medsovetМедицинский СоветMeditsinskiy sovet = Medical Council2079-701X2658-5790REMEDIUM GROUP Ltd.10.21518/2079-701X-2021-12-50-60medsovet-6332Research ArticleНЕВРОЛОГИЯNEUROLOGYВозможности дневных анксиолитиков в коррекции остаточных неврологических проявлений COVID-19Possibilities of daytime anxolytics in the correction of residual neurological manifestations of COVID-19https://orcid.org/0000-0001-5012-945XАлександроваЕ. А.AlexandrovaE. A.

к.м.н., доцент, врач-невролог кабинета экстрапирамидных нарушений, 

603126, Нижний Новгород, ул. Родионова, д. 190

Cand. Sci. (Med.), Associate Professor, Neurologist, Extrapyramidal Disorders Office, 

190, Rodionov St., Nizhny Novgorod, 603126

dalex1970@mail.ruhttps://orcid.org/0000-0001-7033-053XПаршинаЕ. В.ParshinaE. V.

к.м.н., заведующая неврологическим отделением, 

603126, Нижний Новгород, ул. Родионова, д. 190

Cand. Sci. (Med.), Head of the Neurological Department, 

190, Rodionov St., Nizhny Novgorod, 603126

parshina_elena_v@mail.ruБородачеваИ. В.BorodachevaI. V.

к.м.н., врач-невролог неврологического отделения, 

603126, Нижний Новгород, ул. Родионова, д. 190

Cand. Sci. (Med.), Neurologist, Neurological Department, 

190, Rodionov St., Nizhny Novgorod, 603126

borodacheva.333@rambler.ruhttps://orcid.org/0000-0001-7142-5282СусловА. Г.SuslovA. G.

к.м.н., врач-невролог неврологического отделения, 

603028, Нижний Новгород, ул. Московское шоссе, д. 144

Cand. Sci. (Med.), Neurologist, Neurological Department, 

144, Moskovskoe Shosse, Nizhny Novgorod, 603028

suslov99@mail.ruhttps://orcid.org/0000-0002-4768-1355БеляковК. М.BeliakovK. M.

д.м.н., заведующий отделением функциональной диагностики, 

603126, Нижний Новгород, ул. Родионова, д. 190

Dr. Sci. (Med.), Head of the Department of Functional Diagnostics, 

190, Rodionov St., Nizhny Novgorod, 603126

kirmih@mail.ruhttps://orcid.org/0000-0003-3956-2986ЮлинВ. С.YulinV. S.

врач-невролог неврологического отделения, 

603126, Нижний Новгород, ул. Родионова, д. 190

Neurologist, Neurological Department, 

190, Rodionov St., Nizhny Novgorod, 603126

vadik.yulin@yandex.ruФоминС. В.FominS. V.

 врач-невролог неврологического отделения, 

603126, Нижний Новгород, ул. Родионова, д. 190

Neurologist, Neurological Department, 

190, Rodionov St., Nizhny Novgorod, 603126

serjfom30@mail.ruНижегородская областная клиническая больница имени Н.А. СемашкоРоссияNizhny Novgorod Regional Clinical Hospital named after N.A. SemashkoRussian FederationГородская клиническая больница №39РоссияCity Clinical Hospital No. 39Russian Federation2021130920210125060Copyright © Александрова Е.А., Паршина Е.В., Бородачева И.В., Суслов А.Г., Беляков К.М., Юлин В.С., Фомин С.В., 20212021Александрова Е.А., Паршина Е.В., Бородачева И.В., Суслов А.Г., Беляков К.М., Юлин В.С., Фомин С.В.Alexandrova E.A., Parshina E.V., Borodacheva I.V., Suslov A.G., Beliakov K.M., Yulin V.S., Fomin S.V.Данная работа распространяется под лицензией Creative Commons Attribution 4.0.This work is licensed under a Creative Commons Attribution 4.0 License.https://www.med-sovet.pro/jour/article/view/6332Введение

Введение. Помимо остро развивающихся проявлений, коронавирусная инфекция характеризуется длительно сохраняющимися симптомами (астения, соматические вегетативные проявления, нарушения сна и  психоэмоционального фона), вопрос лечебной коррекции которых особенно актуален.

Цель исследования

Цель исследования. Изучить психические, соматоформные и когнитивные аспекты тревожных расстройств после коронавирусной инфекции в процессе лечения тофизопамом (Грандаксин®) по 150 мг/сут.

