[Botulinum toxin type A (Relatox) in transition from medication overuse to non-overuse status in patients with chronic migraine: a subgroup analysis of phase IIIb randomized single-blind multicenter active-controlled parallel-group trial]. / Botulinicheskii toksin tipa A (Relatoks) v preodolenii lekarstvennogo zloupotrebleniya u patsientov s khronicheskoi migren'yu: podgruppovoi analiz rezul'tatov mnogotsentrovogo prostogo slepogo randomizirovannogo sravnitel'nogo issledovaniya IIIb fazy.

OBJECTIVE: To access the effect of Relatox, the first Russian botulinum toxin type A, in patients with chronic migraine (CM) and medication overuse (MO). MATERIAL AND METHODS: In phase IIIb single-blind randomized multicenter active-controlled parallel-group study, patients with CM were randomized to once intramuscular injections of Relatox (n=101) or onabotulinumtoxin A injections - Botox (n=108). This subgroup analysis evaluated the percentage of patients who transition from medication overuse to non overuse status from baseline; mean changes in the number of headache days, migraine headache days, acute headache medication intakes days, headache intensity, proportion of patients who had a ≥50% reduction in headache days, proportion of the patients with severe (≥60) Headache Impact Test-6 score and with a severe (≥21) MIDAS score in a 28-day periods in each treatment among patients with baseline acute medication overuse via repeated measures. RESULTS: Of 209 patients with CM, 100% met medication overuse criteria. Relatox and Botox demonstrated significant improvement for overall least squares mean change in headache days, migraine headache days, headache intensity; and headache-related disability and quality of life in CM patients with baseline MO, without differences between the groups. 75% and 70% patients in the Relatox and Botox groups, respectively, achieved ≥50% reduction in headache days from baseline (OR 1.58, CI 95% 0.84; 3.02, p=0.155). Furthermore, Relatox and Botox significant reduced average medication overuse rates in patient with CM and MO at baseline. 62% of patients in the Relatox group and 48% of patients in the Botox group transitioned from medication overuse to non overuse status compared from baseline (OR 2.07, CI 95% 0.91; 4.62, p=0.044). Relatox group had greater reductions than the Botox group in the percentage of patients with acute migraine-specific medication (triptan) overuse (p=0.050). CONCLUSION: The results demonstrate highly prevalent of medication overuse among individuals with CM. This analysis provides evidence that the Russian botulinum toxin type A Relatox significantly improves measures of headache symptoms, quality of life and headache-related disability, and also significantly greater, compared to Botox, reduces migraine-specific medication consumption in patients with chronic migraine who overuse acute medications.

[Botulinum toxin type A (Relatox) in the treatment of chronic migraine in adults: results of phase IIIb, randomized, one-blind, multicenter, active-controlled, parallel-group trial]. / Botulinicheskii toksin tipa A (Relatoks) v lechenii khronicheskoi migreni u vzroslykh: rezul'taty mul'titsentrovogo prostogo slepogo randomizirovannogo sravnitel'nogo issledovaniya IIIb fazy.

OBJECTIVE: To access the efficacy and safety of the first Russian botulinum toxin type A (Relatox) as a headache prophylaxis in adult with chronic migraine (CM). MATERIAL AND METHODS: The randomized, one-blind, multicenter, active-controlled, parallel-group trial study involved 209 patients with CM aged from 19 to 65 years. The patients were randomized to injections of the Russian botulinum toxin type A - Relatox (n=101) or onabotulinumtoxinA injections - Botox (n=108). The duration of the study was 16 weeks, which included five visits of patients every 4 weeks. Relatox and Botox were injected once into seven muscle groups of the head and neck at a dose of 155-195 units. Primary efficacy variable was mean change from baseline in frequency of headache days after 12 weeks. Secondary efficacy variables were mean changes from the baseline to week 12 in frequency of migraine days, acute headache pain medication intakes days; headache intensity; proportion of patients achieving ≥50% reduction from baseline in headache days, the proportion of the patients with medication overuse, the proportion of the patients with severe (≥60) Headache Impact Test-6 score and with a severe (≥21) MIDAS score. RESULTS: Analyses demonstrated a large mean decrease from baseline in frequency of headache days, without statistically significant between-group differences Relatox vs Botox at week 12 (-10.89 vs -10.06; p=0.365) and at other time points. Significant differences from baseline were also observed for all secondary efficacy variables at all time points without differences between the groups. The proportion of patients achieving ≥50% reduction from baseline in headache days was 75.0% and 70% in the Relatox and Botox groups, respectively (OR, CI 95% 1.58 [0.84; 3.02], p=0.155). Adverse events (AE) occurred in 15.8% of Relatox patients and 15.7% of Botox patients (p=1.000). No unexpected AE were identified. CONCLUSION: The results demonstrate that the first Russian botulinum toxin type A (Relatox) is an effective prophylactic treatment for CM in adult patients. Relatox led to significant improvements from baseline in multiple measures of headache symptoms, headache-related disability and quality of life. For the first time, a comparative analysis of two botulinum toxin type A products in parallel groups showed no less (not inferior) efficacy and safety of Relatox relative to Botox in the treatment of CM in adults.

