Current and innovative pharmacological options to treat typical and atypical trigeminal neuralgia

Trigeminal neuralgia is a representative neuropathic facial pain condition, characterised by unilateral paroxysmal pain in the distribution territory of one or more divisions of the trigeminal nerve, triggered by innocuous stimuli. A subgroup of patients with trigeminal neuralgia [TN (previously defined as atypical TN)] also suffer from concomitant continuous pain, i.e. a background pain between the paroxysmal attacks. The aim of this review is to provide current, evidence-based, knowledge about the pharmacological treatment of typical and atypical TN, with a specific focus on drugs in development. We searched for relevant papers within PubMed, EMBASE, the Cochrane Database of Systematic Reviews and the Clinical Trials database (ClinicalTrials.gov), taking into account publications up to February 2018. Two authors independently selected studies for inclusions, data extraction, and bias assessment. Carbamazepine and oxcarbazepine are the first-choice drugs for paroxysmal pain. When sodium channel blockers cannot reach full dosage because of side effects, an add-on treatment with lamotrigine or baclofen should be considered. In patients with atypical TN, both gabapentin and antidepressants are expected to be efficacious and should be tried as an add-on to oxcarbazepine or carbamazepine. Although carbamazepine and oxcarbazepine are effective in virtually the totality of patients, they are responsible for side effects causing withdrawal from treatment in an important percentage of cases. A new, better tolerated, Nav1.7 selective state-dependent, sodium channel blocker (vixotrigine) is under development. Future trials testing the effect of combination therapy in patients with TN are needed, especially in patients with concomitant continuous pain and in TN secondary to multiple sclerosis

Iatrogenic damage to the mandibular nerves as assessed by the masseter inhibitory reflex

Iatrogenic injury of the inferior alveolar or lingual nerves frequently leads to legal actions for damage and compensation for personal suffering. The masseter inhibitory reflex (MIR) is the most used neurophysiological tool for the functional assessment of the trigeminal mandibular division. Aiming at measuring the MIR sensitivity and specificity, we recorded this reflex after mental and tongue stimulations in a controlled, blinded study in 160 consecutive patients with sensory disturbances following dental procedures. The MIR latency was longer on the affected than the contralateral side (P < 0.0001). The overall specificity and sensitivity were 99 and 51%. Our findings indicate that MIR testing, showing an almost absolute specificity, reliably demonstrates nerve damage beyond doubt, whereas the relatively low sensitivity makes the finding of a normal MIR by no means sufficient to exclude nerve damage. Probably, the dysfunction of a small number of nerve fibres, insufficient to produce a MIR abnormality, may still engender important sensory disturbances. We propose that MIR testing, when used for legal purposes, be considered reliable in one direction only, i.e. abnormality does prove nerve damage, normality does not disprove it

Pain outside the body: defensive peripersonal space deformation in trigeminal neuralgia

Perception of space has been guiding effective therapeutic interventions in a number of unilateral chronic pain conditions. However little is known about how trigeminal neuralgia (TN), a condition in which trigeminal stimulation triggers paroxysmal facial pain, affects defensive peripersonal space (DPPS), the portion of space surrounding the body within which defensive responses are enhanced. Given that TN is unilateral, in TN patients the DPPS of the face might not be horizontally symmetric as in pain-free individuals, but instead larger around the affected side. We tested this a priori hypothesis by measuring the proximity-dependent modulation of the hand-blink reflex. Stimuli delivered to the hand ipsilateral to TN elicited a stronger blink, particularly when it was measured from the eye ipsilateral to TN and the hand was closer to the face. Geometric modelling revealed (1) that DPPS was larger on the side of space ipsilateral to TN, and (2) this asymmetry was consequent to an increased estimated potential of sensory events to cause harm when they occur ipsilaterally to TN. These observations demonstrate that neural mechanisms underlying body protection in TN are adjusted to reduce the likelihood that external events evoke the painful paroxysm typical of this condition

Tools for Assessing Neuropathic Pain

Giorgio Cruccu and Andrea Truini discuss a new pain assessment tool published in PLoS Medicine called Standardized Evaluation of Pain and they review other tools to assess neuropathic pain

Painful stimulation increases spontaneous blink rate in healthy subjects

Spontaneous blink rate is considered a biomarker of central dopaminergic activity. Recent evidence suggests that the central dopaminergic system plays a role in nociception. In the present study, we aimed to investigate whether pain modulates spontaneous blink rate in healthy subjects. We enrolled 15 participants. Spontaneous blink rate was quantified with an optoelectronic system before and after: (1) a painful laser stimulation, and (2) an acoustic startling stimulation. In control experiments, we investigated whether laser stimulation effects depended on stimulation intensity and whether laser stimulation induced any changes in the blink reflex recovery cycle. Finally, we investigated any relationship between spontaneous blink rate modification and pain modulation effect during the cold pressor test. Laser, but not acoustic, stimulation increased spontaneous blink rate. This effect was independent of stimulation intensity and negatively correlated with pain perception. No changes in trigeminal-facial reflex circuit excitability were elicited by laser stimulation. The cold pressor test also induced an increased spontaneous blink rate. Our study provides evidence on the role of dopamine in nociception and suggests that dopaminergic activity may be involved in pain modulation. These findings lay the groundwork for further investigations in patients with pathological conditions characterized by dopaminergic deficit and pain

l-Acetyl-carnitine in Patients with Carpal Tunnel Syndrome: Effects on Nerve Protection, Hand Function and Pain

