Differential gene expression in trigeminal ganglia of male and female rats following chronic constriction of the infraorbital nerve.

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 naïve 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.

Tic, Triggering, and Tearing: From CTN to SUNHA.

PREMISE: Classical trigeminal neuralgia (CTN) and the short-lasting unilateral neuralgiform headache attacks (SUNHA) are clinically similar. PROBLEM: The SUNHAs include short-lasting unilateral neuralgiform headache attacks with conjunctival injection and tearing (SUNCT) and short-lasting unilateral neuralgiform headache attacks with cranial autonomic symptoms (SUNA). Shared clinical signs with CTN include severe, unilateral trigeminal pain that is often triggered by innocuous stimuli and accompanied by a dull persistent background pain. Recent reports on trigeminal neuralgia cases with atypical features such as autonomic signs and prolonged attack duration further blur the clinical distinction between CTN and SUNHAs. POTENTIAL SOLUTIONS: Are the similarities greater than their differences? If so, this may reflect a spectrum of disease ranging from typical CTN attacks to typical SUNHAs with a mixed phenotype in the middle. In this review they will summarize the overlap between these entities and contrast the pathophysiology and treatment approach.

An update of management of insomnia in patients with chronic orofacial pain.

In this review, we discuss the management of chronic orofacial pain (COFP) patients with insomnia. Diagnostic work-up and follow-up routines of COFP patients should include assessment of sleep problems. Management is based on a multidisciplinary approach, addressing the factors that modulate the pain experience as well as insomnia and including both non-pharmacological and pharmacological modalities. Parallel to treatment, patients should receive therapy for comorbid medical and psychiatric disorders, and possible substance abuse that may be that may trigger or worsen the COFP and/or their insomnia. Insomnia treatment should begin with non-pharmacological therapy, to minimize potential side effects, drug interactions, and risk of substance abuse associated with pharmacological therapy. Behavioral therapies for insomnia include the following: sleep hygiene, cognitive behavioral therapy for insomnia, multicomponent behavioral therapy or brief behavioral therapy for insomnia, relaxation strategies, stimulus control, and sleep restriction. Approved U.S. Food and Drug Administration medications to treat insomnia include the following: benzodiazepines (estazolam, flurazepam, temazepam, triazolam, and quazepam), non-benzodiazepine hypnotics (eszopiclone, zaleplon, zolpidem), the melatonin receptor agonist ramelteon, the antidepressant doxepin, and the orexin receptor antagonist suvorexant. Chronic orofacial pain can greatly improve following treatment of the underlying insomnia, and therefore, re-evaluation of COFP is advised after 1 month of treatment.

Trigeminal neuralgia (part II): Factors affecting early pharmacotherapeutic outcome.

AIMS: We conducted a cohort study to examine demographic and clinical features associated with the pharmacotherapeutic outcome in classical trigeminal neuralgia (CTN) patients. METHODS: Patients with a clinical profile indicating a diagnosis of CTN, as per the International Headache Society's published classification, were enrolled prospectively. Demographic and pain-related characteristics were carefully collected. For the purposes of the study, patients with features such as autonomic signs and longer attack duration were included. All patients were then initiated on a standardised and accepted stepped pharmacotherapeutic protocol for the management of CTN. Initial pain scores and prospectively collected pain scores from pain diaries were used to assess the treatment outcome, with a ≥50% reduction considered significant. RESULTS: A total of 86 patients were seen, of whom five had an underlying disorder that could account for the pain. The study cohort therefore consisted of 81 patients, and based on attack duration these were divided into short (≤2 minutes, n = 61) and long (>2 minutes, n = 20) groups, for further analysis. The features of these patients and a discussion on the differential diagnosis have been presented in part 1 of this report. Employing an accepted stepped pharmacotherapeutic protocol for the management of CTN, significant improvement was more frequent in the short (74%) than in the long attack group (50%, p = 0.05). In the short attack group there were statistically significant associations between a poor treatment response and longer disease duration, the presence of autonomic signs and atypical pain descriptors for pain quality (p < 0.05). CONCLUSION: This report supports previous findings that prolonged disease duration and autonomic signs are negative prognostic indicators. The present study now adds long attack duration as a further negative prognostic sign.