[Method of onabotulinumtoxin type A injection in chronic migraine: the PREEMPT protocol in clinical practice]. / Metodika in"ektsii onabotulotoksina tipa A (Botoks) pri khronicheskoi migreni ­ protokol PREEMPT v real'noi praktike.

Chronic migraine (CM), a condition where patients experience over 15 days of headache per month, was identified as a separate disease in the International Classification of Headache Disorders 3-beta version. Onabotulinumtoxin type A was approved for the treatment of CM in 2010 after the completion of the extensive PREEMPT (Phase III Research Evaluating Migraine Prophylaxis Therapy) clinical program. The efficacy of onabotulinumtoxin type A was demonstrated in numerous studies in CM and medication-overuse headache. The paper focuses on the PREEMPT injection paradigm and provides guidance for successful and safe treatment of CM.

[Migraine burden and clinical inertia: what can we do?] / Migren' i klinicheskaia inertsiia: chto my mozhem sdelat'?

AIM: To study the compliance of neurologists and headache specialists to chronic headache and chronic migraine (CM) diagnosis and treatment guidelines. MATERIAL AND METHODS: The survey included 634 neurologists from all regions of the Russian Federation. Mean age of respondents was 40.7±8.5 years, mean years of experience 14.2±7.8 years. RESULTS: Most doctors work in outpatient or hospital settings (49% and 24%, respectively), 7% were headache specialists. Tension-type headache (TTH) was diagnosed in 30% and CM in 17% of patients while 44% of patients were presumed to have a mixed headache disorder (TTH+CM). Only 10% of physicians do not use instrumental diagnostic methods in chronic headache. This study has shown sufficient attention to comorbid conditions and frequent prescription of headache preventative treatment. Botox prescription data is equivocal: 35% of physicians recommend such treatment, 27% do not, while other doctors prescribe it for off-label indications. CONCLUSION: To overcome clinical inertia, further education in chronic headaches and their optimal treatment is warranted.

[Memory and attention deficit in migraine: overlooked symptoms]. / Narusheniia pamiati i vnimaniia u patsientov s migren'iu: nedootsenennye simptomy.

AIM: To evaluate the prevalence of objective cognitive impairment (CI) in patients with episodic migraine (EM) during the interictal period and in the chronic migraine (CM) population. MATERIAL AND METHODS: Sixty-four patients with CM and 42 patients with low-frequency EM (less than 4 headache days a month), aged 18-59, were enrolled. Depression and anxiety were assessed with the Hospital Anxiety and Depression Scale (HADS). Cognitive functions were evaluated with the Montreal Cognitive Assessment scale (MoCA), Digit Symbol Substitution Test (DSST) and the Rey Auditory Verbal Learning Test (RAVLT). RESULTS: In the CM group DSST and MoCA performance as well as the RAVLT total learning index were significantly decreased compared to EM; 38% of CM patients scored lower than 26 points of the MoCA scale. Negative correlations between headache frequency and DSST and MoCA results were observed. There was no correlation between cognitive test performance and anxiety/depression levels. CONCLUSION: Patients with EM and CM present with objective CI. The prevalence and severity of cognitive deficits rise with increasing headache frequency.

