Novine u terapiji multiple skleroze

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system, which usually affects young adults. The most common clinical course of the disease is the relapsing-remitting form of multiple sclerosis (RRMS). Although there is no causative therapy, treatment outcomes in patients with RRMS have been significantly improved with the introduction of disease modifying therapy (DMT), which decreases disease activity and delays progression of disability. Drugs used as DMT are immune modulator and immunosuppressive drugs. The conventional immunomodulatory drugs, interferons (IFN-β 1b and IFN-β 1a) and glatiramer acetate, applied parenterally, have been the first line therapy for many years in patients with RRMS. IFN-β and GA are generally safe and well-tolerated. However, due to the heterogeneity of the pathophysiology and clinical presentation of MS, their efficacy is modest, which requires substitution of IFN-β with GA or the use of certain novel immunomodulatory therapies: monoclonal antibodies, alemtuzumab and natalizumab, (parenteral administration) or teriflunomide, dimethyl-fumarate and fingolimod (peroral administration). The antineoplastic agent, mitoxantrone, is used for the treatment of aggressive forms of MS. The overall benefit/risk ratio for novel approaches in the treatment of MS has yet to be determined.Multipla skleroza (MS) je hronično autoimunsko oboljenje centralnog nervnog sistema koje uglavnom pogađa mlade odrasle osobe. Najčešća klinička forma bolesti je relapsno- remitentna multipla skleroza (RRMS). Iako ne postoji kauzalna terapija, ishod lečenja pacijenata sa RRMS značajno je poboljšan uvođenjem terapije koja modifikuje prirodni tok bolesti (disease modifying therapy, DMT), u smislu smanjenja aktivnosti bolesti i odlaganja razvoja progresivne onesposobljenosti pacijenata. Lekovi koji se koriste u DMT su imunomodulatori i imunosupresivi. Standardni imunomodulatorni lekovi, interferoni (IFN-β 1b i IFN-β 1a) i glatiramer acetat (GA), koji se primenjuju parenteralno, prva su terapijska linija dugi niz godina kod pacijenata sa RRMS. Bezbednosni profil IFN-β i GA je generalno dobar. Međutim, zbog heterogenosti patogeneze i kliničke prezentacije MS, njihova efikasnost je delimična, što nameće potrebu za međusobnom zamenom IFN-β i GA ili za ustupanjem mesta nekoj od novih odobrenih imunomodulatornih terapija: alemtuzumab i natalizumab (parenteralna primena) ili teriflunomid, dimetil-fumarat i fingolimod (peroralna primena). Citostatik, mitoksantron, primenjuje se kod agresivne forme MS. Odnos korist/rizik novih terapijskih opcija u MS tek treba da se proceni/potvrdi

Writing letters to patients as an educational tool for medical students

BACKGROUND: Despite rapid growth and development of medical technology, personal relationship between the patient and physician remains the basis of high quality treatment. The aim of our study was to develop, implement and evaluate patient therapeutic letters written by students as a tool in teaching family medicine. METHODS: The study included all 6(th) year students attending their rounds in family medicine, structured into two 10-day cycles, one in urban offices and one in offices on the Adriatic islands (rural). After receiving detailed instructions, students wrote letters to two patients after a consultation in the office. The letters were audited by patients and 3 family medicine experts who used a grading instrument (scale 0 – poor, 1 – medium, 2 – good) for 1) adequacy and clarity of description of patients’ disease/state, 2) knowledge, 3) adequacy of recommendations, 4) courtesy and respect and 5) language and style. Patients and experts were also asked to underline phrases they thought would be difficult to understand; the underlined text was subjected to content analysis. RESULTS: Both the patients and the experts gave high scores for the value and quality of the letters in terms of the description of the problem, adequacy of recommendations given, and courtesy and respect (mean (±standard deviation) 5.65 ± 0.79 for patients vs. 4.87 ± 0.79 for experts out of maximum score of 6). Family medicine experts were stricter than patients in their evaluation of the content of the letters (adequacy and clarity of disease description (P < 0.001) and adequacy of recommendations (P < 0.001). Both the patients and the experts seemed to like longer letters as the length of the letter showed significant positive correlation with the quality summary score (correlation r = 0.492 vs. r = 0.338, respectively, P < 0.010). Overlapping of the text underlined as difficult to understand by patients and experts was found in 10 (11.6%) out of 86 letters. The highest overlap (20 terms) was found for the category “Technical terms unclear to a lay reader”. CONCLUSIONS: Writing of a letter to their first patients may be a useful tool for students to personally experience the practice of medicine and establish better partnership with patients in health care