Trigeminal neuralgia (part I): Revisiting the clinical phenotype.

AIMS: We conducted a cross-sectional study to re-examine the clinical profile of patients with a clinical diagnosis of classical trigeminal neuralgia (CTN). METHODS: Inclusion criteria consisted of the International Headache Society's published classification of CTN. For the specific purposes of the study, features such as autonomic signs, persistent background pain, attack durations of >2 minutes and reports of pain-related awakening were included. The demographic and clinical phenotype of each patient were carefully recorded for analysis. RESULTS: The study cohort consisted of 81 patients and based on reported attack duration these were divided into short (≤ 2 minutes, n = 61) and long (> 2 minutes, n = 20) groups for further analysis. The group with short attack duration neatly fit most of the criteria for CTN while the long attack group presents a more challenging diagnosis. There were no significant differences in pain severity, quality and location between the short and long attack groups. The frequency of persistent background pain was significantly higher in the long (70%) compared to the short attack group (29.5%, p = 0.001). There were significantly more reports of pain-related awakenings in the long (55%) than in the short attack groups (29.5%, p = 0.04). There were no significant differences in the frequency of autonomic signs between the short (21.3%) and long attack groups (40%, p = 0.1). In the short attack group, the presence of autonomic signs was significantly associated with longer disease duration, increased pain-related awakenings, and a reduced prognosis. CONCLUSION: There are clear diagnostic criteria for CTN but often patients present with features, such as long pain attacks, that challenge such accepted criteria. In our cohort the clinical phenotype of trigeminal, neuralgiform pain with or without autonomic signs and background pain was observed across both short and long attack groups and the clinical implications of this are discussed.

Perspectives on next steps in classification of oro-facial pain - part 2: role of psychosocial factors.

This study was initiated by a symposium, in which the present authors contributed, organised by the International RDC/TMD Consortium Network in March 2013. The purpose of the study was to review the status of biobehavioural research - both quantitative and qualitative - related to oro-facial pain (OFP) with respect to the aetiology, pathophysiology, diagnosis and management of OFP conditions, and how this information can optimally be used for developing a structured OFP classification system for research. In particular, we address representation of psychosocial entities in classification systems, use of qualitative research to identify and understand the full scope of psychosocial entities and their interaction, and the usage of classification system for guiding treatment. We then provide recommendations for addressing these problems, including how ontological principles can inform this process.

A 2-year mean follow-up of oral appliance therapy for severe obstructive sleep apnea: a cohort study.

OBJECTIVE: Oral appliances for treating severe obstructive sleep apnea (OSA) are recommended for patients who failed to comply with continuous positive airway pressure (CPAP) treatment. The objective of this study was to evaluate medium long-term outcome and success rates of oral appliances in patients with severe OSA. METHODS: In a retrospective study, 52 OSA patients with an apnea-hypopnea index (AHI) ≥40, who did not tolerate CPAP treatment, were enrolled and fitted with a modified Herbst oral appliance. A 2-year mean follow-up including a second somnography was conducted in 36 of the patients. RESULTS: A significant reduction (P < 0.0001) in the AHI was demonstrated between the initial somnography (55.25 ± 10.79,) and the followed one (17.74 ± 11.0, n = 36). Overall, 57.7% of total study subjects (n = 52) and 63.9% (n = 36) that had sequential sonmogarphy continued using the device. The reduction in AHI in the user group was 42.4 ± 3.1 (n = 23), which was significantly higher (P = 0.013) than in the non-user group (28.9 ± 17.2; n = 13). Moreover, 53% (n = 19) reached AHI of <15. CONCLUSIONS: Oral appliances were found to be successful for treating for severe OSA after first-line treatment had failed.