Материалы и методы

Материалы и методы. В исследовании приняли участие пациенты, перенесшие новую коронавирусную инфекцию, у которых спустя 4 нед. после окончания лечения по поводу основного заболевания были жалобы, позволяющие предполагать наличие тревожного расстройства. Для оценки уровня тревоги использовалась шкала Гамильтона. Обследование пациентов проводилось до начала лечения, спустя 2, 4 и 6 нед. терапии.

Результаты

Результаты. До начала терапии у всех больных отмечался общий высокий уровень тревоги: средний балл по HAM-A составил 31,72 ± 2,24 балла. При завершении терапии препаратом Грандаксин® у всех больных отмечалось снижение уровня тревоги: средний балл по HAM-A составил 12,68 ± 2,04 балла (p 

< 0,001)

< 0,001). По окончании курса терапии пациенты отмечали повышение умственной работоспособности, улучшение памяти и  внимания, т. е. уменьшение выраженности когнитивных расстройств, ассоциативных с тревогой, носило отчетливый характер – средний балл по субшкале «когнитивные нарушения» снизился в три раза – с 1,6 ± 0,12 до 0,5 ± 0,09 (р >< 0,001). Выводы. Нарушения психоэмоционального фона (чаще в виде повышения личностной тревожности), расстройства сна, вегетативные нарушения, астенический синдром весомо влияют на качество жизни пациентов, перенесших новую коронавирусную инфекцию. Необходим комплексный подход в клинической диагностике отдаленных последствий новой коронавирусной инфекции и их последующая коррекция лекарственной терапией. 

Introduction

Introduction. In  addition to acute manifestations, coronavirus infection is characterized by long-lasting symptoms: asthenia, somatic vegetative manifestations, sleep disorders and psychoemotional background, the  question of  therapeutic correction of which is especially relevant.

The aim of the study was to study the mental, somatoform and cognitive aspects of anxiety disorders after coronavirus infection during treatment with tofizopam (Grandaxin®) at 150 mg / day.

Materials and methods

Materials and methods. The study involved patients who had a new coronavirus infection, who 4 weeks after the end of treatment for the underlying disease had complaints that suggest the presence of an anxiety disorder. The Hamilton scale was used to assess the level of anxiety. The patients were examined before the start of treatment, after 2, 4 and 6 weeks of therapy.

Results

Results. Prior to the start of therapy, all patients had an overall high level of anxiety: the average HAM-A score was 31.72 ± 2.24  points. At the  end of  Grandaxin® therapy, all patients showed a  decrease in  the  level of  anxiety: the  average score for HAM-A was 12.68 ± 2.04 points (p < 0.001). At the end of the course of therapy, patients noted an increase in mental performance, improved memory and attention, that is, a decrease in the severity of cognitive disorders associated with anxiety was> distinct – the average score on the “cognitive disorders” subscale decreased three times – from 1.6 ± 0.12 to 0.5 ± 0.09 (p˂0.001).

Conclusions

Conclusions. Disorders of the psychoemotional background (more often in the form of increased personal anxiety), sleep disorders, autonomic disorders, asthenic syndrome significantly affect the quality of life of patients who have suffered a new coronavirus infection. A comprehensive approach is needed in the clinical diagnosis of the long-term consequences of a new coronavirus infection and their subsequent correction with drug therapy. 