[Temporomandibular disorder and cervicalgia: pathophysiology underlying the comorbidity with chronic migraine]. / Disfunktsiia visochno-nizhnecheliustnogo sustava i tservikalgiia: patofiziologicheskie mekhanizmy i komorbidnaia sviaz' s khronicheskoi migren'iu.

AIM: To analyze the prevalence of various clinical forms of temporomandibular disorder (TMD) and cervicalgia in episodic (EM) and chronic migraine (CM). MATERIAL AND METHODS: Ninety patients with CM and 42 patients with EM as defined by the International Classification of Headache Disorders (ICHD)-3 beta were recruited. TMD and sleep bruxism were diagnosed according to the DC/TMD criteria and the International Classification of Sleep Disorders (ICSD-R), respectively. RESULTS: Myofascial pain was the most prevalent form of TMD in both EM and CM. The prevalence of TMD was higher in CM as compared to EM (60% vs. 21.4%, respectively, p=0.0001). The prevalence of bruxism was comparable across EM and CM (14.3% vs. 28.8%, respectively, p=0.08) and significantly lower than that of TMD in the CM population (28.8% vs. 60%, respectively, p=0.0001). Frequent cervicalgia (≥15 days per month) was reported by 65.5% and 21.4% of CM and EM patients, respectively (p=0.0001); 44.4% of CM patients reported neck pain immediately before or during migraine attacks only, 14.4% during the headache and interictal phases. CONCLUSION: The higher prevalence of pain-related TMD and cervicalgia in CM population compared to EM and the general population was shown. In CM, myofascial pain and tenderness in the masticatory and neck muscles may be caused by central sensitization (CS) with no link to temporomandibular joint or spinal pathology. Myofascial TMD and neck muscle dysfunction are an integral part of CM pathophysiology underlying headache chronification.

[Real-world migraine burden: clinical and economic aspects]. / Bremia migreni v real'noi klinicheskoi praktike: klinicheskie i ékonomicheskie aspekty.

AIM: To evaluate the rationale for different approaches to preventive chronic migraine (CM) treatment by comparing clinical outcomes and financial burden of the disease in the real-world practice. MATERIAL AND METHODS: Sixty-six patients with CM were enrolled at the Alexander Vein Headache Clinic (60 women and 6 men, aged 28-51). All patients were divided into 3 groups: group 1 (n=22) received oral preventative treatment with topiramate, up to 100 mg daily, for three months; group 2 (n=20) received 12 acupuncture sessions (3 sessions a week); group 3 (n=24) received 155-195 units of botulinum toxin type A (botox, BTA). The follow-up period in all groups was 3 months. Efficacy was evaluated by clinical examination, the Headache Impact Test (HIT-6) and questionnaires to assess subjective patient satisfaction and treatment tolerability. RESULTS: BTA demonstrated the highest efficacy in this study. Compared to the oral preventative treatment and acupuncture, BTA reduced the frequency of headache faster and more significantly facilitating CM transformation into episodic migraine (headache frequency was 16.1±0.1; 18.0±0.02; and 13.9±0.3 in groups 1, 2 and 3, respectively, after one month of treatment). BTA also improved the quality of life faster and more significantly and was better tolerated (good - 51%, 75% and 85% in groups 1, 2 and 3, respectively; satisfactory - 35%, 25% and 15% in groups 1, 2 and 3, respectively; bad 14% in the oral prevention group). In the BTA group, the majority of patients demonstrated earlier treatment satisfaction. Despite higher (compared to topiramate) direct costs in the BTA group (RUB 29 931.51 and RUB 32 085.87, respectively), the predicted cost of a headache-free day was the smallest and totaled RUB 652.15 (compared to RUB 692.86 and RUB 1017.60 in the topiramate and acupuncture groups, respectively). CONCLUSION: The data on the efficacy and costs of different CM prevention strategies would facilitate optimal treatment choice for neurologists and patients.

