ObjectiveTo evaluate the efficacy and safety of adjunctive eslicarbazepine acetate (ESL) in patients with refractory partial-onset seizures.MethodsThis randomized, placebo-controlled, double-blind, parallel-group, phase III study was conducted at 173 centers in 19 countries, including the United States and Canada. Eligible patients were aged ≥16 years and had uncontrolled partial-onset seizures despite treatment with 1–2 antiepileptic drugs (AEDs). After an 8-week baseline period, patients were randomized to once-daily placebo (n = 226), ESL 800 mg (n = 216), or ESL 1,200 mg (n = 211). Following a 2-week titration period, patients received ESL 800 or 1,200 mg once-daily for 12 weeks. Seizure data were captured and documented using event-entry or daily entry diaries.ResultsStandardized seizure frequency (SSF) during the maintenance period (primary end point) was reduced with ESL 1,200 mg (p = 0.004), and there was a trend toward improvement with ESL 800 mg (p = 0.06), compared with placebo. When data for titration and maintenance periods were combined, ESL 800 mg (p = 0.001) and 1,200 mg (p < 0.001) both reduced SSF. There were no statistically significant interactions between treatment response and geographical region (p = 0.38) or diary version (p = 0.76). Responder rate (≥50% reduction in SSF) was significantly higher with ESL 1,200 mg (42.6%, p < 0.001) but not ESL 800 mg (30.5%, p = 0.07) than placebo (23.1%). Incidence of treatment-emergent adverse events (TEAEs) and TEAEs leading to discontinuation increased with ESL dose. The most common TEAEs were dizziness, somnolence, nausea, headache, and diplopia.SignificanceAdjunctive ESL 1,200 mg once-daily was more efficacious than placebo in adult patients with refractory partial-onset seizures. The once-daily 800 mg dose showed a marginal effect on SSF, but did not reach statistical significance. Both doses were well tolerated. Efficacy assessment was not affected by diary format used.

Cranial sensory innervation is supplied mainly by the trigeminal nerves and by the first cervical nerves. Excitatory and inhibitory interactions among those nerve roots may occur in a mechanism called nociceptive convergence, leading to loss of somato-sensory spatial specificity. Three volunteers in an experimental trial had sterile water injected over their greater occipital nerve on one side of the neck. Pain intensity was evaluated 10, 30 and 120 s after the injection. Two of the patients reported intense pain. Trigeminal autonomic features, suggestive of parasympathetic activation, were seen associated with trigeminally distributed pain. These data add to and reinforce previous evidence of convergence of cervical afferents on the trigeminal sensory circuit.

Thirteen subjects with trigeminal neuralgia were treated with botulinum-A neurotoxin (BoNT/A) in an open-label pilot study. After BoNT/A, visual analog scale score, surface area of pain, and therapeutic coefficient were reduced in all patients and for all branch trigeminal nerves studied. Therefore, BoNT/A is an efficient treatment. There were no major side effects. A placebo-controlled clinical trial is needed to confirm these findings.

Cranial nociceptive perception shows a distinct topographic distribution, with the trigeminal nerve receiving sensory information from the anterior portions of the head, the greater occipital nerve, and branches of the upper cervical roots in the posterior regions. However, this distribution is not respected during headache attacks, even if the etiology of the headache is specific for only one nerve. Nociceptive information from the trigeminal and cervical territories activates the neurons in the trigeminal nucleus caudalis that extend to the C2 spinal segment and lateral cervical nucleus in the dorsolateral cervical area. These neurons are classified as multimodal because they receive sensory information from more than one afferent type. Clinically, trigeminal activation produces symptoms in the trigeminal and cervical territory and cervical activation produces symptoms in the cervical and trigeminal territory. The overlap between the trigeminal nerve and cervical is known as a convergence mechanism. For some time, convergence mechanisms were thought to be secondary to clinical observations. However, animal studies and clinical evidence have expanded our knowledge of convergence mechanisms. In this paper, the role of convergence mechanisms in nociceptive physiology, physiopathology of the headaches, clinical diagnosis, and therapeutic conduct are reviewed.

Thirty-three migraineurs and 23 healthy controls were submitted to pressure algometry before and after light-induced discomfort was elicited by progressive light stimulation in a monoblind fashion. Pressure algometries were performed on the emergence of the supraorbital, infraorbital, mental and greater occipital nerves, and over the temporal muscles, always throughout the same sequence and from right to left. Measurements were carried out before and immediately after light stimulation and after 10 min of the second algometry. The final result for each site measured at each time-point was the mean of the three measurements. Light stimulation was carried out progressively until light-induced discomfort was reported, to a maximum of 20,000 lux. A heat-blocking glass protected patients' eyes. Migraineurs presented significant and persistent drops in pain perception thresholds after light stimulation, at all sites tested (P = 0.002 to < 0.0001). These drops were not seen in controls, in whom, conversely, a less significant increase was seen on right infraorbital and left temporal muscle sites. Our results indicate that in migraineurs, light may have a relevant role in trigeminal and cervical pain perception thresholds.