астениятревогавегетативные нарушениярасстройства снаCOVID-19тофизопам>astheniaanxietyautonomic disorderssleep disordersCOVID-19tofisopamReferencesGreenhalgh T., Knight M., A’Court C., Buxton M., Husain L. Management of post-acute Covid-19 in primary care. BMJ. 2020;370:m3026. https://doi.org/10.1136/bmj.m3026.Greenhalgh T., Knight M., A’Court C., Buxton M., Husain L. Management of post-acute Covid-19 in primary care. BMJ. 2020;370:m3026. https://doi.org/10.1136/bmj.m3026.Chan A.T., Drew D.A., Nguyen L.H., Joshi A.D., Ma W., Guo C.G. et. al. COPE Consortium. The COronavirus Pandemic Epidemiology (COPE) Consortium: A Call to Action. Cancer Epidemiol Biomarkers Prev. 2020;29(7):1283–1289. https://doi.org/10.1158/1055-9965.EPI-20-0606.Chan A.T., Drew D.A., Nguyen L.H., Joshi A.D., Ma W., Guo C.G. et. al. COPE Consortium. The COronavirus Pandemic Epidemiology (COPE) Consortium: A Call to Action. Cancer Epidemiol Biomarkers Prev. 2020;29(7):1283–1289. https://doi.org/10.1158/1055-9965.EPI-20-0606.Dani M., Dirksen A., Taraborrelli P., Torocastro M., Panagopoulos D., Sutton R., Lim P.B. Autonomic dysfunction in “long COVID”: rationale, physiology and management strategies. Clin Med (Lond). 2021;21(1):e63–e67. https://doi.org/10.7861/clinmed.2020-0896.Dani M., Dirksen A., Taraborrelli P., Torocastro M., Panagopoulos D., Sutton R., Lim P.B. Autonomic dysfunction in “long COVID”: rationale, physiology and management strategies. Clin Med (Lond). 2021;21(1):e63–e67. https://doi.org/10.7861/clinmed.2020-0896.Kroenke K., Spitzer R.L., Williams J.B., Monahan P.O., Löwe B. Anxiety disorders in primary care: prevalence, impairment, comorbidity, and detection. Ann Intern Med. 2007;146(5):317–325. https://doi.org/10.7326/0003-4819- 146-5-200703060-00004.Kroenke K., Spitzer R.L., Williams J.B., Monahan P.O., Löwe B. Anxiety disorders in primary care: prevalence, impairment, comorbidity, and detection. Ann Intern Med. 2007;146(5):317–325. https://doi.org/10.7326/0003-4819-146-5-200703060-00004.Goldstein D.S. The extended autonomic system, dyshomeostasis, and COVID-19. Clin Auton Res. 2020;30(4):299–315. https://doi.org/10.1007/s10286-020-00714-0.Goldstein D.S. The extended autonomic system, dyshomeostasis, and COVID-19. Clin Auton Res. 2020;30(4):299–315. https://doi.org/10.1007/s10286-020-00714-0.Fudim M., Qadri Y.J., Ghadimi K., MacLeod D.B., Molinger J., Piccini J.P. et al. Implications for Neuromodulation Therapy to Control Inflammation and Related Organ Dysfunction in COVID-19. J Cardiovasc Transl Res. 2020;13(6):894–899. https://doi.org/10.1007/s12265-020-10031-6.Fudim M., Qadri Y.J., Ghadimi K., MacLeod D.B., Molinger J., Piccini J.P. et al. Implications for Neuromodulation Therapy to Control Inflammation and Related Organ Dysfunction in COVID-19. J Cardiovasc Transl Res. 2020;13(6):894–899. https://doi.org/10.1007/s12265-020-10031-6.Staedtke V., Bai R.Y., Kim K., Darvas M., Davila M.L., Riggins G.J. et al. Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome. Nature. 2018;564(7735):273–277. https://doi.org/10.1038/s41586-018-0774-y.Staedtke V., Bai R.Y., Kim K., Darvas M., Davila M.L., Riggins G.J. et al. Disruption of a self-amplifying catecholamine loop reduces cytokine release syndrome. Nature. 2018;564(7735):273–277. https://doi.org/10.1038/s41586-018-0774-y.Guilmot A., Maldonado Slootjes S., Sellimi A., Bronchain M., Hanseeuw B., Belkhir L. et al. Immune-mediated neurological syndromes in SARS-CoV-2- infected patients. J Neurol. 2021;268(3):751–757. https://doi.org/10.1007/s00415-020-10108-x.Guilmot A., Maldonado Slootjes S., Sellimi A., Bronchain M., Hanseeuw B., Belkhir L. et al. Immune-mediated neurological syndromes in SARS-CoV2-infected patients. J Neurol. 