disease pandemics. This study was to evaluate CO2 levels in dental operatories and determine the accuracy of using CO2 levels to assess ventilation rate in dental clinics. Mechanical ventilation rate in air change per hour (ACHVENT) was measured with an air velocity sensor and airflow balancing hood. CO2 levels were measured in these rooms to analyze factors that contributed to CO2 accumulation. Ventilation rates were estimated using natural steady-state CO2 levels during dental treatments and experimental CO2 concentration decays by dry ice or mixing baking soda and vinegar. We compared the differences and assessed the correlations between ACHVENT and ventilation rates estimated by the steady-state CO2 model with low (0.3 L/min, ACHSS30) or high (0.46 L/min, ACHSS46) CO2 generation rates, by CO2 decay constants using dry ice (ACHDI) or baking soda (ACHBV), and by time needed to remove 63% of excess CO2 generated by dry ice (ACHDI63%) or baking soda (ACHBV63%). We found that ACHVENT varied from 3.9 to 35.0 in dental operatories. CO2 accumulation occurred in rooms with low ventilation (ACHVENT ≤6) and overcrowding but not in those with higher ventilation. ACHSS30 and ACHSS46 correlated well with ACHVENT ( r = 0.83, P = 0.003), but ACHSS30 was more accurate for rooms with low ACHVENT. Ventilation rates could be reliably estimated using CO2 released from dry ice or baking soda. ACHVENT was highly correlated with ACHDI ( r = 0.99), ACHBV ( r = 0.98), ACHDI63% ( r = 0.98), and ACHBV63% ( r = 0.98). There were no statistically significant differences between ACHVENT and ACHDI63% or ACHBV63%. We conclude that ventilation rates could be conveniently and accurately assessed by observing the changes in CO2 levels after a simple mixing of household baking soda and vinegar in dental settings.

Background: This study aimed to examine the association between somatosensory dysfunction and burning mouth syndrome (BMS) in premenopausal, early postmenopausal, and late postmenopausal patients, using a standardized Quantitative Sensory Testing (QST) protocol, and to determine the predictive value of thermal or mechanical perception by QST for detecting BMS.Methods: The study included 36 female participants with BMS (12 premenopausal, 10 early postmenopausal, and 14 late postmenopausal) and 42 age- and sex- matched healthy volunteers (21 premenopausal, 10 early postmenopausal, and 11 late postmenopausal). Neurophysiological tests were used to evaluate somatosensory dysfunction at the tongue.Results: Z-scores in the late postmenopausal BMS group revealed a gain of function for the cold pain threshold and heat pain threshold (Z=2.08 and 3.38, respectively). In the multiple regression analysis with the Visual Analogue Scale as the dependent variable, the vibration detection threshold predicted severity of burning mouth sensation in the premenopausal group.Conclusions: Late postmenopausal patients with BMS showed an increased response of the tongue to noxious thermal stimuli. This supports the theory that changes in sex hormones may affect trigeminal somatosensory function in particular, during the late postmenopausal stage in patients with BMS.

Background Pain may undergo modulation in the central nervous system prior to reaching the primary somatosensory cortex and being perceived as pain. Faulty pain modulation mechanisms have been linked to various chronic pain conditions. Cytokines such as IL-10 and IL-1beta, are known to be involved in initiation and maintenance of neuropathic pain. In this study, we investigated the association between pain modulation profile, pain intensity and cytokines (IL-10 and IL-1beta) levels in a rat model of neuropathic pain. Methods Exercise-Induced Hypoalgesia (EIH) was assessed by evaluating the percentage of responses to a train of 60g mechanical stimuli before and after 180 seconds of exercise on a rotating rod. The differences in the response rates before and after the exercise were used to divide the rats into low and high EIH responders. Rats from low and high EIH groups underwent constriction injury of the left sciatic nerve. Pain behavior (allodynia and hyperalgesia) were assessed by measuring responses to mechanical and thermal stimuli applied to the plantar surface of the foot. Serum, sciatic nerve and the related Dorsal Root Ganglia (DRG) levels of IL-10 and IL-1beta were determined by ELISA. The DRG mRNA levels of IL-10 and IL-1beta measured with PCR. A comparison between the low and high EIH rats of all measured parameters was made. Results The low EIH rats developed significantly more severe allodynia and hyperalgesia in the affected paw and allodynia in the contralateral paw compared to the high EIH rats, 7 days following the injury. The low EIH rats had higher IL-1beta protein levels in serum prior to and following injury, higher affected and contralateral sciatic nerve IL-1beta levels following injury and higher IL-1beta levels in the contralateral DRG (protein and mRNA) following injury when compared to high EIH rats. The high EIH rats had higher affected sciatic nerve IL-10 levels following nerve injury and higher IL-10 levels of both protein and mRNA in the affected and contralateral DRG at baseline and following injury. Conclusion EIH profile was found to be predictive of pain behavior following nerve injury, low EIH rats developed more severe allodynia and hyperalgesia. IL-1beta may be associated with painful neuropathy developed in rats with low EIH while the anti-inflammatory cytokine IL-10 may have a protective role, inhibiting the development of painful.

