Bruxism and oro-facial pain not related to temporomandibular disorder conditions: Comorbidities or risk factors?

INTRODUCTION: Bruxism has historically been of particular interest to the field of dentistry, primarily due to the inferred damage it may cause to the dentition and supporting periodontal structures. The definition of bruxism itself has undergone multiple changes over time. In addition, the effects of bruxism as it relates to oro-facial pain conditions has remained a debatable topic. PURPOSE: To review the available literature relating to bruxism and non-temporomandibular disorder (TMD) pain conditions. METHODS: A literature search was conducted with the assistance of an expert librarian. The following databases were reviewed: PubMed, MEDLINE, EMBASE and Google Scholar. For additional references, articles were also retrieved by hand search from the selected papers. Any articles that were not published in English, or the focus were related to temporomandibular disorders were excluded. CONCLUSIONS: While bruxism and certain headache conditions do tend to occur together frequently, evidence relating to any clear common pathophysiological mechanism has yet to be fully elucidated. Robust evidence as it relates to the relationship between bruxism and other non-TMD oro-facial pains is also lacking.

Research routes on awake bruxism metrics: Implications of the updated bruxism definition and evaluation strategies.

BACKGROUND: With time, due to the poor knowledge on it epidemiology, the need to focus on awake bruxism as a complement of sleep studies emerged. OBJECTIVE: In line with a similar recent proposal for sleep bruxism (SB), defining clinically oriented research routes to implement knowledge on awake bruxism (AB) metrics is important for an enhanced comprehension of the full bruxism spectrum, that is better assessment and more efficient management. METHODS: We summarised current strategies for AB assessment and proposed a research route for improving its metrics. RESULTS: Most of the literature focuses on bruxism in general or SB in particular, whilst knowledge on AB is generally fragmental. Assessment can be based on non-instrumental or instrumental approaches. The former include self-report (questionnaires, oral history) and clinical examination, whilst the latter include electromyography (EMG) of jaw muscles during wakefulness as well as the technology-enhanced ecological momentary assesment (EMA). Phenotyping of different AB activities should be the target of a research task force. In the absence of available data on the frequency and intensity of wake-time bruxism-type masticatory muscle activity, any speculation about the identification of thresholds and criteria to identify bruxers is premature. Research routes in the field must focus on the improvement of data reliability and validity. CONCLUSIONS: Probing deeper into the study of AB metrics is a fundamental step to assist clinicians in preventing and managing the putative consequences at the individual level. The present manuscript proposes some possible research routes to advance current knowledge. At different levels, instrumentally based and subject-based information must be gathered in a universally accepted standardised approach.

Standardised Tool for the Assessment of Bruxism.

OBJECTIVE: This paper aims to present and describe the Standardised Tool for the Assessment of Bruxism (STAB), an instrument that was developed to provide a multidimensional evaluation of bruxism status, comorbid conditions, aetiology and consequences. METHODS: The rationale for creating the tool and the road map that led to the selection of items included in the STAB has been discussed in previous publications. RESULTS: The tool consists of two axes, specifically dedicated to the evaluation of bruxism status and consequences (Axis A) and of bruxism risk and etiological factors and comorbid conditions (Axis B). The tool includes 14 domains, accounting for a total of 66 items. Axis A includes the self-reported information on bruxism status and possible consequences (subject-based report) together with the clinical (examiner report) and instrumental (technology report) assessment. The Subject-Based Assessment (SBA) includes domains on Sleep Bruxism (A1), Awake Bruxism (A2) and Patient's Complaints (A3), with information based on patients' self-report. The Clinically Based Assessment (CBA) includes domains on Joints and Muscles (A4), Intra- and Extra-Oral Tissues (A5) and Teeth and Restorations (A6), based on information collected by an examiner. The Instrumentally Based Assessment (IBA) includes domains on Sleep Bruxism (A7), Awake Bruxism (A8) and the use of Additional Instruments (A9), based on the information gathered with the use of technological devices. Axis B includes the self-reported information (subject-based report) on factors and conditions that may have an etiological or comorbid association with bruxism. It includes domains on Psychosocial Assessment (B1), Concurrent Sleep-related Conditions Assessment (B2), Concurrent Non-Sleep Conditions Assessment (B3), Prescribed Medications and Use of Substances Assessment (B4) and Additional Factors Assessment (B5). As a rule, whenever possible, existing instruments, either in full or partial form (i.e. specific subscales), are included. A user's guide for scoring the different items is also provided to ease administration. CONCLUSIONS: The instrument is now ready for on-field testing and further refinement. It can be anticipated that it will help in collecting data on bruxism in such a comprehensive way to have an impact on several clinical and research fields.