2021;268(3):751–757. https://doi.org/10.1007/s00415-020-10108-x.Ruzieh M., Batizy L., Dasa O., Oostra C., Grubb B. The role of autoantibodies in the syndromes of orthostatic intolerance: a systematic review. Scand Cardiovasc J. 2017;51(5):243–247. https://doi.org/10.1080/14017431.2017.1 355068.Ruzieh M., Batizy L., Dasa O., Oostra C., Grubb B. The role of autoantibodies in the syndromes of orthostatic intolerance: a systematic review. Scand Cardiovasc J. 2017;51(5):243–247. https://doi.org/10.1080/14017431.2017.1 355068.Li H., Kem D.C., Reim S., Khan M., Vanderlinde-Wood M., Zillner C. et al. Agonistic autoantibodies as vasodilators in orthostatic hypotension: a new mechanism. Hypertension. 2012;59(2):402–408. https://doi.org/10.1161/HYPERTENSIONAHA.111.184937.Li H., Kem D.C., Reim S., Khan M., Vanderlinde-Wood M., Zillner C. et al. Agonistic autoantibodies as vasodilators in orthostatic hypotension: a new mechanism. Hypertension. 2012;59(2):402–408. https://doi.org/10.1161/HYPERTENSIONAHA.111.184937.Chigr F., Merzouki M., Najimi M. Autonomic Brain Centers and Pathophysiology of COVID-19. ACS Chem Neurosci. 2020;11(11):1520– 1522. https://doi.org/10.1021/acschemneuro.0c00265.Chigr F., Merzouki M., Najimi M. Autonomic Brain Centers and Pathophysiology of COVID-19. ACS Chem Neurosci. 2020;11(11):1520– 1522. https://doi.org/10.1021/acschemneuro.0c00265.Carfi A., Bernabei R., Landi F. Рersistent symptoms in patients after acute COVID-19. JAMA. 2020;324(6):603–605. https://doi.org/10.1001/jama.2020.12603.Carfi A., Bernabei R., Landi F. Рersistent symptoms in patients after acute COVID-19. JAMA. 2020;324(6):603–605. https://doi.org/10.1001/jama.2020.12603.El Sayed S., Shokry D., Gomaa S.M. Post-COVID-19 fatigue and anhedonia: A cross-sectional study and their correlation to post-recovery period. Neuropsychopharmacol Rep. 2021;41(1):50–55. https://doi.org/10.1002/npr2.12154.El Sayed S., Shokry D., Gomaa S.M. Post-COVID-19 fatigue and anhedonia: A cross-sectional study and their correlation to post-recovery period. Neuropsychopharmacol Rep. 2021;41(1):50–55. https://doi.org/10.1002/npr2.12154.Ferraro F., Calafiore D., Dambruoso F., Guidarini S., de Sire A. COVID-19 related fatigue: Which role for rehabilitation in post-COVID-19 patients? A case series. J Med Virol. 2021;93(4):1896–1899. https://doi.org/10.1002/ jmv.26717.Ferraro F., Calafiore D., Dambruoso F., Guidarini S., de Sire A. COVID-19 related fatigue: Which role for rehabilitation in post-COVID-19 patients? A case series. J Med Virol. 2021;93(4):1896–1899. https://doi.org/10.1002/jmv.26717.Ortelli P., Ferrazzoli D., Sebastianelli L., Engl M., Romanello R., Nardone R. et al. Neuropsychological and neurophysiological correlates of fatigue in post-acute patients with neurological manifestations of COVID-19: insights into a challenging symptom. J Neurol Sci. 2021;420:117271. https://doi.org/10.1016/j.jns.2020.117271.Ortelli P., Ferrazzoli D., Sebastianelli L., Engl M., Romanello R., Nardone R. et al. Neuropsychological and neurophysiological correlates of fatigue in post-acute patients with neurological manifestations of COVID-19: insights into a challenging symptom. J Neurol Sci. 2021;420:117271. https://doi.org/10.1016/j.jns.2020.117271.Townsend L., Dyer A.H., Jones K., Dunne J., Mooney A., Gaffney F. et al. Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PLoS One. 2020;15(11):е0240784. https://doi.org/10.1371/journal.pone.0240784.Townsend L., Dyer A.H., Jones K., Dunne J., Mooney A., Gaffney F. et al. Persistent fatigue following SARS-CoV-2 infection is common and independent of severity of initial infection. PLoS One. 2020;15(11):е0240784. https://doi.org/10.1371/journal.pone.0240784.Helms J., Kremer S., Merdji H., Clere-Jehl R., Schenck M., Kummerlen C. et al. Neurologic Features in Severe SARS-CoV-2 Infection. N Engl J Med. 2020;382(23):2268–2270. https://doi.org/10.1056/nejmc2008597.Helms J., Kremer S., Merdji H., Clere-Jehl R., Schenck M., Kummerlen C. et al. Neurologic Features in Severe SARS-CoV-2 Infection. N Engl J Med. 2020;382(23):2268–2270. https://doi.org/10.1056/nejmc2008597.Benussi A., Di Lorenzo F., Dell’Era V., Cosseddu M., Alberici A., Caratozzolo S. et al. Transcranial magnetic stimulation distinguishes Alzheimer disease from frontotemporal dementia. Neurology. 2017;89(7):665–672. https://doi.org/10.1212/WNL.0000000000004232.Benussi A., Di Lorenzo F., Dell’Era V., Cosseddu M., Alberici A., Caratozzolo S. et al. Transcranial magnetic stimulation distinguishes Alzheimer disease from frontotemporal dementia. Neurology. 2017;89(7):665–672. https://doi.org/10.1212/WNL.0000000000004232.Sumner P., Edden R.A., Bompas A., Evans C.J., Singh K.D. More GABA, less distraction: a neurochemical predictor of motor decision speed. Nat Neurosci. 2010;13(7):825–827. https://doi.org/10.1038/nn.2559.Sumner P., Edden R.A., Bompas A., Evans C.J., Singh K.D. More GABA, less distraction: a neurochemical predictor of motor decision speed. Nat Neurosci. 2010;13(7):825–827. https://doi.org/10.1038/nn.2559.Porges E.C., Woods A.J., Edden R.A., Puts N.A., Harris A.D., Chen H. et al. Frontal gamma-aminobutyric acid concentrations are associated with cognitive performance in older adults. Biol Psychiatry Cogn Neurosci Neuroimaging. 2017;2(1):38–44. https://doi.org/10.1016/j.bpsc.2016.06.004.Porges E.C., Woods A.J., Edden R.A., Puts N.A., Harris A.D., Chen H. et al. Frontal gamma-aminobutyric acid concentrations are associated with cognitive performance in older adults. Biol Psychiatry Cogn Neurosci Neuroimaging. 2017;2(1):38–44. https://doi.org/10.1016%2Fj.bpsc.2016.06.004.Versace V., Sebastianelli L., Ferrazzoli D., Romanello R., Ortelli P., Saltuari L. et al. Intracortical GABAergic dysfunction in patients with fatigue and dysexecutive syndrome after COVID-19. Clin Neurophysiol. 2021;132(5):1138–1143. https://doi.org/10.1016/j.clinph.2021.03.001.Versace V., Sebastianelli L., Ferrazzoli D., Romanello R., Ortelli P., Saltuari L. et al. Intracortical GABAergic dysfunction in patients with fatigue and dysexecutive syndrome after COVID-19. Clin Neurophysiol. 2021;132(5):1138–1143. https://doi.org/10.1016/j.clinph.2021.03.001.Stellwagen D., Malenka R.C. Synaptic scaling mediated by glial TNF-α Nature. 2006;440(7087):1054–1059. https://doi.org/10.1038/nature04671.Stellwagen D., Malenka R.C. Synaptic scaling mediated by glial TNF-α Nature. 2006;440(7087):1054–1059. https://doi.org/10.1038/nature04671.Nikbakht F., Mohammadkhanizadeh A., Mohammadi E. How does the COVID-19 cause seizure and epilepsy in patients? The potential mechanisms. Mult Scler Relat Disord. 2020;46:102535. Avialable at: https://pubmed.ncbi.nlm.nih.gov/33010584/.Nikbakht F., Mohammadkhanizadeh A., Mohammadi E. How does the COVID-19 cause seizure and epilepsy in patients? The potential mechanisms. Mult Scler Relat Disord. 2020;46:102535. Avialable at: https://pubmed.ncbi.nlm.nih.gov/33010584/.Tian J., Milddleton B., Kaufman D.L. GABA administration prevents severe illness and death following coronavirus infection in mice. bioRxiv. 2020:2020.10.04.325423. https://doi.org/10.1101/2020.10.04.325423.Tian J., Milddleton B., Kaufman D.L. GABA administration prevents severe illness and death following coronavirus infection in mice. bioRxiv. 2020:2020.10.04.325423. https://doi.org/10.1101/2020.10.04.325423.Baller E.B., Hogan C.S., Fusunyan M.A., Ivkovic A., Luccarelli J.W., Madva E. et al. Neurocovid: Pharmacological Recommendations for Delirium Associated with COVID-19. Psychosomatics. 