ObjectivesThe purpose of the present study was to monitor and evaluate CO2 levels in dental operatories using a consumer-grade CO2 sensor and determine the utility and accuracy of various methods using CO2 levels to assess ventilation rate in dental clinics. We aim to find a practical tool for dental practitioners to conveniently and accurately monitor CO2 levels and assess the ventilation rates in their office in order to devise a pragmatic and effective strategy for ventilation improvement in their work environment.MethodsMechanical ventilation rate in air change per hour (ACHVENT) of 10 dental operatories was first measured with an air velocity sensor and air flow balancing hood. CO2 levels were measured in these rooms to analyze the effects of ventilation rate and number of persons in the room on CO2 accumulation. Ventilation rates were estimated using natural steady state CO2 levels during dental treatments and experimental CO2 concentration decays by dry ice or mixing baking soda and vinegar. We compared the differences and assessed the correlations between ACHVENT and ventilation rates estimated by steady states CO2 model with low (0.3 L/min, ACHSS30) or high (0.46 L/min, ACHSS46) CO2 generation rates, by CO2 decay constants using dry ice (ACHDI) or baking soda (ACHBV), and by time needed to remove 63% of excess CO2 generated by dry ice (ACHDI63%) or baking soda (ACHBV63%).ResultsACHVENT varied from 3.9 to 35.0 with a mean of 13.2 (±10.6) in the 10 dental operatories. CO2 accumulation occurred in rooms with low ventilation (ACHVENT≤6) and more persons (n>3) but not in those with higher ventilation and less persons. ACHSS30 and ACHSS46 correlated well with ACHVENT (r=0.83, p=0.003), but ACHSS30 was more accurate for rooms with low ACHVENT. Ventilation rates could be reliably estimated using CO2 released from dry ice or baking soda. ACHVENT was highly correlated with ACHDI (r=0.99), ACHBV(r=0.98), ACHDI63%(r=0.98), and ACHBV63% (r=0.98). There were no statistically significant differences between ACHVENT and ACHDI63% or ACHBV63%.ConclusionsDental operatories with low ventilation rates and overcrowding facilitate CO2 accumulations. Ventilation rates could be reliably calculated by observing the changes in CO2 levels after a simple mixing of household baking soda and vinegar in dental settings. Time needed to remove 63% of excess CO2 generated by baking soda could be used to accurately assess the ventilation rates using a consumer-grade CO2 sensor and a basic calculator.

Design Volumetric air flow was measured in a number of dental surgeries to calculate the air change rate per hour (ACHvent). In each surgery, measurements of aerosol removal by ventilation alone, and then with ventilation provided by a high-efficiency particulate air filter (PAC), were completed. The concentrations of aerosol particles of various sizes were recorded at baseline, after an initial period of incense burn, and then after 30 minutes of observation with and without the use of the PAC or ventilation system.Sample selection Ten dental surgeries with differing baseline ventilation rates had the concentrations of 0.3, 0.5 and 1.0 μm aerosol particles measured at 0 minutes, after 5 minutes of incense burn and then after 30 minutes of observation, firstly without the PAC system in operation and then with the PAC system in use.Data analysis For the 0.3 μm particles, velocities of aerosol removal were assessed by analysing the concentration decay constants with ventilation alone and ventilation with the PAC. Aerosol removal velocities were assessed by the time needed to reach 95% and 100% removal of accumulated aerosol particles.Results ACHvent in the ten different surgeries varied from 3-45. The concentration decay constants for the 0.3 μm particles with ventilation alone and ventilation with the PAC were correlated to the mechanical ventilation rate and combined respectively. For rooms with ACHvent of less than 15, accumulated aerosol particles could not be removed by ventilation alone in 30 minutes. The PAC accelerated aerosol removal and reduced aerosol accumulation, and with the use of the PAC in addition to ventilation, accumulated aerosols were removed completely in 4-12 minutes. The PAC was shown to be more beneficial in rooms with poor ventilation and the added effectiveness of the PAC in aerosol removal was inversely correlated with the ACHvent by ventilation.Conclusions Although the air change rate differed considerably among dental surgeries, this study suggests that the addition of the PAC with a HEPA filter significantly increased aerosol removal and lessened aerosol accumulation, particularly in rooms with low ventilation rates.

Coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused much anxiety and confusion in the community and affected the delivery of vital health care services, including dental care. We reviewed current evidence related to the impact of SARS-CoV-2/COVID-19 on dental care and oral health with the aim to help dental professionals better understand the risks of disease transmission in dental settings, strengthen protection against nosocomial infections, and identify areas of COVID-19–related oral health research. When compared with other recent pandemics, COVID-19 is less severe but spreads more easily, causing a significantly higher number of deaths worldwide. Protection of dental patients and staff during COVID-19 is challenging due to the existence of patients who are infectious yet asymptomatic. Dental professionals are ill prepared for the pandemic, as they are not routinely fitted for the N95 respirators now required for preventing contagion during dental treatments. Biological and clinical evidence supports that oral mucosa is an initial site of entry for SARS-CoV-2 and that oral symptoms, including loss of taste/smell and dry mouth, might be early symptoms of COVID-19, presenting before fever, dry cough, fatigue, shortness breath, and other typical symptoms. Oral health researchers may play a more active role in early identification and diagnosis of the disease through deciphering the mechanisms of dry mouth and loss of taste in patients with COVID-19. Rapid testing for infectious diseases in dental offices via saliva samples may be valuable in the early identification of infected patients and in disease progress assessment. Knowledge Transfer Statement: This commentary provides a timely evidence-based overview on the impact of COVID-19 on dental care and oral health and identifies gaps in protection of patients and staff in dental settings. Oral symptoms are prominent before fever and cough occur. Dental professionals may play an important role in early identification and diagnosis of patients with COVID-19.

Background and Overview Orofacial pain has multifactorial causes and is often a diagnostic challenge. Misdiagnosis can result in morbidity or mortality due to misdirected and inappropriate treatment. A delay of necessary treatment, in cases of ominous illnesses, may result in its perpetuation or progression. The authors present a case report that illustrates these possibilities. Case Description This case report describes a 36-year-old woman with the chief symptom of painless, limited mandibular movement. She also reported restricted movement of the left eye. She was previously diagnosed and treated for a traumatic right inferior alveolar nerve neuropathy, migraine, myofascial pain, and bilateral temporomandibular joint disk displacement with minimal benefit. Eventually she sought an orofacial pain evaluation, presuming her problems were related to a temporomandibular disorder. A complete history and comprehensive clinical evaluation including a cranial nerve screening evaluation, intraoral and extraoral examinations, an evaluation of the masticatory system, and dental radiographs were performed. The cranial nerve screening examination found painful, restricted eye movements. Magnetic resonance revealed a large, soft tissue mass in the inferolateral wall of the left orbit with soft tissue components in the infratemporal fossa and pterygoid space, involving the lateral pterygoid muscle and insertion of the temporalis muscle. The patient was referred to appropriate medical specialties and the diagnosis of orbital pseudotumor was confirmed and the patient was treated appropriately. Conclusions and Practical Implications The case emphasizes the importance of a comprehensive evaluation of a patient with preexisting orofacial pain when new symptoms arise or if there is a change in existing symptoms.

Background The mechanisms underlying sex-based differences in pain and analgesia are poorly understood. In this study, we investigated gene expression changes in trigeminal ganglia (TG) of male and female rats exposed to infraorbital nerve chronic constriction injury (IoN-CCI). Methods Somatosensory assessments were performed prior to IoN-CCI and at selected time points postsurgery. Selected gene expression changes were examined with real-time quantitative polymerase chain reaction (RT-PCR) in ipsilateral TG at 21 days postsurgery. Results Rats exposed to IoN-CCI developed significant mechanical allodynia and hyperalgesia on days 19 and 21 postsurgery. During this period, females developed significantly more allodynia but not hyperalgesia compared to males. At 21 days postsurgery, expression levels of 44 of the 84 investigated pain-related genes in ipsilateral TG were significantly regulated relative to naive rats in either sex. Csf1 and Cx3cr1 were up-regulated in both sexes, but the magnitude of regulation was significantly higher in females (p = 0.02 and p = 0.001, respectively). Htr1a and Scn9a were down-regulated in both sexes, but the down-regulation was significantly more pronounced in males (p = 0.04 and p = 0.02, respectively). Additionally, Cck, Il1a, Pla2g1b and Tnf genes were significantly regulated in females but not in males, and Chrna4 gene was significantly down-regulated in males but not in females. Conclusions Our findings suggest sex-dependent gene regulation in response to nerve injury, which may contribute to sex dimorphism of trigeminal neuropathic pain. Further studies are needed to establish gene expression changes over time and correlate these with hormonal and other physiological parameters in male and female. Significance We present novel sex-specific transcriptional regulation in trigeminal ganglia that may contribute to male-/female-based differences in trigeminal neuropathic pain. These findings are expected to open new research horizons, particularly in male versus female targeted therapeutic regimens.