Peripheral painful traumatic trigeminal neuropathies.

The aim of this article is to review the clinical, pathophysiological, and therapeutic aspects of traumatically induced trigeminal nerve pain. We introduce a new and, in our view, more accurate terminology: peripheral painful traumatic trigeminal neuropathy (PPTTN) to define this patient group. The proposed pathophysiology of PPTTN is largely based on studies in spinal nerve injury models. However, trigeminal nerve injury studies have shown some subtle differences in response to physical and inflammatory insults, and these are discussed. The treatment of painful neuropathies is difficult and carries a poor prognosis. Based on the available literature on efficacy and side effects, we propose a treatment algorithm for traumatic trigeminal neuropathies.

Sialochemistry and cortisol levels in patients with Sjogren's syndrome.

OBJECTIVES: (i) To determine whether salivary cortisol and electrolyte levels differ between patients with Sjogren's syndrome (SjS) and healthy individuals. (ii) To assess correlations between whole-saliva cortisol and some clinical manifestations in patients with SjS. METHODS: A total of 24 healthy women (mean age 49.3±9.8) served as controls (C) vis-à-vis 17 patients with SjS (mean age 55.5±15.7). Salivary cortisol concentration was determined, and sialochemistry analysis was performed. RESULTS: Significantly lower saliva flow rates and higher salivary chloride (Cl(-) ), potassium (K(+) ), and Ca(2+) levels were found in the SjS group. No significant differences or correlations were found in other parameters, including sodium (Na(+) ), magnesium (Mg(2+) ), phosphate ((-) ), urea (U), and salivary cortisol levels. CONCLUSION: Increased whole-salivary output of Cl(-) and K(+) in SjS may reflect release from apoptotic rests of acinar cells after secondary necrosis. Normal levels of salivary Na(+) , Mg(2+) , and (-) argue against concentration effect, deranged tubular function or cortisol (mineralocorticosteroid) effect as the cause for these findings. Increased salivary Ca(2+) levels probably reflect leakage of plasma Ca(2+) through the injured oral mucosa in SjS. In spite of disease-associated stress, salivary cortisol, a stress biomarker, was not increased, suggesting insufficient hypothalamus-pituitary-adrenal (HPA) axis response and/or local consumption of cortisol by lymphocyte infiltrates.

Persistent orofacial muscle pain.

The pathophysiology of persistent orofacial myalgia has been the centre of much controversy. In this article we suggest a novel descriptive term; 'persistent orofacial muscle pain' (POMP) and review current evidence that supports the hypothesis that the induction of POMP involves the interplay between a peripheral nociceptive source in muscle, a faulty central nervous system component and decreased coping ability. In this context it is widely accepted that a complex interaction of variable intrinsic and extrinsic factors act to induce POMP and dysfunction.

Comparison of oral mucosal pH values in bulimia nervosa, GERD, BMS patients and healthy population.

OBJECTIVES: The aim of this study was to compare the oral mucosal pH in healthy individuals to patients with gastroesophageal reflux disease (GERD), Bulimia nervosa (BN) and burning mouth syndrome (BMS). SUBJECTS AND METHODS: Using a flat pH meter sensor, pH levels were established in eight mucosal sites in 26 healthy individuals, 26 GERD patients, 22 BN patients and 29 BMS patients. RESULTS: A significantly lower pH was found in the BN and GERD groups (6.38 ± 00.45, 6.51 ± 0.32 respectively, P < 0.05) and a higher, but non-significant, pH level in the BMS group (7.01 ± 0.34, P > 0.05) compared with the control (C) group (6.82 ± 0.33). CONCLUSIONS: BMS patients showed no pH differences from C group. The mucosa of BN and GERD patients was significantly acidic relative with controls; thus this simple technique may serve as a diagnostic tool for identifying gastro-esophageal conditions.