2020;61(6):585–596. https://doi.org/10.1016/j.psym.2020.05.013.Baller E.B., Hogan C.S., Fusunyan M.A., Ivkovic A., Luccarelli J.W., Madva E. et al. Neurocovid: Pharmacological Recommendations for Delirium Associated with COVID-19. Psychosomatics. 2020;61(6):585–596. https://doi.org/10.1016/j.psym.2020.05.013.Смулевич А.Б., Дробижев М.Ю., Иванов С.В. Клинические эффекты бензодиазепиновых транквилизаторов в психиатрии и общей медицине. М.: Медиа-Сфера; 2005. 88 с. Режим доступа: https://otherreferats.allbest.ru/medicine/00516644_0.html.Smulevich A.B., Drobizhev M.Yu., Ivanov S.V. Clinical effects of benzodiazepine tranquilizers in psychiatry and general medicine. Moscow: Media-Sfera; 2005. 88 р. (In Russ.) Avialable at: https://otherreferats.allbest.ru/medicine/00516644_0.html.Bandelow B., Sher L., Bunevicius R., Hollander E., Kasper S., Zohar J. et al. Guidelines for the pharmacological treatment of anxiety disorders, obsessive-compulsive disorder and posttraumatic stress disorder in primary care. Int J Psychiatry Clin Pract. 2012;16(2):77–84. https://doi.org/10.3 109/13651501.2012.667114.Bandelow B., Sher L., Bunevicius R., Hollander E., Kasper S., Zohar J. et al. Guidelines for the pharmacological treatment of anxiety disorders, obsessive-compulsive disorder and posttraumatic stress disorder in primary care. Int J Psychiatry Clin Pract. 2012;16(2):77–84. https://doi.org/10.3109/13651501.2012.667114.Корнеева А. Безопасное лечение стрессогенных расстройств в практике психиатров и психологов. Лечащий врач. 2018;(6):22. Режим доступа: https://www.lvrach.ru/partners/grandaxin/15437004.Korneeva A. Safe treatment of stress disorders in the practice of psychiatrists and psychologists. Lechaschi Vrach. 2018;(6):22. (In Russ.) Available at: https://www.lvrach.ru/partners/grandaxin/15437004.Дума С.Н., Лисиченко О.В., Лукьянова Г.В. Психовегетативные, астенические и когнитивные нарушения при дисплазии соединительной ткани: выбор оптимальной терапии. Фарматека. 2012;(7):131–135. Режим доступа: https://pharmateca.ru/ru/archive/article/8436.Duma S.N., Lisichenko O.V., Lukyanova G.V. Psychovegetative, asthenic and cognitive disorders in connective tissue dysplasia: the choice of optimal therapy. Farmateka. 2012;(7):131–135. (In Russ.) Available at: https://pharmateca.ru/ru/archive/article/8436.Густов А.В., Александрова Е.А., Паршина Е.В., Бородачева И.В., Беляков К.М. Эффективность Сертралина в качестве ко-анальгетика при хронических болевых синдромах нижней части спины. Международный журнал прикладных и фундаментальных исследований. 2016;8(2):158– 161. Режим доступа: https://www.applied-research.ru/ru/article/view?id=9995.Gustov A.V., Alexandrova E.A., Parshina E.V., Borodacheva I.V., Belyakov K.M. The effectiveness of Sertraline as a co-analgesic in chronic pain syndromes of the lower back. International Journal of Applied and Fundamental Research. 2016;8(2):158–161. (In Russ.) Available at: https://www.appliedresearch.ru/ru/article/view?id=9995.Sierralta F., Miranda H.F. Analgesic effect of benzodiazepines and flumazenil. Gen Pharmacol. 1992;23(4):739–742. https://doi.org/10.1016/0306- 3623(92)90158-g.Sierralta F., Miranda H.F. Analgesic effect of benzodiazepines and flumazenil. Gen Pharmacol. 1992;23(4):739–742. https://doi.org/10.1016/0306- 3623(92)90158-g.Dolezal T., Krsiak M. Augmentation of analgesic effect of ibuprofen by alprazolam in experimental model of pain. Physiol Res. 2002;51(2):179– 184. Available at: https://pubmed.ncbi.nlm.nih.gov/12108928/.Dolezal T., Krsiak M. Augmentation of analgesic effect of ibuprofen by alprazolam in experimental model of pain. Physiol Res. 2002;51(2):179– 184. Available at: https://pubmed.ncbi.nlm.nih.gov/12108928/.Rad R.E., Ghaffari F., Fotokian Z., Ramezani A. The effectiveness of ibuprofen and lorazepam combination therapy in treating the symptoms of acute Migraine: A randomized clinical trial. Electron Physician. 