Orofacial pain can often be the chief complaint of many systemic disorders. Cysticercosis involving the lateral pterygoids may cause limitation of mouth opening and may mimic clinical symptoms of a temporomandibular disorder. A 37-year-old female presented with 1-month-old complaint of limited mandibular range of motion. She reported a similar episode a year earlier and was diagnosed with a temporomandibular joint disorder by her primary dentist. Comprehensive intra- and extra-oral examinations were performed, which revealed a limitation of mouth opening accompanied by mild limitation of contralateral excursion. A magnetic resonance imaging revealed a ring-enhancing lesion within the left pterygoid muscle suggestive of cysticercosis. The patient was referred to her primary care physician for further treatment and given physical therapy (stretching exercises) to improve mouth opening. One week later, she developed lesions in the arm and trunk. Further ultrasound imaging of the abdomen and the forearms confirmed the diagnosis of cysticercosis. She was treated with albendazole, physiotherapy, joint stabilization appliance, and had eventual complete recovery. This case emphasizes the importance of diagnosis of a systemic condition that may have serious implications, if untreated, and the importance of a comprehensive evaluation, workup, and multidisciplinary management.

Interleukin-8 (IL-8) is a pro-inflammatory cytokine that has been shown to play a role in inflammatory and autoimmune disorders. The objective of the present study was to assess the levels of IL-8 in rat serum, dorsal root ganglion (DRG) and the sciatic nerve following four different forms of sciatic nerve injury. The models used to induce the injury included partial sciatic ligation (PSL), chronic constriction injury (CCI), perineural inflammation (neuritis) and complete sciatic transection (CST). Mechanical and thermal hyperalgesia were detected by measuring withdrawal responses from a mechanical stimulus and withdrawal latency from thermal stimulation. Enzyme-linked immunosorbent assays (ELISA) was used to assess the IL-8 levels in the affected and contralateral sciatic nerves. Rats exposed to PSL and neuritis developed significant nociceptive response (mechanical and thermal hyperalgesia) in the affected side at three days post-surgery whereas the CCI group at eight days post-surgery. No mechanical or thermal hyperalgesia was observed in rats exposed to CST at either three or eight days postsurgery. Additionally, IL-8 levels were significantly increased in the injured sciatic nerve at 3 and 8days following PSL and neuritis as well as at 8days following CCI when compared to naïve animals. A significant up regulation of IL-8 levels was observed in the ipsilateral DRG at 3 and 8days following CST compared to naïve animals. The serum IL-8 levels remained unchanged in all models of nerve damage. The results of this study suggest that IL-8's role in the neuropathic pain etiology may be specific to nerve injury type.

Background The dorsal root (DRG) and trigeminal (TG) ganglia contain cell bodies of sensory neurons of spinal and trigeminal systems, respectively. They are homologs of each other; however, differences in how the two systems respond to injury exist. Trigeminal nerve injuries rarely result in chronic neuropathic pain (NP). To date, no genes involved in the differential response to nerve injury between the two systems have been identified. We examined transcriptional changes involved in the development of trigeminal and spinal NP. Methods Trigeminal and spinal mononueropathies were induced by chronic constriction injury to the infraorbital or sciatic nerve. Expression levels of 84 genes in the TG and DRG at 4, 8 and 21 days post-injury were measured using real-time PCR. Results We found time-dependent and ganglion-specific transcriptional regulation that may contribute to the development of corresponding neuropathies. Among genes significantly regulated in both ganglia Cnr2, Grm5, Htr1a, Il10, Oprd1, Pdyn, Prok2 and Tacr1 were up-regulated in the TG but down-regulated in the DRG at 4 days post-injury; at 21 days post-injury, Adora1, Cd200, Comt, Maob, Mapk3, P2rx4, Ptger1, Tnf and Slc6a2 were significantly up-regulated in the TG but down-regulated in the DRG. Conclusions Our findings suggest that spinal and trigeminal neuropathies due to trauma are differentially regulated. Subtle but important differences between the two ganglia may affect NP development. Significance We present distinct transcriptional alterations in the TG and DRG that may contribute to differences observed in the corresponding mononeuropathies. Since the trigeminal system seems more resistant to developing NP following trauma our findings lay ground for future research to detect genes and pathways that may act in a protective or facilitatory manner. These may be novel and important therapeutic targets.

