Dominik A. Ettlin

Early diagnosis of temporomandibular joint involvement in juvenile idiopathic arthritis: a pilot study comparing clinical examination and ultrasound to magnetic resonance imaging

Objectives. To study the validity of both rheumatological and orthodontic examinations and ultrasound (US) as screening methods for early diagnosis of TMJ arthritis against the gold standard MRI. Methods. Thirty consecutive juvenile idiopathic arthritis (JIA) patients were included in this pilot study. Rheumatological and orthodontic examinations as well as US were performed within 1 month of the MRI in a blinded fashion. Joint effusion and/or increased contrast enhancement of synovium or bone were considered signs of active arthritis on MRI. Results. A total of 19/30 (63%) patients and 33/60 (55%) joints had signs of TMJ involvement on MRI. This was associated with condylar deformity in 9/19 (47%) patients and 15/33 (45%) joints. Rheumatological, orthodontic and US examinations correctly diagnosed 11 (58%), 9 (47%) and 6 (33%) patients, respectively, with active TMJ arthritis, but misdiagnosed 8 (42%), 10 (53%) and 12 (67%) patients, respectively, as having no signs of inflammation. The best predictor for active arthritis on MRI was a reduced maximum mouth opening. Conclusion. None of the methods tested was able to reliably predict the presence or absence of MRI-proven inflammation in the TMJ in our cohort of JIA patients. US was the least useful of all methods tested to exclude active TMJ arthritis.

Classifying orofacial pains: a new proposal of taxonomy based on ontology.

We propose a new taxonomy model based on ontological principles for disorders that manifest themselves through the symptom of persistent orofacial pain and are commonly seen in clinical practice and difficult to manage. Consensus meeting of eight experts from various geographic areas representing different perspectives (orofacial pain, headache, oral medicine and ontology) as an initial step towards improving the taxonomy. Ontological principles were introduced, reviewed and applied during the consensus building process. Diagnostic criteria for persistent dento-alveolar pain disorder (PDAP) were formulated as an example to be used to model the taxonomical structure of all orofacial pain conditions. These criteria have the advantage of being (i) anatomically defined, (ii) in accordance with other classification systems for the provision of clinical care, (iii) descriptive and succinct, (iv) easy to adapt for applications in varying settings, (v) scalable and (vi) transferable for the description of pain disorders in other orofacial regions of interest. Limitations are that the criteria introduce new terminology, do not have widespread acceptance and have yet to be tested. These results were presented to the greater conference membership and were unanimously accepted. Consensus for the diagnostic criteria of PDAP was established within this working group. This is an initial first step towards developing a coherent taxonomy for orofacial pain disorders, which is needed to improve clinical research and care.

Do illness perceptions predict pain-related disability and mood in chronic orofacial pain patients? A 6-month follow-up study

In our study, we investigated the predictive value of illness beliefs as measured by the revised illness perception questionnaire (IPQ‐R) in the context of other clinical predictors in patients with chronic orofacial pain over a 6‐month follow‐up period. Consecutive patients (152) referred to the interdisciplinary orofacial pain service at the Centre for Dental and Oral Medicine and Cranio‐Maxillofacial Surgery, University of Zurich received questionnaires to assess pain and pain‐related disability, anxiety, depression as well as physical and mental quality of life at three time points: prior to treatment, 3 and 6 months after beginning of treatment. Results: significant improvement was found over time for all outcome measures except mental quality of life. Results of the regression analysis indicated that believing pain could have serious consequences on ones life (IPQ subscale consequences) is one of the most important predictors for treatment outcome. The belief in low personal control and in a chronic timeline is also shown to be predictive for outcome, though explaining a smaller proportion of variance. These results provided evidence that beliefs about pain are important predictors for treatment outcome even when controlled for pain and mood. They therefore need to be considered in the management of patients with chronic orofacial pain. Assessing patients’ illness beliefs can provide essential information on these important psychological determinants of adjustment to chronic pain and may be specific targets for individualised treatment approaches.

Cortical Activation Resulting from Painless Vibrotactile Dental Stimulation Measured by Functional Magnetic Resonance Imaging (fMRI)

There have been few investigations on hemodynamic responses in the human cortex resulting from dental stimulation. Identification of cortical areas involved in stimulus perception may offer new targets for pain treatment. This initial study aimed at establishing a cortical map of dental representation, based on non-invasive fMRI measurements. Five right-handed subjects were studied. Eight maxillary and 8 mandibular teeth were stimulated after the vibratory perception threshold was determined for each tooth. Suprathreshold stimulation was repeated thrice per session, in a total of three sessions performed on three consecutive days. Statistical inference on cluster level identified increased blood-oxygen-level-dependent signal during vibratory dental stimulation, primarily in the insular cortex bilaterally and in the supplementary motor cortex. No significant brain activation was observed in the somatosensory cortex with this stimulation protocol. These results agree with previous findings obtained from invasive direct electrical cortical stimulation of the human insula.