Regional differences in incidence and clinical presentation of type 1 diabetes in children aged under 15 years in Croatia

AIM: To determine regional differences in the incidence, incidence trends, and clinical presentation of type 1 diabetes in children under the age of 15 years in Croatia in a 9-year period (1995-2003). ----- METHODS: We included the patients who had been diagnosed with the disease and had started the insulin treatment before they were 15 years old. Regional differences between eastern, central, and southern Croatia were observed. The gross incidence was expressed by the number of newly diagnosed type 1 diabetes patients in 100000 children of the same age and sex per year, ie, for the 0-14 age group, and for the 0-4, 5-9, and 10-14 subgroups. ----- RESULTS: The highest incidence was observed in southern Croatia (10.91 per 100000/y) and the lowest in central Croatia (8.64 per 100000/y), and in eastern Croatia the incidence was 8.93 per 100000/y. All three regions showed a growing incidence trend, which was significant only in eastern and southern Croatia. There was 35.9% of patients with diabetic ketoacidosis in eastern Croatia, 41.7% in central Croatia, and 31.28% in southern Croatia. ----- CONCLUSION: Croatian regions show differences in the incidence, incidence trends, and disease presentation of type 1 diabetes. A further follow-up is needed to establish whether the regional differences are a consequence of the population dynamics in the observed period or they will continue to exist, pointing to differences in environmental risk factors

Synergism between metformin and analgesics/vitamin B12 in a model of painful diabetic neuropathy

Metformin (a widely used antidiabetic drug) has demonstrated efficacy in models of painful diabetic neuropathy (PDN), as well as certain clinical efficacy in relieving/preventing PDN. This study aimed to determine the type of interaction between metformin and duloxetine/oxycodone/eslicarbazepine acetate [ESL]/vitamin B12 in relieving diabetic pain hypersensitivity. Antihyperalgesic efficacy was determined using a Von Frey apparatus in mice with streptozotocin-induced PDN. We examined metformin’s efficacy following oral (acute and prolonged 7-day treatment) and local (spinal and peripheral) application. The examined analgesics were administered in a single oral dose, whereas vitamin B12 was intraperitoneally administered for 7 days. In combination experiments, metformin (prolonged treatment) and analgesics/vitamin B12 were co-administered in fixed-dose fractions of their ED50 values and the type of interaction was determined using isobolographic analysis. Metformin produced dose-dependent antihyperalgesic effects in diabetic mice after oral (acute and prolonged 7-day treatment) and local spinal/peripheral application. Two-drug metformin combinations with analgesics/vitamin B12 also dose- dependently reduced mechanical hyperalgesia. The isobolographic analysis revealed that metformin synergises with analgesics/vitamin B12, with a 6–7 fold dose reduction of both drugs in the examined combinations. In conclusion, metformin reduces hyperalgesia in diabetic animals, most likely by acting at the spinal and pe- ripheral level. Additionally, it synergizes with duloxetine/oxycodone/ESL/vitamin B12 in reducing hyperalgesia. Metformin co-treatment may increase analgesic efficacy and enable the use of lower (and potentially safer) analgesic doses for treating PDN. Combined metformin-vitamin B12 use may provide more effective pain relief and mitigate metformin-induced vitamin B12 deficiency