Objectives The aim of this study was to examine temporal summation (TS) and conditioned pain modulation (CPM) in patients with burning mouth syndrome (BMS) and healthy controls using intra-epidermal electrical stimulation (IES). Materials and methods Twenty-six female patients with BMS and 27 healthy female controls participated in this study. A single stimulus with electrical stimulation followed by a train of 10 successive stimuli was administered to the right chin of participants in both the BMS and control groups. CPM was evaluated with the changes of TS calculated from the difference in numerical pain scale data between these two test stimuli and the following warm (40°C) and hot (47°C) conditioning stimuli applied at the non-dominant hand in both the BMS and control groups. Results TS was present in both the BMS and control groups. CPM in the BMS group was significantly less efficient at the 47°C condition than that in the control group, while no significant difference was observed in the CPM between the BMS and the control groups at the 40°C condition. Conclusion These findings indicate that BMS is associated with a deficit inhibitory CPM and implicate the involvement of the central nervous system in the pathophysiology of BMS.

Aims To evaluate the effect of nonstrenuous aerobic exercise on chronic masticatory myalgia (CMM) patients and healthy controls (HC) by means of mechanical temporal summation (TS) and response to mechanical stimulation (RMS) performed on the dominant forearm. Methods A total of 30 patients diagnosed with CMM and 30 pain-free HCs were first evaluated for maximum number of steps (MNS) on a stepper machine for 1 minute. Additionally, they completed the Generalized Anxiety Disorder (GAD-7), Graded Chronic Pain Scale (GCPS), and Jaw Functional Limitation Scale (JFL) questionnaires. On the second visit, RMS, mechanical TS, exercise-induced hypoalgesia (EIH), blood pressure, pulse pressure, and heart rate were assessed prior to and immediately, 5, 15, and 30 minutes following 5 minutes of stepper exercise at 50% MNS. Results Compared to HCs, CMM patients demonstrated increased mechanical TS and less efficient EIH. Mechanical TS scores were reduced in both groups; however, the HC reduction was more robust and persistent. CMM patients demonstrated a delayed reduction in RMS following exercise in contrast to an immediate reduction in HCs. GAD-7, GCPS, and JFL scores for CMM patients were higher than for HCs and were associated with baseline pain intensity but not with EIH or TS. Conclusion These findings suggest that, compared to HC, CMM patients' pain modulation is both suppressed and has a different effect duration and timing pattern. Further research should explore the mechanisms and clinical relevance of the delayed hypoalgesia and the inhibitory effect on TS induced by nonstrenuous aerobic exercise in CMM patients.

Neuropathic pain encompasses a spectrum of conditions that can arise from a lesion or dysfunction of the central or the peripheral nervous system, and it may develop at variable intervals after nerve injury or inflammation. Nerve injuries arising from surgical procedures commonly occur secondary to the surgical trauma, and in rare instances they are a complication of intubation during general anesthesia or endoscopic procedures. A series of 2 cases of bilateral glossopharyngeal neuropathic pain subsequent to endoscopic procedures is presented with a review of the literature concerning the mechanisms of development of neuropathic pain after these procedures. The purpose of these case reports is to make dentists aware of the occurrence, the mechanisms of nerve injuries, and the treatment of neuropathic pain after endoscopic procedures. In the first case, the patient had relief of pain with a combination therapy of clonazepam 1.0 mg in divided doses twice daily and gabapentin 300 mg in divided doses 3 times daily. In the second case, the patient had significant relief of pain with a monotherapy of gabapentin 1200 mg in divided doses 3 times daily.