Overcoming EGFR(T790M) and EGFR(C797S) resistance with mutant-selective allosteric inhibitors.

The epidermal growth factor receptor (EGFR)-directed tyrosine kinase inhibitors (TKIs) gefitinib, erlotinib and afatinib are approved treatments for non-small cell lung cancers harbouring activating mutations in the EGFR kinase, but resistance arises rapidly, most frequently owing to the secondary T790M mutation within the ATP site of the receptor. Recently developed mutant-selective irreversible inhibitors are highly active against the T790M mutant, but their efficacy can be compromised by acquired mutation of C797, the cysteine residue with which they form a key covalent bond. All current EGFR TKIs target the ATP-site of the kinase, highlighting the need for therapeutic agents with alternative mechanisms of action. Here we describe the rational discovery of EAI045, an allosteric inhibitor that targets selected drug-resistant EGFR mutants but spares the wild-type receptor. The crystal structure shows that the compound binds an allosteric site created by the displacement of the regulatory C-helix in an inactive conformation of the kinase. The compound inhibits L858R/T790M-mutant EGFR with low-nanomolar potency in biochemical assays. However, as a single agent it is not effective in blocking EGFR-driven proliferation in cells owing to differential potency on the two subunits of the dimeric receptor, which interact in an asymmetric manner in the active state. We observe marked synergy of EAI045 with cetuximab, an antibody therapeutic that blocks EGFR dimerization, rendering the kinase uniformly susceptible to the allosteric agent. EAI045 in combination with cetuximab is effective in mouse models of lung cancer driven by EGFR(L858R/T790M) and by EGFR(L858R/T790M/C797S), a mutant that is resistant to all currently available EGFR TKIs. More generally, our findings illustrate the utility of purposefully targeting allosteric sites to obtain mutant-selective inhibitors.

Optical calibration of the SuperCam instrument body unit spectrometers.

The SuperCam remote sensing instrument on NASA's Perseverance rover is capable of four spectroscopic techniques, remote micro-imaging, and audio recording. These analytical techniques provide details of the chemistry and mineralogy of the rocks and soils probed in the Jezero Crater on Mars. Here we present the methods used for optical calibration of the three spectrometers covering the 243-853 nm range used by three of the four spectroscopic techniques. We derive the instrument optical response, which characterizes the instrument sensitivity to incident radiation as a function of a wavelength. The instrument optical response function derived here is an essential step in the interpretation of the spectra returned by SuperCam as it converts the observed spectra, reported by the instrument as "digital counts" from an analog to digital converter, into physical values of spectral radiance.

A Pre-Existing Myogenic Temporomandibular Disorder Increases Trigeminal Calcitonin Gene-Related Peptide and Enhances Nitroglycerin-Induced Hypersensitivity in Mice.

Migraine is commonly reported among patients with temporomandibular disorders (TMDs), especially myogenic TMD. The pathophysiologic mechanisms related to the comorbidity of the two conditions remain elusive. In the present study, we combined masseter muscle tendon ligation (MMTL)-produced myogenic TMD with systemic injection of nitroglycerin (NTG)-induced migraine-like hypersensitivity in mice. Facial mechanical allodynia, functional allodynia, and light-aversive behavior were evaluated. Sumatriptan, an FDA-approved medication for migraine, was used to validate migraine-like hypersensitivity. Additionally, we examined the protein level of calcitonin gene-related peptide (CGRP) in the spinal trigeminal nucleus caudalis using immunohistochemistry. We observed that mice with MMTL pretreatment have a prolonged NTG-induced migraine-like hypersensitivity, and MMTL also enabled a non-sensitizing dose of NTG to trigger migraine-like hypersensitivity. Systemic injection of sumatriptan inhibited the MMTL-enhanced migraine-like hypersensitivity. MMTL pretreatment significantly upregulated the protein level of CGRP in the spinal trigeminal nucleus caudalis after NTG injection. Our results indicate that a pre-existing myogenic TMD can upregulate NTG-induced trigeminal CGRP and enhance migraine-like hypersensitivity.

CRITICAL APPRAISAL. Sleep Bruxism and Sleep-Disordered Breathing.