The International Classification of Headache Disorders: accurate diagnosis of orofacial pain?

The aim was to apply diagnostic criteria, as published by the International Headache Society (IHS), to the diagnosis of orofacial pain. A total of 328 consecutive patients with orofacial pain were collected over a period of 2 years. The orofacial pain clinic routinely employs criteria published by the IHS, the American Academy of Orofacial Pain (AAOP) and the Research Diagnostic Criteria for Temporomandibular Disorders (RDCTMD). Employing IHS criteria, 184 patients were successfully diagnosed (56%), including 34 with persistent idiopathic facial pain. In the remaining 144 we applied AAOP/RDCTMD criteria and diagnosed 120 as masticatory myofascial pain (MMP) resulting in a diagnostic efficiency of 92.7% (304/328) when applying the three classifications (IHS, AAOP, RDCTMD). Employing further published criteria, 23 patients were diagnosed as neurovascular orofacial pain (NVOP, facial migraine) and one as a neuropathy secondary to connective tissue disease. All the patients were therefore allocated to predefined diagnoses. MMP is clearly defined by AAOP and the RDCTMD. However, NVOP is not defined by any of the above classification systems. The features of MMP and NVOP are presented and analysed with calculations for positive (PPV) and negative predictive values (NPV). In MMP the combination of facial pain aggravated by jaw movement, and the presence of three or more tender muscles resulted in a PPV = 0.82 and a NPV = 0.86. For NVOP the combination of facial pain, throbbing quality, autonomic and/or systemic features and attack duration of > 60 min gave a PPV = 0.71 and a NPV = 0.95. Expansion of the IHS system is needed so as to integrate more orofacial pain syndromes.

[Antibiotic prophylaxis for the prevention of infective endocarditis--new guidelines of the American Heart Association].

Within the last twelve month both the working party of the British Society for Antimicrobial Chemotherapy and the American Heart Association have changed their attitude towards antibiotic prophylaxis for the prevention of infective endocarditis dramatically. The major change is the exclusion of the groups of patients formerly known as the "low and medium" risk groups from the new treatment group. A brief summary of the American as well as the British recommendations for adults and children is reported.

Orofacial pain in cancer: part I--mechanisms.

The mechanisms involved, and possible treatment targets, in orofacial pain due to cancer are poorly understood. The aim of the first of this two-part series is to review the involved pathophysiological mechanisms and explore their possible roles in the orofacial region. However, there is a lack of relevant research in the trigeminal region, and we have therefore applied data accumulated from experiments on cancer pain mechanisms in rodent spinal models. In the second part, we review the clinical presentation of cancer-associated orofacial pain at various stages: initial diagnosis, during therapy (chemo-, radiotherapy, surgery), and in the post-therapy period. In the present article, we provide a brief outline of trigeminal functional neuro-anatomy and pain-modulatory pathways. Tissue destruction by invasive tumors (or metastases) induces inflammation and nerve damage, with attendant acute pain. In some cases, chronic pain, involving inflammatory and neuropathic mechanisms, may ensue. Distant, painful effects of tumors include paraneoplastic neuropathic syndromes and effects secondary to the release of factors by the tumor (growth factors, cytokines, and enzymes). Additionally, pain is frequent in cancer management protocols (surgery, chemotherapy, and radiotherapy). Understanding the mechanisms involved in cancer-related orofacial pain will enhance patient management.

Orofacial pain in cancer: part II--clinical perspectives and management.