We examined the short-term surgical effects of orthognathic surgery on somatosensory function. Observations were made over a short period: 3 months postoperatively. In total, 14 patients and 32 healthy controls participated. Among the 14 patients, one underwent bilateral sagittal split osteotomy alone and 13 underwent bilateral sagittal split osteotomy in combination with a Le Fort I osteotomy. A modified quantitative sensory testing (QST) protocol (the German Research Network on Neuropathic Pain, DFNS) was used to evaluate clinically the skin of the chin for sensory disturbances before surgery and at 1 week, 1 month, and 3 months postoperatively. A visual analog scale and the Japanese Version of the McGill Pain Questionnaire were completed by all participants. Both sides of the mandible showed postoperative functional loss in cold detection threshold, warmth detection threshold, thermal sensory limen, and mechanical detection threshold. All function gradually recovered to baseline conditions at 3 months postoperatively. Cold detection threshold, warmth detection threshold, thermal sensory limen, and mechanical detection threshold appeared to be useful QST parameters for evaluating neurosensory disturbances during the early postoperative period. (J Oral Sci 58, 177-184, 2016).

A standardized battery of quantitative sensory tests developed by the German Research Network on Neuropathic Pain (DFNS) was used to assess the association between somatosensory dysfunction and disease duration in patients with burning mouth syndrome (BMS). The 28 female participants with BMS were classified according to disease duration: ≤ 6 months (subchronic BMS, n = 15) and > 6 months (chronic BMS, n = 13); 29 age- and sex-matched healthy volunteers (control group) were recruited from staff of a dental hospital. The DFNS quantitative sensory testing protocol was applied at the ulnar surface of the right forearm and the tip of the tongue. Values for BMS patients and controls were compared and analyzed. The mechanical detection threshold (MDT) was significantly higher (i.e., loss of sensation) at the tongue tip in the chronic BMS group than in the control group (p = 0.011), whereas mechanical pain sensitivity (MPS) at the forearm was significantly higher (i.e., gain of sensation) in the chronic BMS group than in the control group (Z score = − 2.13 and 1.99, respectively). Multivariate analyses revealed that BMS patients could be discriminated from controls by using pressure pain threshold at the tongue (79.3%) (in the subchronic BMS group) and by MDT and MPS at the tongue tip and MPS at the forearm (96.6 and 89.7%, respectively) (in the chronic BMS group). In BMS patients with long disease duration, MDT showed loss of sensation. Increased MPS suggests that a neuropathic mechanism in the peripheral and central nervous systems is involved in BMS development.

Despite the advancement of early childhood caries (ECC) prediction and treatment, ECC remains a significant public health burden in need of more effective preventive strategies. Pregnancy is an ideal period to promote ECC prevention given the profound influence of maternal oral health and behaviors on children’s oral health. However, studies have shown debatable results with respect to the effectiveness of ECC prevention by means of prenatal intervention. Therefore, this study systematically reviewed the scientific evidence relating to the association between prenatal oral health care, ECC incidence, and Streptococcus mutans carriage in children. Five studies (3 randomized control trials, 1 prospective cohort study, and 1 nested case-control study) were included for qualitative assessment. Tested prenatal oral health care included providing fluoride supplements, oral examinations/cleanings, oral health education, dental treatment referrals, and xylitol gum chewing. Four studies that assessed ECC incidence reduction were included in meta-analysis using an unconditional generalized linear mixed effects model with random study effects and age as a covariate. The estimated odds ratio and 95% confidence intervals suggested a protective effect of prenatal oral health care against ECC onset before 4 years of age: 0.12 (0.02, 0.77) at 1 year of age, 0.18 (0.05, 0.63) at 2 years of age, 0.25 (0.09, 0.64) at 3 years of age, and 0.35 (0.12, 1.00) at 4 years of age. Children’s S. mutans carriage was also significantly reduced in the intervention group. Future studies should consider testing strategies that restore an expectant mother’s oral health to a disease-free state during pregnancy.

Orofacial pain has multifactorial causes and is often a diagnostic challenge. Misdiagnosis can result in morbidity or mortality due to misdirected and inappropriate treatment. A delay of necessary treatment, in cases of ominous illnesses, may result in its perpetuation or progression. The authors present a case report that illustrates these possibilities.This case report describes a 36-year-old woman with the chief symptom of painless, limited mandibular movement. She also reported restricted movement of the left eye. She was previously diagnosed and treated for a traumatic right inferior alveolar nerve neuropathy, migraine, myofascial pain, and bilateral temporomandibular joint disk displacement with minimal benefit. Eventually she sought an orofacial pain evaluation, presuming her problems were related to a temporomandibular disorder. A complete history and comprehensive clinical evaluation including a cranial nerve screening evaluation, intraoral and extraoral examinations, an evaluation of the masticatory system, and dental radiographs were performed. The cranial nerve screening examination found painful, restricted eye movements. Magnetic resonance revealed a large, soft tissue mass in the inferolateral wall of the left orbit with soft tissue components in the infratemporal fossa and pterygoid space, involving the lateral pterygoid muscle and insertion of the temporalis muscle. The patient was referred to appropriate medical specialties and the diagnosis of orbital pseudotumor was confirmed and the patient was treated appropriately.The case emphasizes the importance of a comprehensive evaluation of a patient with preexisting orofacial pain when new symptoms arise or if there is a change in existing symptoms.