Sleep bruxism (SB) is a repetitive jaw muscle activity with clenching or grinding of the teeth during sleep. SB is characterized by what is known as rhythmic masticatory muscle activity (RMMA). RMMA is the laboratory polysomnographic finding that differentiates SB from other oromandibular movements seen during sleep. Most often RMMA episodes are associated with sleep arousal. Some patients will report similar complaints related to both SB and sleep disordered breathing (SDB). There are some reports that would suggest that SB is a result of SDB. It has has been postulated that SB is a compensatory mechanism to re establish muscle tone of the upper airway. While these disorders do in fact often present concomitantly, the relationship between the two is yet to be fully elucidated. This Critical Appraisal reviews 3 recent publications with the intent to better define what relationships may exists between SDB and SB. While the current evidence appears to support the notion that these are often concomitant disorders, it also makes clear that evidence to support the hypothesis that SDB is causative for SB is currently lacking.

Trigger point injections for headache disorders: expert consensus methodology and narrative review.

OBJECTIVE/BACKGROUND: To review the existing literature and describe a standardized methodology by expert consensus for the performance of trigger point injections (TPIs) in the treatment of headache disorders. Despite their widespread use, the efficacy, safety, and methodology of TPIs have not been reviewed specifically for headache disorders by expert consensus. METHODS: The Peripheral Nerve Blocks and Other Interventional Procedures Special Interest Section of the American Headache Society over a series of meetings reached a consensus for nomenclature, indications, contraindications, precautions, procedural details, outcomes, and adverse effects for the use of TPIs for headache disorders. A subcommittee of the Section also reviewed the literature. RESULTS: Indications for TPIs may include many types of episodic and chronic primary and secondary headache disorders, with the presence of active trigger points (TPs) on physical examination. Contraindications may include infection, a local open skull defect, or an anesthetic allergy, and precautions are necessary in the setting of anticoagulant use, pregnancy, and obesity with unclear anatomical landmarks. The most common muscles selected for TPIs include the trapezius, sternocleidomastoid, and temporalis, with bupivacaine and lidocaine the agents used most frequently. Adverse effects are typically mild with careful patient and procedural selection, though pneumothorax and other serious adverse events have been infrequently reported. CONCLUSIONS: When performed in the appropriate setting and with the proper expertise, TPIs seem to have a role in the adjunctive treatment of the most common headache disorders. We hope our effort to characterize the methodology of TPIs by expert opinion in the context of published data motivates the performance of evidence-based and standardized treatment protocols.

Orofacial pain and headache: a review and look at the commonalities.

Headache and facial pain - in particular, temporomandibular disorders (TMDs) - are very prevalent conditions in the general population. TMDs are defined as a collection of symptoms and signs involving masticatory muscles, the temporomandibular joints (TMJs), or both. The pain reported by TMD patients is typically located in the muscles of mastication, in the preauricular area, or in the TMJs. In many cases, headaches and facial pain will occur in the same patient. Much of the research relative to the relationship of these disorders focuses on statistics of association and prevalence data. This review will provide a brief description of the types and classifications of orofacial pains (OFPs), as well as point to relevant research describing the commonalities and potential comorbid nature of these maladies. Finally, several recent papers describing morphologic changes to the brain in headache and TMD individuals will be discussed in an effort to stimulate further research into the potential common pathophysiologic mechanism that may explain the comorbid nature of these disorders.

Ketogenic diet mitigates opioid-induced hyperalgesia by restoring short-chain fatty acids-producing bacteria in the gut.

ABSTRACT: Opioids are commonly prescribed to patients with chronic pain. Chronic opioid usage comes with a slew of serious side effects, including opioid-induced hyperalgesia (OIH). The patients with long-term opioid treatment experience paradoxical increases in nociceptive hypersensitivity, namely, OIH. Currently, treatment options for OIH are extremely lacking. In this study, we show that the ketogenic diet recovers the abnormal pain behavior caused by chronic morphine treatment in male mice, and we further show that the therapeutic effect of the ketogenic diet is mediated through gut microbiome. Our 16S rRNA sequencing demonstrates that chronic morphine treatment causes changes in mouse gut microbiota, specifically a decrease in short-chain fatty acids-producing bacteria, and the sequencing data also show that the ketogenic diet rescues those bacteria in the mouse gut. More importantly, we show that supplementation with short-chain fatty acids (butyrate, propionate, and acetate) can delay the onset of OIH, indicating that short-chain fatty acids play a direct role in the development of OIH. Our findings suggest that gut microbiome could be targeted to treat OIH, and the ketogenic diet can be used as a complementary approach for pain relief in patients with chronic opioid treatment. We only used male mice in this study, and thus, our findings cannot be generalized to both sexes.