Impact of a collagen matrix on early healing, aesthetics and patient morbidity in oral mucosal wounds – a randomized study in humans

AIM To test whether a collagen matrix (CM) can improve early wound healing and aesthetics, and decrease wound sensitivity compared with spontaneous healing. METHODS In 15 volunteers, 6-mm punch biopsies were harvested at both palatal sites. A CM was sutured in one site; the other one was left untreated (control). Measurements included the remaining defect area, the colour match to surrounding tissue and somatosensory parameters at various time-points (pre-operative, post-operative, 4, 8, 15, 29 days). RESULTS The defect area decreased over time for both treatments. Re-epithelization was completed in all subjects by day 15. The defect area was significantly smaller for CM (mean ± SD: 19.3 ± 3.4 mm(2)) compared with control (21.3 ± 3.3 mm(2)) at day 4 (p < 0.05), and at day 8 (CM: 11.7 ± 2.5 mm(2) ; control: 13.6 ± 2.9 mm(2) ; p < 0.01). The colour match was more favourable for CM at day 4, 8 and 29 (p > 0.05). Somatosensory measurements revealed slightly lower wound sensitivity at day 4 for CM compared with control. CONCLUSIONS The use of CM can enhance wound healing compared with spontaneous healing during the first week. This was mainly documented by a faster re-epithelization. Colour match and wound sensitivity measurements did not reach statistical significance between CM and control sites.

Enhanced negative feedback sensitivity of the hypothalamus–pituitary–adrenal axis in chronic myogenous facial pain⋆

Dysregulations of the hypothalamus–pituitary–adrenal (HPA) axis, as a physiological substrate of stress, have been observed in patients with different stress‐related and chronic pain disorders. In this study, we investigated possible dysregulations of the HPA axis in patients with masticatory muscles pain. In 20 patients with myogenous facial pain and 20 healthy controls, awakening cortisol responses, i.e. cortisol rise in the first hour after awakening, as well as a short circadian free cortisol profile, i.e. four cortisol samples over 12h during the day, were assessed before and after administration of 0.5mg dexamethasone. Results: In comparison to controls, chronic myogenous facial pain patients showed enhanced and prolonged suppression of cortisol after the administration of 0.5mg dexamethasone. Unstimulated cortisol response (before dexamethasone‐intake) to awakening and cortisol levels during the day did not differ between the groups. Dysregulation in terms of enhanced negative feedback suppression exists in chronic myogenous facial pain. These results are in line with a multifactorial etiology of chronic facial pain, shifting the perspective away from a local towards a more central etiology with dysregulations in the stress and pain modulating system.

Stereometric Assessment of TMJ Space Variation by Occlusal Splints

Occlusal splints are used for the management of temporomandibular disorders, although their mechanism of action remains controversial. This study investigated whether insertion of an occlusal splint leads to condyle-fossa distance changes, and to mandibular rotation and/or translation. By combining magnetic resonance images with jaw tracking (dynamic stereometry), we analyzed the intra-articular distances of 20 human temporomandibular joints (TMJs) before and after insertion of occlusal splints of 3 mm thickness in the first molar region. For habitual closure, protrusion, and laterotrusion in the contralateral joint, occlusal splints led to minor—yet statistically significant—increases of global TMJ space and to larger increases at defined condylar areas. Condylar end rotation and translation in habitual closure were reduced. Hence, the insertion of a 3-mm-thick occlusal splint led to a change in the topographical condyle-fossa relationship, and therefore to a new distribution of contact areas between joint surfaces.

Safety and efficacy of a Nav1.7 selective sodium channel blocker in patients with trigeminal neuralgia: a double-blind, placebo-controlled, randomised withdrawal phase 2a trial