Background and Aim: l-Acetyl-carnitine (LAC) exerts an energetic effect on nerves and muscles. Recently, preclinical experiments have demonstrated a central anti-nociceptive action. Objective: Our objective was to assess the effects of LAC on neuroprotection, pain, and function in carpal tunnel syndrome (CTS), a very frequent chronic compressive neuropathy. Methods: In a multicentre, examiner-blinded, clinical and neurophysiological 4-month study, we enrolled 82 patients and examined 120 hands with CTS of mild to moderate severity. Patients were assessed at baseline and 10, 60 and 120\uc2&nbsp;days after treatment with LAC 500\uc2&nbsp;mg twice daily (BID). All patients underwent a conduction study of the median nerve, the Boston Carpal Tunnel Questionnaire (BCTQ) and the Neuropathic Pain Symptom Inventory (NPSI). The primary endpoint was the sensory conduction velocity (SCV) of the median nerve. Results: The primary endpoint was met, with significant improvement of the SCV (P\uc2&nbsp

Familial trigeminal neuralgia - a systematic clinical study with a genomic screen of the neuronal electrogenisome

OBJECTIVE: This cross-sectional study examined, for the first time, a large cohort of patients with trigeminal neuralgia, to ascertain the occurrence of familial cases, providing a systematic description of clinical features of familial disease. Since there is evidence linking hyperexcitability of trigeminal ganglion neurons to trigeminal neuralgia, we also carried out an exploratory genetic analysis of the neuronal electrogenisome in these patients. METHODS: We recorded familial occurrence by systematically interviewing all patients with a definite diagnosis of classical or idiopathic trigeminal neuralgia. We found 12 occurrences of trigeminal neuralgia with positive family history out of 88 enrolled patients. Whole-exome sequencing was carried out in 11 patients. We concentrated on the genetic variants within

Capsaicin 8% dermal patch in clinical practice: an expert opinion

Introduction: Neuropathic pain (NP) is caused by a lesion or disease of the somatosensory system, which can severely impact patients’ quality of life. The current-approved treatments for NP comprise of both centrally acting agents and topical drugs, including capsaicin 8% dermal patches, which is approved for the treatment of peripheral NP. / Areas covered: The authors summarize literature data regarding capsaicin use in patients who suffer from NP and discuss the clinical applications of this topical approach. / Expert opinion: Overall, the capsaicin 8% dermal patch is as effective in reducing pain intensity as other centrally active agents (i.e. pregabalin). Some studies have also reported fewer systemic side effects, a faster onset of action and superior treatment satisfaction compared with systemic agents. In our opinion, capsaicin 8% dermal patches also present additional advantages, such as a good systemic tolerability, the scarcity of adverse events, the possibility to combine it with other agents, and a good cost-effective profile. It is important to note that, as the mechanism of action of capsaicin 8% is the ‘defunctionalization’ of small afferent fibers through interaction with TRPV1 receptors, the peripheral expression of this receptor on nociceptor fibers, is crucial to predict patient’s response to treatment

Trigeminal neuralgia: New classification and diagnostic grading for practice and research

Trigeminal neuralgia (TN) is an exemplary condition of neuropathic facial pain. However, formally classifying TN as neuropathic pain based on the grading system of the International Association for the Study of Pain is complicated by the requirement of objective signs confirming an underlying lesion or disease of the somatosensory system. The latest version of the International Classification of Headache Disorders created similar difficulties by abandoning the term symptomatic TN for manifestations caused by major neurologic disease, such as tumors or multiple sclerosis. These diagnostic challenges hinder the triage of TN patients for therapy and clinical trials, and hamper the design of treatment guidelines. In response to these shortcomings, we have developed a classification of TN that aligns with the nosology of other neurologic disorders and neuropathic pain. We propose 3 diagnostic categories. Classical TN requires demonstration of morphologic changes in the trigeminal nerve root from vascular compression. Secondary TN is due to an identifiable underlying neurologic disease. TN of unknown etiology is labeled idiopathic. Diagnostic certainty is graded possible when pain paroxysms occur in the distribution of the trigeminal nerve branches. Triggered paroxysms permit the designation of clinically established TN and probable neuropathic pain. Imaging and neurophysiologic tests that establish the etiology of classical or secondary TN determine definite neuropathic pain