Expert consensus recommendations for the performance of peripheral nerve blocks for headaches--a narrative review.

OBJECTIVE: To describe a standardized methodology for the performance of peripheral nerve blocks (PNBs) in the treatment of headache disorders. BACKGROUND: PNBs have long been employed in the management of headache disorders, but a wide variety of techniques are utilized in literature reports and clinical practice. METHODS: The American Headache Society Special Interest Section for PNBs and other Interventional Procedures convened meetings during 2010-2011 featuring formal discussions and agreements about the procedural details for occipital and trigeminal PNBs. A subcommittee then generated a narrative review detailing the methodology. RESULTS: PNB indications may include select primary headache disorders, secondary headache disorders, and cranial neuralgias. Special procedural considerations may be necessary in certain patient populations, including pregnancy, the elderly, anesthetic allergy, prior vasovagal attacks, an open skull defect, antiplatelet/anticoagulant use, and cosmetic concerns. PNBs described include greater occipital, lesser occipital, supratrochlear, supraorbital, and auriculotemporal injections. Technical success of the PNB should result in cutaneous anesthesia. Targeted clinical outcomes depend on the indication, and include relief of an acute headache attack, terminating a headache cycle, and transitioning out of a medication-overuse pattern. Reinjection frequency is variable, depending on the indications and agents used, and the addition of corticosteroids may be most appropriate when treating cluster headache. CONCLUSIONS: These recommendations from the American Headache Society Special Interest Section for PNBs and other Interventional Procedures members for PNB methodology in headache disorder treatment are derived from the available literature and expert consensus. With the exception of cluster headache, there is a paucity of evidence, and further research may result in the revision of these recommendations to improve the outcome and safety of these interventions.

Biomechanics and Derangements of the Temporomandibular Joint.

The human temporomandibular joint, is a ginglymo-arthrodial joint. The articular disk serves as a fibrous, viscoelastic structure that allows force distribution and smooth movement of the joint in its normal arrangement during mandibular movements. Most studies suggest that in the normal disk position the posterior band is located at the 12'o clock position within the glenoid fossa in the closed mouth posture. When the biomechanics of the joint is altered, the disk may be displaced creating an abnormal relationship between the disk, condyle, and the eminence that is often referred to as an internal derangement. This article reviews the various presentations of internal derangements.

Temporomandibular disorders, facial pain, and headaches.

Headaches and facial pain are common in the general population. In many cases, facial pain can be resultant from temporomandibular joint disorders. Studies have identified an association between headaches and temporomandibular joint disorders suggesting the possibility of shared pathophysiologic mechanisms of these 2 maladies. The aim of this paper is to elucidate potential commonalities of these disorders and to provide a brief overview of an examination protocol that may benefit the headache clinician in daily practice.

Data compressive paradigm for multispectral sensing using tunable DWELL mid-infrared detectors.

While quantum dots-in-a-well (DWELL) infrared photodetectors have the feature that their spectral responses can be shifted continuously by varying the applied bias, the width of the spectral response at any applied bias is not sufficiently narrow for use in multispectral sensing without the aid of spectral filters. To achieve higher spectral resolutions without using physical spectral filters, algorithms have been developed for post-processing the DWELL's bias-dependent photocurrents resulting from probing an object of interest repeatedly over a wide range of applied biases. At the heart of these algorithms is the ability to approximate an arbitrary spectral filter, which we desire the DWELL-algorithm combination to mimic, by forming a weighted superposition of the DWELL's non-orthogonal spectral responses over a range of applied biases. However, these algorithms assume availability of abundant DWELL data over a large number of applied biases (>30), leading to large overall acquisition times in proportion with the number of biases. This paper reports a new multispectral sensing algorithm to substantially compress the number of necessary bias values subject to a prescribed performance level across multiple sensing applications. The algorithm identifies a minimal set of biases to be used in sensing only the relevant spectral information for remote-sensing applications of interest. Experimental results on target spectrometry and classification demonstrate a reduction in the number of required biases by a factor of 7 (e.g., from 30 to 4). The tradeoff between performance and bias compression is thoroughly investigated.

Topical review: cluster headache and sleep-related breathing disorders.