BACKGROUND Current standard of care for trigeminal neuralgia is treatment with the sodium channel blockers carbamazepine and oxcarbazepine, which although effective are associated with poor tolerability and the need for titration. BIIB074, a Nav1.7-selective, state-dependent sodium-channel blocker, can be administered at therapeutic doses without titration, and has shown good tolerability in healthy individuals in phase 1 studies. We therefore assessed the safety and efficacy of BIIB074 in patients with trigeminal neuralgia in a phase 2a study. METHODS We did a double-blind, multicentre, placebo-controlled, randomised withdrawal phase 2a trial in 25 secondary care centres in Denmark, Estonia, France, Germany, Italy, Latvia, Lithuania, Romania, South Africa, Spain, Switzerland, and the UK. After a 7-day run-in phase, eligible patients aged 18-80 years with confirmed trigeminal neuralgia received open-label, BIIB074 150 mg three times per day, orally, for 21 days. Patients who met at least one response criteria were then randomly assigned (1:1) to BIIB074 or placebo for up to 28 days in a double-blind phase. We used an interactive web response system to assign patients with a computer-generated schedule, with stratification (presence or absence of existing pain medication). Patients, clinicians, and assessors were masked to treatment allocation. The primary endpoint was the difference between groups in the number of patients classified as treatment failure during the double blind phase assessed in the modified intention-to-treat population. We assessed safety in all patients who received one or more doses of BIIB074. This study is registered with ClinicalTrials.gov (NCT01540630) and EudraCT (2010-023963-16). FINDINGS The first patient was enrolled on April 23, 2012, and the last patient completed the study on February 26, 2014. We enrolled 67 patients into the open-label phase; 44 completed open-label treatment, and 29 were randomly assigned to double-blind treatment (15 to BIIB074 and 14 to placebo). During the double-blind phase, five (33%) patients assigned to BIIB074 versus nine (64%) assigned to placebo were classified as treatment failures (p=0·0974). BIIB074 was well tolerated, with similar adverse events in the double-blind phase to placebo. Headache was the most common adverse event with BIIB074 in the open-label phase (in 13 [19%] of 67 patients), followed by dizziness (in six [9%] patients). In the double-blind phase, headache, pyrexia, nasopharyngitis, sleep disorder, and tremor were the most frequent adverse events in patients assigned to BIIB074 (in one [7%] of 15 patients for each event), and headache, dizziness, diarrhoea, and vomiting were the most frequent adverse events in patients assigned to placebo (in one [7%] of 14 patients for each event). No severe or serious adverse events were reported in the BIIB074 group during the double-blind phase. One patient assigned to placebo reported intestinal adhesions with obstruction as a severe and serious adverse event, which was considered as unrelated to study medication. INTERPRETATION The primary endpoint of treatment failure was not significantly lower in the BIIB074 group than in the placebo group. However, our findings provide a basis for continued investigation of BIIB074 in patients with trigeminal neuralgia in future clinical trials. FUNDING Convergence Pharmaceuticals.

Taking Sides with Pain – Lateralization aspects Related to Cerebral Processing of Dental Pain

The current fMRI study investigated cortical processing of electrically induced painful tooth stimulation of both maxillary canines and central incisors in 21 healthy, right-handed volunteers. A constant current, 150% above tooth specific pain perception thresholds was applied and corresponding online ratings of perceived pain intensity were recorded with a computerized visual analog scale during fMRI measurements. Lateralization of cortical activations was investigated by a region of interest analysis. A wide cortical network distributed over several areas, typically described as the pain or nociceptive matrix, was activated on a conservative significance level. Distinct lateralization patterns of analyzed structures allow functional classification of the dental pain processing system. Namely, certain parts are activated independent of the stimulation site, and hence are interpreted to reflect cognitive emotional aspects. Other parts represent somatotopic processing and therefore reflect discriminative perceptive analysis. Of particular interest is the observed amygdala activity depending on the stimulated tooth that might indicate a role in somatotopic encoding.

Novel design for a phase IIa placebo-controlled, double-blind randomized withdrawal study to evaluate the safety and efficacy of CNV1014802 in patients with trigeminal neuralgia

BackgroundTrigeminal neuralgia (TN) is a rare severe unilateral facial pain condition. Current guidelines in trigeminal neuralgia management recommend sodium channel blockers – carbamazepine or oxcarbazepine – as the first-line treatment. However, the currently available drugs are often associated with poor tolerability resulting in sub-optimal pain control. CNV1014802 is a novel sodium channel blocker that is being assessed in the treatment of trigeminal neuralgia. Due to the severity of the condition, it is not ethical to conduct a traditional placebo-controlled randomized controlled trial. It is also difficult to use an active control such as carbamazepine, the current gold standard, because of its complex pharmacology and potential for drug interactions.Methods/DesignThe trial uses a randomized withdrawal design to assess efficacy in this rare condition. There is a 21-day open-label phase followed by a randomized 28-day placebo-controlled phase for responders. Thirty patients will be randomized. The primary outcome measure will be pain relief, but secondary measures of quality of life will be of significant importance given the effect of this condition on activities of daily living. Safety and adverse event endpoints are described.DiscussionThere have been very few well-controlled, randomized, placebo-controlled studies in trigeminal neuralgia, and the majority of drugs have had other primary uses. Due to the severity of the pain, minimizing the time a patient is administered placebo was a key factor in designing this study. This study will not only provide data on the efficacy of CNV1014802 in trigeminal neuralgia, but will also provide information on the effectiveness and acceptability of a novel trial design in trigeminal neuralgia.Trial registrationTrial number NCT01540630