2017;9(3):3912–3917. https://doi.org/10.19082/3912.Rad R.E., Ghaffari F., Fotokian Z., Ramezani A. The effectiveness of ibuprofen and lorazepam combination therapy in treating the symptoms of acute Migraine: A randomized clinical trial. Electron Physician. 2017;9(3):3912–3917. https://doi.org/10.19082/3912.Talarek S., Fidecka S. Role of nitric oxide in benzodiazepines-induced antinociception in mice. Pol J Pharmacol. 2002;54(1):27–34. Available at: https://pubmed.ncbi.nlm.nih.gov/12020041/.Talarek S., Fidecka S. Role of nitric oxide in benzodiazepines-induced antinociception in mice. Pol J Pharmacol. 2002;54(1):27–34. Available at: https://pubmed.ncbi.nlm.nih.gov/12020041/.Jiménez-Velázquez G., López-Muñoz F.J., Fernández-Guasti A. Participation of the GABA/benzodiazepine receptor and the NO-cyclic GMP pathway in the “antinociceptive-like effects” of diazepam. Pharmacol Biochem Behav. 2008;91(1):128–133. https://doi.org/10.1016/j.pbb.2008.06.021.Jiménez-Velázquez G., López-Muñoz F.J., Fernández-Guasti A. Participation of the GABA/benzodiazepine receptor and the NO-cyclic GMP pathway in the “antinociceptive-like effects” of diazepam. Pharmacol Biochem Behav. 2008;91(1):128–133. https://doi.org/10.1016/j.pbb.2008.06.021.Green S.J. Covid-19 accelerates endothelial dysfunction and nitric oxide deficiency. Microbes Infect. 2020;22(4–5):149–150. https://doi.org/10.1016/j.micinf.2020.05.006.Green S.J. Covid-19 accelerates endothelial dysfunction and nitric oxide deficiency. Microbes Infect. 2020;22(4–5):149–150. https://doi.org/10.1016/j.micinf.2020.05.006.Martel J., Ko Y.F., Young J.D., Ojcius D.M. Could nasal nitric oxide help to mitigate the severity of COVID-19? Microbes Infect. 2020;22(4–5):168–171. https://doi.org/10.1016/j.micinf.2020.05.002.Martel J., Ko Y.F., Young J.D., Ojcius D.M. Could nasal nitric oxide help to mitigate the severity of COVID-19? Microbes Infect. 2020;22(4–5):168–171. https://doi.org/10.1016/j.micinf.2020.05.002.Wu R., Wang L., Kuo H.D., Shannar A., Peter R., Chou P.J. et al. An Update on Current Therapeutic Drugs Treating COVID-19. Curr Pharmacol Rep. 2020;1–15. https://doi.org/10.1007/s40495-020-00216-7.Wu R., Wang L., Kuo H.D., Shannar A., Peter R., Chou P.J. et al. An Update on Current Therapeutic Drugs Treating COVID-19. Curr Pharmacol Rep. 2020;1–15. https://doi.org/10.1007/s40495-020-00216-7.Adusumilli N.C., Zhang D., Friedman J.M., Friedman A.J. Harnessing nitric oxide for preventing, limiting and treating the severe pulmonary consequences of COVID-19. Nitric Oxide. 2020;103:4–8. https://doi.org/10.1016/j.niox.2020.07.003.Adusumilli N.C., Zhang D., Friedman J.M., Friedman A.J. Harnessing nitric oxide for preventing, limiting and treating the severe pulmonary consequences of COVID-19. Nitric Oxide. 2020;103:4–8. https://doi.org/10.1016/j.niox.2020.07.003.Shanthanna H., Strand N.H., Provenzano D.A., Lobo C.A., Eldabe S., Bhatia A. et al. Caring for patients with pain during the COVID-19 pandemic: consensus recommendations from an international expert panel. Anaesthesia. 2020;75(7):935–944. https://doi.org/10.1111/anae.15076.Shanthanna H., Strand N.H., Provenzano D.A., Lobo C.A., Eldabe S., Bhatia A. et al. Caring for patients with pain during the COVID-19 pandemic: consensus recommendations from an international expert panel. Anaesthesia. 2020;75(7):935–944. https://doi.org/10.1111/anae.15076.

The authors declare that there are no conflicts of interest present.