Učešće serotonergičkih mehanizama u antinociceptivnom dejstvu metformina

Metformin, a well-known antidiabetic drug, has been shown to possess analgesic properties in inflammatory pain models, but the mechanisms of its antinociceptive effects are not completely understood (1,2). We aimed to examine the involvement of serotonergic mechanisms in metformin-induced antinociception in a model of inflammatory pain, using the formalin test in mice. Firstly, we examined the antinociceptive effects of intraperitoneally administered metformin in the first and second phase of the test. Then, the involvement of serotonergic receptors was evaluated by intraperitoneally pretreating mice with a 5-HT1B/1D (GR127935) or 5-HT1A receptor antagonist (WAY100635). Further, we examined the effect of metformin after depletion of endogenous serotonin with a tryptophan-hydroxylase inhibitor (PCPA; applied intraperitoneally for 4 days). Additionally, to avoid misinterpretation of motor incoordination, we performed the rotarod test with the highest tested metformin dose. Metformin (50-200 mg/kg) produced significant and dose-dependent antinociceptive effects (17-81%) in the second (inflammatory) phase of the test. Pretreatment with antagonists significantly reduced the antinociceptive effect of metformin (150 mg/kg). GR127935 inhibited the effects of metformin by 67% (1 mg/kg) and 100% (3 mg/kg), whereas the inhibitory effects for WAY100635 were 19% (1 mg/kg) and 68% (3 mg/kg). Depletion of serotonin with PCPA (100 mg/kg/day) significantly reduced the antinociceptive effects of higher metformin doses (150 and 200 mg/kg). Metformin (200 mg/kg) had no influence on rotarod performance. This study demonstrates that 5-HT1B/1D and 5-HT1A receptors are involved in metformin’s antinociceptive effects and that metformin’s action on these receptors seems to be indirect (mediated by endogenous serotonin released by metformin).Metformin je dobro poznat antidijabetik, za koji je pokazano da poseduje analgetička svojstva u modelima inflamatornog bola. Međutim, mehanizmi njegovog antinociceptivnog dejstva nisu u potpunosti rasvetljeni (1,2). Cilj ovog rada je bio ispitati učešće serotonergičkih mehanizama u antinociceptivnom dejstvu metformina u inflamatornom modelu bola – korišćenjem formalinskog testa kod miševa. Inicijalno su ispitani antinociceptivni efekti metformina, nakon intraperitonealne primene, u prvoj i drugoj fazi testa. Uključenost serotoninskih receptora je procenjena nakon intraperitonealne primene antagonista 5-HT 1B/1D (GR127935) ili 5-HT1A (WAY100635) receptora. U nastavku eksperimenata, efekat metformina je ispitan nakon deplecije endogenog serotonina, primenom inhibitora triptofan-hidroksilaze (PCPA; primenjen intraperitonealno tokom 4 dana). Dodatno, efekat najveće testirane doze metformina je ispitan u rotarod testu, kako bi se isključila mogućnost pogrešnog tumačenja motorne inkoordinacije. Metformin (50-200 mg/kg) je pokazao značajno i dozno-zavisno antinociceptivno dejstvo (17-81%) u drugoj (inflamatornoj) fazi testa. Primena antagonista je značajno smanjila antinociceptivni efekat metformina (150 mg/kg). GR127935 je inhibirao efekte metformina za 67% (1 mg/kg) i 100% (3 mg/kg), dok su inhibitorni efekti WAY100635 bili 19% (1 mg/kg) i 68% (3 mg/kg). Deplecija serotonina korišćenjem PCPA (100 mg/kg/dan) je značajno smanjila antinociceptivne efekte metformina primenjenog u većim dozama (150 i 200 mg/kg). Metformin (200 mg/kg) nije imao značajan uticaj na performanse miševa u rotarod testu. Ova studija je pokazala uključenost 5-HT1B/1D i 5-HT1A receptora u antinociceptivnom dejstvu metformina, koje je verovatno posledica indirektnog uticaja leka na receptore (posredstvom oslobađanja endogenog serotonina od strane metformina).VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Multimodalna kontrola hroničnog bola i komorbiditeta sa atipičnim analgeticima ‐,,više muva jednim udarcem“