Patients suffering from persistent pain after endodontic treatment have less efficient pain modulation system compared with healthy controls., Persistent pain may follow nerve injuries associated with invasive therapeutic interventions. About 3% to 7% of the patients remain with chronic pain after endodontic treatment, and these are described as suffering from painful posttraumatic trigeminal neuropathy (PTTN). Unfortunately, we are unable to identify which patients undergoing such procedures are at increased risk of developing PTTN. Recent findings suggest that impaired endogenous analgesia may be associated with the development of postsurgical chronic pain. We hypothesized that patients with PTTN display pronociceptive pain modulation, in line with other chronic pain disorders. Dynamic (conditioned pain modulation, temporal summation) and static (response to mechanical and cold stimulation) psychophysical tests were performed intraorally and in the forearm of 27 patients with PTTN and 27 sex- and age-matched controls. The dynamic sensory testing demonstrated less efficient conditioned pain modulation, suggesting reduced function of the inhibitory endogenous pain-modulatory system, in patients with PTTN, mainly in those suffering from the condition for more than a year. The static sensory testing of patients with PTTN demonstrated forearm hyperalgesia to mechanical stimulation mainly in patients suffering from the condition for less than a year and prolonged painful sensation after intraoral cold stimulus mainly in patients suffering from the condition for more than a year. These findings suggest that PTTN is associated more with the inhibitory rather than the facilitatory arm of pain modulation and that the central nervous system has a role in PTTN pathophysiology, possibly in a time-dependent fashion.

BACKGROUND Although inflammation can alter cytokines release and nerve function, it is not yet fully established if orthodontic-induced inflammation can cause significant extraoral trigeminal somatosensory alterations and release of inflammatory chemical mediators. OBJECTIVE The primary aim of this study was to investigate the impact of orthodontic separator and short-term fixed orthodontic appliance on the extraoral trigeminal somatosensory function and concentrations of cytokines in the gingival crevicular fluid (GCF). METHODS Twenty-two female patients were evaluated as follow: baseline, 24 hour-after elastomeric separator (-aES), 24 hour- and 1 month-after bonding brackets (-aBB) at both arches. The outcome variables were as follows: self-reported pain (Visual Analog Scale), QSTs (current perception threshold-CPT, cold detection threshold-CDT, warm detection threshold-WDT, mechanical detection threshold-MDT, mechanical suprathreshold-MST and wind-up ratio-WUR. All QSTs were performed at infra-orbital and mental nerve entry zone at patient`s dominant side. In addition, GCF samples in order to assess cytokines profile (IL-1β,IL-8,IL-6 and TNF-α) were collected. ANOVA and Tukey's post hoc analyses were performed (a = 5%). RESULTS Patients reported higher pain intensity 24 hour-aBB compared to baseline and 24 hour-aES (P