Cancer-associated pain is extremely common and is associated with significant physical and psychological suffering. Unfortunately, pain associated with cancer or its treatment is frequently under-treated, probably due to several factors, including phobia of opioids, under-reporting by patients, and under-diagnosis by healthcare workers. The most common etiology of cancer pain is local tumor invasion (primary or metastatic), involving inflammatory and neuropathic mechanisms; these have been reviewed in Part I. As malignant disease advances, pain usually becomes more frequent and more intense. Additional expressions of orofacial cancer pain include distant tumor effects, involving paraneoplastic mechanisms. Pain secondary to cancer therapy varies with the treatment modalities used: Chemo-radiotherapy protocols are typically associated with painful mucositis and neurotoxicity. Surgical therapies often result in nerve and tissue damage, leading, in the long term, to myofascial and neuropathic pain syndromes. In the present article, we review the clinical presentation of cancer-associated orofacial pain at various stages: initial diagnosis, during therapy (chemo-, radiotherapy, surgery), and in the post-therapy period. As a presenting symptom of orofacial cancer, pain is often of low intensity and diagnostically unreliable. Diagnosis, treatment, and prevention of pain in cancer require knowledge of the presenting characteristics, factors, and mechanisms involved.

The distribution of oral mucosal pH values in healthy saliva secretors.

OBJECTIVES: To establish the normal range of oral mucosal pH and to correlate these measurements to salivary flow rate in healthy individuals according to age and gender. SUBJECTS AND METHODS: Measurements of pH levels using a flat pH meter and salivary secretion rates were established in eight mucosal sites from a total of 50 healthy individuals. RESULTS: The mean pH (+/-s.d.) of all sites was 6.78 +/- 0.04 with significant differences between mean pH values in the palate (7.34 +/- 0.38), the floor of the mouth (6.5 +/- 0.3), the buccal mucosa (6.28 +/- 0.36) and the tongue (6.8 +/- 0.26). A significant correlation was found between age and pH at palatal and tongue sites but no gender effects were noted. CONCLUSIONS: This method is easy and relatively quick to manipulate, and may offer many diagnostic possibilities for oral related diseases and disorders such as oral malodour, mouth breathing, dysgeusia, acidic diet consumption and gastrointestinal disorders affecting the mouth.

[Impaired sense of taste--diagnosis and treatment].

The sense of taste has great importance in health and disease. Complaints of oral discomfort associated with taste disturbances are increasingly met in the clinical setting. Altered taste perception can result from various underlying local or systemic pathology, as well as serious sensorial syndromes. Although they are not straightforward to diagnose and manage, it is important for the clinician to understand the pathphysiology of this chemosensory system, and to be able to use objective measures in order to quantify and classify the apparent symptoms, thus making the first step to correct diagnosis and treatment.

Inflammation with no axonal damage of the rat saphenous nerve trunk induces ectopic discharge and mechanosensitivity in myelinated axons.

Inflammation along a nerve trunk with no frank axonal nerve damage produced by complete Freund's adjuvant (CFA) or Carrageenan is known to induce a painful peripheral neuropathy. In the present study, we examined the electrophysiological properties of myelinated axons (spontaneous discharge and mechanical sensitivity) at the inflamed nerve site. The rat saphenous nerves were exposed at mid-thigh level and wrapped in 2 mm wide bands of haemostatic oxidized cellulose (Oxycel) that were saturated with undiluted CFA. In the control rats the Oxycel) was saturated with saline. At postoperative days (PODs) 2-5 and 6-10, fine axon bundles were teased from the nerve, and electrophysiological recordings performed. At both time points spontaneous activity at the site of the application in CFA rats (PODs 2-5=9.9+/-2.5%: PODs 6-10=6.1+/-1.4%) was significantly higher than in the control animals (PODs 2-5=2.9+/-1.1%: PODs 6-10=1.6+/-1.4%: P=0.03, P=0.02, respectively). Mechanical sensitivity at both time points was significantly higher in CFA rats (PODs 2-5=12.6+/-3.1%: PODs 6-10=10.3+/-3.1%) than in saline rats (PODs 2-5=3.4+/-2.91%: PODs 6-10=0.8+/-1.0%: P=0.03, P=0.04, respectively). This study clearly shows that perineural inflammation with no axonal nerve damage induced by CFA application around the nerve trunk elevates spontaneous activity and induces mechanosensitivity in myelinated axons.