Osteoarthritis (OA) is the most common rheumatic disease, affecting over 300 million people worldwide. It causes chronic pain, disability and is commonly associated with comorbid diseases (CMD) that cause worse health outcomes, more complex management, and increased healthcare costs. Current treatments (typical/atypical analgesics) have limited efficacy and/or tolerability and usually do not affect or can even worse CMD. In era of longer life expectancy, extended professional life and reduced pension funds in Serbia and Europe, there is a compelling need for maintaining functionality and working capability of older population. Our aim is to search for novel treatments that could concomitantly treat chronic pain and its major CMD: depression, cognitive impairment and/or cardiovascular disease (CVD). It was planned to test the effects of vortioxetine, a novel antidepressant with multimodal mechanism of action, on pain, depressive and cognitive-impairment behaviour and CV status in rat model of knee OA. Its effects will be compared to the effects of duloxetine, the only antidepressant used for pain relief in OA. Next, we will test the effects of 2-component combinations of vortioxetine/duloxetine with adjuvant treatments (regular exercise/metformin/nicotinamide), that showed the potential to alleviate pain, depression, reduced cognition and/or CVD in preclinical/clinical research. If proved effective and well tolerated, new treatment(s) could be implemented in clinical practice much faster and with significantly less investment, than those required to develop brand new drug, as they consist of drugs already approved for human use and safe, widely available and inexpensive non- pharmacologic measures.Osteoartritis (OA) je najčešć a reumatska bolest, koja pogađa preko 300 miliona ljudi širom sveta. Prouzrokuje hronični bol, invaliditet i obično je povezan sa komorbiditetima koji dovode do lošijih zdravstvenih ishoda, složenijeg lečenja i povećanja troškova zdravstvene zaštite. Trenutno dostupne terapijske opcije (tipični/atipični analgetici) imaju ograničenu efikasnost i/ili lošu podnošljivost, i obično ne utiču ili čak mogu pogoršati komorbiditete. U vremenu kada su ljudski i radni vek produženi, a penzioni fondovi u Srbiji i Evropi smanjeni, postoji velika potreba za održavanjem funkcionalnosti i radne sposobnosti starije populacije. Naš cilj je da pronađemo nove terapijske opcije koje bi istovremeno mogle da leče hronični bol i njegove glavne komorbiditete: depresiju, kognitivno oštećenje i/ili kardiovaskularne bolesti (KVB). Planirano je ispitivanje efekata vortioksetina, novog antidepresiva sa multimodalnim mehanizmom delovanja, na bol, depresivno ponašanje, kognitivno ošteć enje i kardiovaskularni status pacova u modelu OA kolena. Efekti vortioksetina biće poređeni sa efektima duloksetina, jedinog antidepresiva koji se koristi za ublažavanje bola kod OA. Zatim će biti ispitani efekti dvokomponentnih kombinacija vortioksetina/duloksetina sa adjuvantnim tretmanima (redovna fizička aktivnost/metformin/nikotinamid), koji su pokazali efikasnost u ublažavanju bola, depresije, narušene kognicije i/ili KVB u pretkliničkim/kliničkim istraživanjima. Ukoliko se pokaže da su efikasne i da se dobro tolerišu, nove terapijske opcije bi se mogle implementirati u kliničku praksu mnogo brže i sa znatno manje finansijskih ulaganja u poređenju sa vremenom i ulaganjima koja su potrebna za razvoj novog leka, jer se sastoje od lekova koji su već odobreni za ljudsku upotrebu i bezbednih, široko dostupnih i ekonomski povoljnih nefarmakoloških mera.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Efikasnost vortioksetina u modelu osteoartritisa kod pacova