Aims To investigate the effects and interactions of sex and stress (provoked by chronic restraint [RS]) on pain-like behavior in a rat model of trigeminal neuropathic pain. Methods The effects of sex and RS (carried out for 14 days as a model for stress) on somatosensory measures (reaction to pinprick, von Frey threshold) in a rat model of trigeminal neuropathic pain were examined. The study design was 2 × 4, with surgery (pain) and sham surgery (no pain) interacting with male restrained (RS) and unrestrained (nRS) rats and female RS and nRS rats. A total of 64 Sprague Dawley rats (32 males and 32 females) were used. Half of the animals in each sex group underwent RS, and the remaining half were left unstressed. Following the RS period, trigeminal neuropathic pain was induced by unilateral infraorbital nerve chronic constriction injury (IOCCI). Half of the animals in the RS group and half in the nRS group (both males and females) were exposed to IOCCI, and the remaining halves to sham surgery. Elevated plus maze (EPM) assessment and plasma interferon gamma (IFN-γ) levels were used to measure the effects of RS. Analysis of variance (ANOVA) was used to assess the effects of stress, sex, and their interactions on plasma IFN-γ levels, changes in body weight, EPM parameters, tactile allodynia, and mechanohyperalgesia. Pairwise comparisons were performed by using Tukey post hoc test corrected for multiple comparisons. Results Both male and female RS rats showed significantly altered exploratory behavior (as measured by EPM) and had significantly lower plasma IFN-γ levels than nRS rats. Rats exposed to RS gained weight significantly slower than the nRS rats, irrespective of sex. Following RS but before surgery, RS rats showed significant bilateral reductions in von Frey thresholds and significantly increased pinprick response difference scores compared to nRS rats, irrespective of sex. From 17 days postsurgery, RSIOCCI rats showed significantly reduced von Frey thresholds and significantly increased pinprick response difference scores compared to nRS-IOCCI rats, and the von Frey thresholds were significantly lower in females than in males. RS-sham females-but not RS-sham males-developed persistently reduced thresholds and increased pinprick response difference scores. Conclusion RS produced an increased bilateral sensitivity to stimuli applied to the vibrissal pad following infraorbital nerve injury, irrespective of sex. This observed sensitivity subsequently persisted in RS-sham female rats but not in RS-sham male rats. Stress induced a significant but moderate increase in pain-like behavior in female rats compared to male rats. RS had no significant sex effects on IFN-γ levels, EPM parameters, or body weight gain. This suggests that stress may have a selective effect on pain-like behavior in both sexes, but the possible mechanisms are unclear.

The present study evaluated the effects of systemic pregabalin (PG) and diclofenac (Dic) on neuropathic orofacial pain induced by chronic constriction injury (CCI) of the infraorbital nerve (ION) and on the pro-inflammatory cytokines levels in the affected nerve. Fifty-four rats underwent left infra orbital nerve CCI, and 7 days after the procedure as the pain developed, the rats were randomly assigned to one of the treatment groups: PG 300, 30 or 10 mg/kg, Dic 10, 5 or 1 mg/kg or saline group (Sal) (n/group = 8). Addiitonal 8 rats served as naïve control group. Tactile-allodynia and Mechano-hyperalgesia were tested before the surgical procedure and at days 7, 8, and 9 postoperatively. On the 9th day, the rats were euthanized and the affected and contralateral sciatic nerves were harvested to assess IL-6 and IL-1β nerve levels employing enzyme linked immunosorbent assay (ELISA). Daily injection of PG (all doses) significantly reduced tactile-allodynia and mechano-hyperalgesia (p .05) while Dic did not. On the 9th day, the ipsilateral nerve IL-6 levels were significantly decreased (p .05) in the PG and DIC groups compared to the Sal group. IL-1β levels demonstrated a significant reduction (p .05) in the PG group when compared to saline. These results suggest that PG but not Dic may be effective in reducing neuropathic orofacial pain. The mechanisms of action may be associated to some extent with reduction in IL-1β levels in the affected nerve.

IL-12p70 is a proinflammatory cytokine secreted by dendritic cells, monocytes and macrophages. It plays a crucial role in cell-mediated immunity by inducing proliferation of T cell and natural killer cells, and enhancing their cytotoxic activity. In adaptive immune response, it acts on naive T cells to differentiate into Th1-type cells. It is composed of two subunits, p35 and p40. The latter can be secreted in the form of monodimer or heterodimer, which is also referred as IL-12p80. Recently IL-12p70 has been proven to locally provoke nociceptive effect in naïve rats. This study investigated pain response following systemic administration of IL-12p70 and IL-12p40 homodimer in chronic neuropathic pain model, induced by chronic constriction injury. The doses tested were IL-12p40 homodimer or IL12p70 at 15, 150 and 1500ng/kg, respectively. Pain was assessed at 1, 4, 7 and 24h after injection, in the form of tactile allodynia and mechanical hyperalgesia. The side effect of sensory motor disability was measured by rotarod performance. By all behavioral measures, IL-12p70 of any dosage, at any time point, had no significant effect on tactile allodynia and mechanical hyperalgesia. A high dose of IL-12p40 homodimer induced significant analgesic effect by the measure of hind paw tactile allodynia from 1h to 4h after injection. Medium and low doses of IL-12p40 homodimer exerted their analgesic effect 4h post injection. Mechanical hyperalgesia, following high and medium doses of IL-12p40 administration, was significantly reduced at 4h after application. Also, no significant sensory motor dysfunction was detected for all dosage for both homodimers. These findings suggest that systemic application of IL-12p40 homodimer induces time-dependent analgesia to mechanical stimulation in rats exposed to neuropathic pain.