SummaryObjective: We assessed the efficacy and safety of once-daily eslicarbazepine acetate in comparison with twice-daily (BID) controlled-release carbamazepine (carbamazepine-CR) monotherapy in newly diagnosed focal epilepsy patients. Methods: This randomized, double-blind, noninferiority trial (NCT01162460) utilized a stepwise design with 3 dose levels. Patients who remained seizure-free for the 26-week evaluation period (level A: eslicarbazepine acetate 800 mg/carbamazepine-CR 200 mg BID) entered a 6-month maintenance period. If a seizure occurred during the evaluation period, patients were titrated to the next target level (level B: eslicarbazepine acetate 1200 mg/carbamazepine-CR 400 mg BID, level C: eslicarbazepine acetate 1600 mg/carbamazepine-CR 600 mg BID) and the evaluation period began again. The primary endpoint was the proportion of seizure-free patients for 6 months after stabilization in the per protocol set. The predefined noninferiority criteria were À12% absolute and À20% relative difference between treatment groups. Results: Eight hundred fifteen patients were randomly assigned; 785 (388 in the eslicarbazepine acetate group and 397 in the carbamazepine-CR group) were included in the per protocol set, and 813 (401 in the eslicarbazepine acetate group and 412 in the carbamazepine-CR group) were included in the full analysis set for the primary analysis. Overall, 71.1% of eslicarbazepine acetate-treated patients and 75.6% of carbamazepine-CR-treated patients were seizure-free for ≥6 months at the last evaluated dose (average risk difference = À4.28%, 95% confidence interval [CI] = À10.30 to 1.74; relative risk difference = À5.87%, 95% CI = À13.50 to 2.44) in the per protocol set. Rates of treatment-emergent adverse events were similar between groups for patients in the safety set. Noninferiority was also demonstrated in the full analysis set, as 70.8% of patients with eslicarbazepine acetate and 74.0% with carbamazepine-CR were seizure-free at the last evaluated dose (average risk difference = À3.07, 95% CI = À9.04 to

Many chronic pain patients are refractory to treatment, which leads to the suspicion that somehow they are not fully effective and probably some mechanism of pain generation and/or maintenance is still unknown. The aim of this cross-sectional study was to provide evidence-based data on pain mechanisms in different types of chronic pain conditions. Eighty women, with 18-65 years old, were included, divided into four groups: myofascial pain of the masticatory muscles (n = 20), fibromyalgia (n = 20), chronic daily headache and healthy volunteers (n = 20). All patients were submitted to quantitative sensory tests: pressure pain threshold, mechanical detection threshold, mechanical pain threshold, ischaemic pain tolerance, cold pain sensitivity, aftersensation, wind-up ratio and conditioned pain modulation. Current perception threshold was also determined (Neurometer CPT/C - Neurotron). Three different zones were evaluated: trigeminal (masseter muscle), cervical and extratrigeminal (thenar eminence). Data were recorded and subjected to statistical analysis (anova, Tukey and Student's t-tests). Masticatory myofascial pain, fibromyalgia and chronic daily headache individuals presented lower pressure pain thresholds than healthy volunteers (P = 0.00). Chronic daily headache individuals had a significantly higher mechanical detection threshold than healthy volunteers (P = 0.01). Individuals of the symptomatic groups showed lower values for mechanical pain threshold and for ischaemic pain tolerance (P = 0.00) than healthy volunteers. The ability to activate the mechanism of endogenous modulation is impaired in women with fibromyalgia and myofascial pain (P = 0.00). These results reinforce evidence of central sensitisation and impaired endogenous modulation system in individuals with myofascial pain, fibromyalgia and chronic daily headache.

Chronic migraine is a condition with significant prevalence all around the world and high socioeconomic impact, and its handling has been challenging neurologists. Developments for understanding its mechanisms and associated conditions, as well as that of new therapies, have been quick and important, a fact which has motivated the Latin American and Brazilian Headache Societies to prepare the present consensus. The treatment of chronic migraine should always be preceded by a careful diagnosis review; the detection of possible worsening factors and associated conditions; the stratification of seriousness/impossibility to treat; and monitoring establishment, with a pain diary. The present consensus deals with pharmacological and nonpharmacological forms of treatment to be used in chronic migraine.