Osteoarthritis is the most common rheumatic degenerative condition, with chronic joint pain being the major source of disability. Currently, available treatment options for alleviating pain are often ineffective and/or associated with unfavorable safety profiles (1). Vortioxetine is a novel multimodal antidepressant, an inhibitor of serotonin reuptake, but also an agonist, partial agonist, or antagonist of several serotonin (5-HT) receptors subtypes involved in pain modulation (2). The study aimed to examine the efficacy of vortioxetine compared to duloxetine, an antidepressant recommended for the treatment of osteoarthritis, in the rat model of osteoarthritis. Osteoarthritis was induced by intra-articular injection of monosodium iodoacetate (MIA; 2 mg/25 μL) in the right knee of male Wistar rats. Vortioxetine/duloxetine was administered orally for 28 days following MIA injection. The antinociceptive effect of vortioxetine/duloxetine was assessed using von Frey, acetone, and weight-bearing test. The influence of treatments on animals’ well-being and motor performance was examined in the burrowing and rotarod test, respectively. Vortioxetine (2 and 10 mg/kg) and duloxetine (15 and 25 mg/kg) significantly reduced mechanical and cold allodynia, and improved weight borne on the ipsilateral hind paw in von Frey, acetone, and weight-bearing test, respectively. Vortioxetine had no significant effect on burrowing behavior, whereas duloxetine significantly reduced this inherent rodent activity. The rotarod test did not demonstrate a significant effect of treatment on motor performance/sedation. This study suggests comparable antinociceptive efficacy of vortioxetine with duloxetine, a referent drug, as well as a better impact on the animals’ well-being of vortioxetine.Osteoartritis predstavlja najčešće reumatsko degenerativno oboljenje, praćeno hroničnim bolom, glavnim uzrokom onesposobljenosti pacijenata. Postojeće terapijske opcije za otklanjanje bola su neretko nedovoljno efikasne i/ili udružene sa brojnim neželjenim efektima (1). Vortioksetin je noviji antidepresiv multimodalnog mehanizma dejstva; inhibira transporter za preuzimanje serotonina, a deluje i kao agonist, parcijalni agonist ili antagonist različitih podtipova serotoninskih (5-HT) receptora uključenih u modulaciju bola (2). Cilj ovog rada je bio ispitati efikasnost vortioksetina u poređenju sa duloksetinom, antidepresivom preporučenim za lečenje osteoartritisa, u modelu osteoartritisa kod pacova. Osteoartritis je indukovan intraartikularnom injekcijom natrijum-monojodacetata (MIA; 2 mg/25 μL) u desno koleno mužjaka pacova Wistar soja. Vortioksetin/duloksetin je primenjivan oralno svakodnevno tokom 28 dana nakon injekcije MIA. Procena antinociceptivne efikasnosti vortioksetina/duloksetina ispitivana je korišćenjem von Frey, aceton testa i testa raspodele težine (eng. weight‐bearing). Uticaj tretmana na dobrobit životinja (eng. well‐being), kao i motornu spretnost ispitivan je u testu kopanja i rotarod testu, redom. Vortioksetin (2 i 10 mg/kg) i duloksetin (15 i 25 mg/kg) su značajno smanjili mehaničku i hladnu alodiniju, i poboljšali oslanjanje životinja na ipsilateralnu šapu u von Frey, aceton i testu raspodele težine, redom. Vortioksetin nije imao značajan uticaj na aktivnost životinja u testu kopanja, dok je duloksetin značajno smanjio ovu inherentnu aktivnost glodara. U rotarod testu nije pokazan značajan uticaj tretmana na motorne performanse/sedaciju životinja. Ova studija je pokazala da su antinociceptivni efekti vortioksetina i referentnog leka duloksetina uporedivi, kao i povoljniji uticaj vortioksetina na opštu dobrobit životinja.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Aktivacija perifernih serotoninskih 5‐HT1A i 5‐HT 1B/1D receptora doprinosi antinociceptivnom dejstvu metformina