[Temporomandibular disorder as the most prevalent cause of facial pain: current evidence]. / Disfunktsiia visochno-nizhnecheliustnogo sustava kak naibolee chastaia prichina boli v litse: sovremennoe sostoianie problemy.

Orofacial pain is a comprehensive and multi-faceted syndrome. After dental causes have been excluded, neurologists are challenged to diagnose the cause of pain. The paper gives a detailed review of one of the most common causes of facial pain - temporomandibular disorder (TMD). Current DC/TMD diagnostic criteria, patient examination protocols and a new perspective on TMD pathophysiology based on the recent neurological studies are presented. The article also discusses modern approaches to TMD management.

[Diagnosis and treatment of migraine: Recommendations of the Russian experts]. / Diagnostika i lechenie migreni: rekomendatsii rossiiskikh ékspertov.

These recommendations on the diagnosis and treatment of migraine were elaborated by Russian headache experts in accordance with the evidence-based practice. Together with the latest classification, diagnostic principles and criteria of different clinical sub-forms the consensus contains basic data on migraine epidemiology, pathophysiological mechanisms, differential diagnosis and most effective and evidence based approaches to pharmacological and non-pharmacological management of migraine patients.

[Migraine and temporomandibular joint dysfunction: mechanisms of comorbidity].

OBJECTIVE: to analyze the frequency of different forms of temporomandibular joint dysfunction (TMJD) in episodic and chronic migraine and to study mechanisms of their comorbidity. MATERIAL AND METHODS: Sixty-three patients with chronic migraine (CM) and 40 patients with episodic migraine (EM) were examined. Anxiety and depression were assessed with the HADS, quality-of-life related to headache was measured with the HIT-6. To evaluate the antinociceptive system function, we studied blink reflex (BR) and nociceptive flexion reflex (NFR). RESULTS: The higher frequency of TMJD was identified in patients with CM compared to those with EM (47.5 and 28.5%, respectively), CM patients more frequently had disturbances related to the myofascial pain syndrome of masticatory muscles. R3 BR and NFR thresholds were significantly decreased in CM patients as well. CONCLUSION: TMJD is a component of the pathogenesis in many patients with CM. Masticatory muscles may generate nociceptive impulses in CNS, ie be a source of peripheral sensitization, that promote pain chronification, including migraine. Dysfunction of masticatory muscles may reflect the central sensitization and disturbance of efferent pain control.

[Behavioral dependence on analgesics in medication overuse headache].

Authors conducted a clinical and psychological study in 3 groups of patients: 43 patients with medication overuse headache (MOH), 23 patients with chronic headache without medication overuse and 14 patients with episodic migraine. Along with clinical and neurological examination, the following questionnaires were administered: the McGill questionnaire, the Beck Depression Inventory, the Spielberger-Khanin test, the Toronto alexithymia scale, the Leonhard personality inventory and an inventory based on the Benzodiazepine Dependence Self-Report Questionnaire (BDSRQ). It was demonstrated similar clinical and psychological profiles, with the exception of BDSRQ scores, of patients with chronic headache irrelevant of the presence of headache abortive medication overuse. It was identified a progressive disease course with a formation of a specific behavioral pattern. Further studies are warranted to understand the reasons for acquiring behavioral dependence on analgetic medications, to improve management and prevent relapses of medication overuse headache.

[New approaches to the treatment of chronic daily headache].

Two groups of patients with chronic daily headache have been treated: 16 patients of the first group received katadolon (flupirtin) in dose 300 mg per day during 2 months as an alternative analgesics instead of combined sedative drugs (sedalgin, pentalgin, citramon) that patients abused for many years. The withdrawal period was painless, the use of katadolon resulted in the reduction of attack frequency and the decrease in the amount of traditional analgesics. Katadolon was well tolerated, only two patients reported the total weakness and 1 patient reported diarrhea. Velafax (venlafaxine) in dose 75 mg per day was prescribed to 18 patients of the 2nd group during 6 weeks. The treatment resulted in the decrease of attack frequency and pain intensity. Velafax reduced allodynia which was studied using algometria and touches, and wind-up phenomenon. There was the significant increase of the R3 component of nociceptive blink reflex threshold and pain threshold of nociceptive flexor reflex that indicates the augmentation of antinociceptive protection and decrease in the sensitization of central nociceptive neurons of the trigeminal nerve. Patients treated with Velafax experienced nausea, constipation, impairment of sustained attention, decrease of appetite however these side-effects were mild and passed without treatment during 5-7 days.