This article reviews the existing literature of the common anatomic and physiologic aspects of cluster headache and sleep-related breathing disorders to point out evidence suggesting potential therapies beneficial for both maladies. A search of PubMed, as well as relevant textbooks, was conducted using the terms cluster, headache, sleep, apnea, pain, and chronobiology to find any previously published work that may connect the two disorders. Relevant references in the literature were also investigated. As a group, cluster headache patients tend to have a higher incidence of sleep-related breathing disorders as compared to the noncluster headache population. While commonalities in anatomy and physiology exist, robust evidence linking the two disorders is currently lacking. Many people are unaware that they suffer with a sleep-related breathing disorder. The high incidence of these two disorders occurring together should prompt the clinician who treats cluster headache patients to be acutely aware that a yet undiagnosed sleep disorder may also be present.

Structure-Based Design of Selective LONP1 Inhibitors for Probing In Vitro Biology.

LONP1 is an AAA+ protease that maintains mitochondrial homeostasis by removing damaged or misfolded proteins. Elevated activity and expression of LONP1 promotes cancer cell proliferation and resistance to apoptosis-inducing reagents. Despite the importance of LONP1 in human biology and disease, very few LONP1 inhibitors have been described in the literature. Herein, we report the development of selective boronic acid-based LONP1 inhibitors using structure-based drug design as well as the first structures of human LONP1 bound to various inhibitors. Our efforts led to several nanomolar LONP1 inhibitors with little to no activity against the 20S proteasome that serve as tool compounds to investigate LONP1 biology.

An orally available small-molecule inhibitor of c-Met, PF-2341066, exhibits cytoreductive antitumor efficacy through antiproliferative and antiangiogenic mechanisms.

The c-Met receptor tyrosine kinase and its ligand, hepatocyte growth factor (HGF), have been implicated in the progression of several human cancers and are attractive therapeutic targets. PF-2341066 was identified as a potent, orally bioavailable, ATP-competitive small-molecule inhibitor of the catalytic activity of c-Met kinase. PF-2341066 was selective for c-Met (and anaplastic lymphoma kinase) compared with a panel of >120 diverse tyrosine and serine-threonine kinases. PF-2341066 potently inhibited c-Met phosphorylation and c-Met-dependent proliferation, migration, or invasion of human tumor cells in vitro (IC(50) values, 5-20 nmol/L). In addition, PF-2341066 potently inhibited HGF-stimulated endothelial cell survival or invasion and serum-stimulated tubulogenesis in vitro, suggesting that this agent also exhibits antiangiogenic properties. PF-2341066 showed efficacy at well-tolerated doses, including marked cytoreductive antitumor activity, in several tumor models that expressed activated c-Met. The antitumor efficacy of PF-2341066 was dose dependent and showed a strong correlation to inhibition of c-Met phosphorylation in vivo. Near-maximal inhibition of c-Met activity for the full dosing interval was necessary to maximize the efficacy of PF-2341066. Additional mechanism-of-action studies showed dose-dependent inhibition of c-Met-dependent signal transduction, tumor cell proliferation (Ki67), induction of apoptosis (caspase-3), and reduction of microvessel density (CD31). These results indicated that the antitumor activity of PF-2341066 may be mediated by direct effects on tumor cell growth or survival as well as antiangiogenic mechanisms. Collectively, these results show the therapeutic potential of targeting c-Met with selective small-molecule inhibitors for the treatment of human cancers.

Burning Mouth Syndrome.

Burning mouth syndrome (BMS) is a chronic disorder for which a definitive etiopathology is not known. The BMS patient often experiences a continuous burning pain in the mouth without any clinical signs. This confusing condition can create frustration for both patient and practitioner. Ultimately, it is important for the practitioner who treats head and face pain to become knowledgeable in the recognition of the many complexities and various presentations associated with BMS. In doing so, the practitioner can be better prepared to help patients cope with this confounding disorder and gain a better quality of life.

Assessment of the Orofacial Pain Patient.

The diagnostic process of pain in the oral, facial, and head region is often perceived as more difficult due the numerous, extensively innervated structures located in this area. To successfully manage the patient with these pain presentations, it is critical for the clinician to spend ample time procuring a good medical and dental history. A systematic approach to the physical examination will ensure that sufficient data are acquired without overlooking potentially important contributing factors. The use of adjunctive laboratory tests and imaging studies should be based on the findings in the history and examination.