Several lines of (pre)clinical evidence have emerged that the antidiabetic drug metformin can alleviate inflammatory/neuropathic pain (1). Although the mechanism is not completely understood, there are reports that metformin can affect neurotransmitters involved in pain modulation, such as its ability to increase peripheral serotonin release (2). Here, we evaluated metformin’s efficacy following local peripheral administration in an inflammatory pain model and examined the potential involvement of serotonin receptors. We used the formalin test in mice, where we measured duration of nociceptive behavior in the first and second phase of the test. First, we examined the metformin’s antinociceptive effects following intraplantar administration. Additionally, the highest tested metformin dose was applied contralateral to the formalin-injected side, to exclude possible systemic effects. In the second part, we evaluated the effects of a 5-HT1A (WAY100635) and 5-HT1B/1D antagonist (GR127935) on the antinociceptive effects of a fixed, effective dose of metformin (antagonists were co-administered intraplantarly with metformin). Metformin (0.1-2 mg/paw) produced significant and dose-dependent antinociceptive effects (32-72%) in the second (inflammatory) phase. Contralateral application of metformin (2 mg/paw) had no significant antinociceptive effects. Both antagonists significantly reduced the antinociceptive effects of metformin (1 mg/paw). The levels of inhibition of metformin’s antinociceptive effect produced by WAY100635 were 56% (5 μg/paw) and 82% (7.5 μg/paw), whereas GR127935 inhibited metformin’s efficacy by 24% (3.75 μg/paw) and 80% (5 μg/paw). This study demonstrates that peripheral metformin application can produce antinociceptive effects against inflammatory pain and that activation of peripheral 5-HT 1A and 5-HT1B/1D receptors contributes to these effects.Postoje brojni dokazi iz (pre)kliničkih studija da metformin, lek iz grupe antidijabetika, može ublažiti inflamatorni/neuropatski bol (1). Iako mehanizam dejstva nije u potpunosti razjašnjen, podaci ukazuju da metformin može uticati na neurotransmitere uključene u modulaciju bola, poput sposobnosti da poveća oslobađanje serotonina na periferiji (2). U ovom radu je ispitana efikasnost metformina nakon lokalne periferne primene u modelu inflamatornog bola, kao i potencijalna uključenost serotoninskih receptora. Korišćen je formalinski test kod miševa, u kome je mereno vreme provedeno u nociceptivnom ponašanju, u prvoj i drugoj fazi testa. Prvo su ispitani antinociceptivni efekti metformina nakon intraplantarne primene. Dodatno, najveća testirana doza metformina je primenjena kontralateralno u odnosu na mesto injektovanja formalina, kako bi se isključili mogući sistemski efekti. U drugom delu studije, ispitani su efekti antagoniste 5-HT 1A (WAY100635) i 5-HT1B/1D (GR127935) receptora na antinociceptivno dejstvo fiksne, efektivne doze metformina (antagonisti su primenjeni intraplantarno, istovremeno sa metforminom). Metformin (0,1-2 mg/šapi) je ispoljio značajan i dozno-zavisan antinociceptivni efekat (32-72%) u drugoj (inflamatornoj) fazi testa. Kontralateralna primena metformina (2 mg/šapi) nije imala značajan antinociceptivni efekat. Primenjeni antagonisti su značajno smanjili antinociceptivne efekte metformina (1 mg/šapi). Stepeni inhibicije antinociceptivnog dejstva metformina koje je postigao WAY100635 su bili 56% (5 μg/šapi) i 82% (7,5 μg/šapi), dok je GR127935 inhibirao efikasnost metformina za 24% (3,75 μg/šapi) i 80% (5 μg/šapi). Ova studija je pokazala da periferna primena metformina proizvodi antinociceptivni efekat kod inflamatornog bola i da aktivacija perifernih 5-HT1A i 5- HT1B/1D receptora doprinosi ovom efektu.VIII Kongres farmaceuta Srbije sa međunarodnim učešćem, 12-15.10.2022. Beogra

Vortioxetine reduces the development of pain-related behaviour in a knee osteoarthritis model in rats: Involvement of nerve growth factor (NGF) down-regulation

Background and Purpose: Vortioxetine, a multimodal-acting antidepressant, has recently shown analgesic properties. We aimed to investigate its prophylactic effect in the osteoarthritis (OA) model and gain insights into the underlying molecular mechanisms. Duloxetine was studied as a reference. Experimental Approach: In the monoiodoacetate (MIA)-induced rat model of knee OA, pain-related behaviour was assessed in weight-bearing and Von Frey tests. Antidepressants were administered orally once daily for 28 days. Gene expression of pain-related mediators (Ngf, Il-1β, Tnf-α, Bdnf, and Tac1 encoding substance P) and oxidative stress parameters were determined after completion of the treatment/behavioural testing protocol. Key Results: Vortioxetine and duloxetine dose dependently reduced weight-bearing asymmetry and mechanical hyperalgesia of the paw ipsilateral to the MIA-injected knee. Vortioxetine reduced the increased Ngf mRNA expression in the MIA-injected knees to the level in sham-injected counterparts. It reduced oxidative stress parameters in the affected knees, more effectively in females than males. Duloxetine showed no effect on Ngf mRNA expression and oxidative stress. Both antidepressants decreased mRNA expression of pain-related mediators in the lumbar L3–L5 ipsilateral DRGs and spinal cords, which were up-regulated in MIA-injected rats. This effect was male-specific. Conclusion and Implications: Vortioxetine may be effective against the development of chronic pain in OA. Its antihyperalgesic effect may be mediated, at least in part, by normalization of NGF expression in the affected joint. Decrease of localized oxidative stress and of expression of pain-related mediators that contribute to central sensitization are also involved in vortioxetine's antihyperalgesic effect, in a sex-specific pattern. © 2024 The Author(s). British Journal of Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society