[Peculiarities of verbal activity in migraine patients]. / Osobennosti verbal'noi aktivnosti u patsientov s migren'iu.

We applied associative verbal experiment to analyze verbal activity of migraineurs. A test group consisted of 49 patients with migraine, a control one--of 20 healthy people. Reliable decrease of free associations number, verbs and plants, semantic index and changes of non-productive association index and coefficient were observed. Average depression level, higher anxiety and negative correlations with indexes calculated were found. Verbal activity of migraineurs, their ability to concentrate and to control adequateness of task fulfillment were decreased. That was caused by pain, depression, anxiety and neurotization. Verbal activity is influenced by individual emotional features (calculated indexes do not correlate with the visual analogue scale).

Behavioral analysis of the consequences of chronic blockade of NMDA-type glutamate receptors in the early postnatal period in rats.

Considering data on the possible glutamatergic nature of the pathogenesis of schizophrenia, we attempted to model cognitive derangements in animals by chronic blockade of NMDA glutamate receptors. Wistar rats received daily s.c. injections of the non-competitive NMDA glutamate receptor antagonist MK-801 (0.05 mg/kg) from days 7 to day 49 of postnatal life. One day after the antagonist injections given on days 27 and 28 of life, animals of the experimental group showed decreased levels of spontaneous movement and orientational-investigative activity as compared with controls, where there was no change in the elevated locomotor reaction produced in response to the direct action of MK-801. These animals showed decreases in the level of anxiety (on day 40 of life) and derangement in spatial learning with food reinforcement (days 50-54 of life). It is suggested that early neonatal blockade of NMDA glutamate receptors leads to the development in animals of disturbances to situational perception and assessment of incoming sensory information.

[Behavioral analysis of consequences of chronic blockade of NMDA-type glutamate receptors in the early postnatal period in rats]. / Povedencheskii analiz posledstvii khronicheskoi blokady glutamatnykh retseptorov NMDA-tipa v rannem postnatal'nom periode u krys.

In view of the hypothesis that glutamatergic dysfunction of brain can underlie the negative symptoms of schizophrenia (including cognitive deficit), the aim of this study was to develop a model of cognitive impairment in Wistar male rats after administration of a noncompetitive NMDA-receptor antagonist in early postnatal period. Rat pups were daily subcutaneously injected with 0.05 mg/kg MK-801 on postnatal days 7-49. On the 27th and 28th days 24 h after the last previous injection, the MK-801-treated rats demonstrated lower spontaneous locomotor and exploratory activity in comparison with saline control, however, they retained the reaction of hyperlocomotion which developed immediately after the MK-801 administration. In these rats, the anxiety level in the elevated plus-maze (on the 40th postnatal day) was found to be decreased, and the spatial learning in food rewarded task was negatively affected (on the 50th-54th days). It is suggested that impairment of the input of sensory information and its correct assessment by the animals can be associated with the early neonatal blockade of NMDA glutamate receptors.

[Determination of a dimethylaniline mixture in the intermediate products for the production of semisynthetic penicillins]. / Opredelenie primesi dimetilanilina v poluproduktakh dlia proizvodstva polusinteticheskikh penitsillinov.

A gas-chromatographic method for determination fo the content of dimethylaniline (DMA) in 6-aminopenicillanic acid, a semi-product for production of semi-synthetic antibiotics, was elaborated. The chloroform extracts of DMA from the alkaline solutions of the preparation were analysed in a gas chromatograph with a flame-ionization detector on a stainless steel column 2 m long and the inner diameter of 2 mm filled with 10 per cent OV-17 on chromosorb W-HMDS at a temperature of 112 degrees C. The minimum detectable amount of DMA was 5.10(-9) g. The assay error was +/- 5.35 per cent. The method may be used for the assay of other semi-synthetic antibiotics.