Assessing the Synergistic Effects of Medetomidine and Meloxicam in Adult Horses: A Comprehensive Study on Clinical, Analgesic, and Sedative Outcome

Assessing the Synergistic Effects of Medetomidine and Meloxicam in Adult Horses: A Comprehensive Study on Clinical, Analgesic, and Sedative Outcome | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Short Report Assessing the Synergistic Effects of Medetomidine and Meloxicam in Adult Horses: A Comprehensive Study on Clinical, Analgesic, and Sedative Outcome Shahrzad Babolmorad, Saeed Ozmaie, Alireza Jahandideh, Ahmad Asghari This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-3878144/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract This study investigated medetomidine's clinical, analgesic, and sedative effects with meloxicam in adult horses. 20 horses were divided into four groups; healthy control, received 3.5 µg/kg medetomidine and 0.6 mg/kg meloxicam intravenously, received 5 µg/kg and 0.6 mg/kg meloxicam, and received 7 µg/kg medetomidine and 0.6 mg/kg meloxicam. Heart rate, respiratory rate, temperature, electrocardiographs, and sedation scores were monitored before and after the injection. In the fourth group, the heart rate had a statistically significant decrease after (15, 30, and 60 minutes), and the respiratory rate decreased after (1 and 120 minutes) compared to other groups. The body temperature compared to the first group (1, 30, and 120 minutes) and the second group (15, 30, 60, and 120 minutes) after injection showed a decrease. Response to contact stimuli was examined, and only sedation with 7 µg/kg medetomidine had no stimulation. There were no significant changes in the position of the limbs, anal reflex, perineal reflex, ataxia, abdominal auscultation, and abnormal sounds. Meloxicam and medetomidine induced appropriate relaxation and reduced side effects (e.g., respiratory depression and bradycardia) in horses. Analgesia Horses Medetomidine Meloxicam Sedation Figures Figure 1 Figure 2 Figure 3 1. Introduction An “irritating sensory and emotional experience related to authentic or possible damages to the tissues” is described as pain (Clark and Clark 1999 ). Pain is a helpful mechanism that protects horses. Inducing withdrawal or struggling to escape is a consequence of acute pain, although subacute pain promotes the safeguarding of the injured region to facilitate the recovery process (Gleerup and Lindegaard 2016 ). Horses have obvious pain behaviors such as rolling, kicking the belly, looking sideways, limping, or blepharospasm, which is essential to recognize and diagnose these reactions. Pain in these animals can be identified by alterations in facial expressions, head positioning, stall location, and reactions to touch or human engagement (Sanchez and Robertson 2014 ). Pharmaceutical substances used for pain control in horses fall into categories including opioids, nonsteroidal anti-inflammatory agents (NSAIDs), and alpha-2 agonists (Clark and Clark 1999 ). The objective of combining sedation and analgesia is to render the horse unreactive to painful procedures and external stimuli, allowing it to remain standing with minimal loss of coordination while avoiding excessive or insufficient sedation. Sedative and analgesic medications are typically delivered via intravenous administration, as this offers the highest bioavailability and the quickest onset of action. (Michou and Leece 2012). The introduction of alpha2-adrenoceptor agonists in the field of veterinary medicine was initially documented by Clark and Hall in the 1960s, as they evaluated the sedative effects of xylazine in horses and cattle. Additional alpha-2 agonists such as detomidine, medetomidine, and dexmedetomidine have been introduced and become essential resources for veterinarians in both small and large animal practices (Grimsrud et al. 2015 ). Medetomidine is the most powerful and specific alpha-2 adrenoreceptor agonist used in veterinary sedation and provides potent analgesia in horses. With medetomidine, adjustment of anesthesia depth is more accessible, and fewer additional drugs are needed to deepen anesthesia (Ringer et al. 2007 ). The use of non-steroidal inflammatory drugs (NSAIDs) is extremely common due to their beneficial anti-inflammatory, analgesia, and antipyretic effects (Goodrich et al. 1998 ). The therapeutic index of meloxicam is higher than that of other NSAIDs, including piroxicam, diclofenac, and indomethacin (Ulrich Busch et al. 1998 ). As far as the author is aware, concomitant use of medetomidine and meloxicam on horses has not been conducted until this date. The importance of conducting this research lies in the fact that, unlike opioids, medetomidine and meloxicam did not induce bradycardia, ataxia, and respiratory depression. This research can be conducted using dexmedetomidine in higher doses and the results can be compared to the current article. 2. Materials and Methods 2.1. Materials Dorbene vet 1mg/ml medetomidine hydrochloride (Cat No: 5160, United Kingdom); meloxicam (Cat No: 92-197-S, L.99BI0005); Phosphate-Buffered Saline (PBS) (Gibco, Germany) was purchased. 2.2. Experimental Animals Study Design After aseptic preparation of the jugular vein site of each horse, an 18th gauge polyvinyl chloride catheter was placed in the jugular vein for drug administration. Intravenous (IV) injections of medetomidine and meloxicam were performed for one week to evaluate the clinical, analgesic, and sedative effects. Group Ӏ: Healthy control. Group II: 3.5 µg/kg of medetomidine was diluted with 8 ml of normal saline and was injected with 0.6 mg/kg of meloxicam (V Gunes, M Cinar, AC Onmaz, G Atalan, U Yavuz, n.d.; Yamashita et al. 2000 ). Group III: 5 µg/kg of medetomidine was diluted with 8 ml of normal saline and was injected with 0.6 mg/kg of meloxicam. Group IV: 7 µg/kg of medetomidine was diluted with 8 ml of normal saline and was injected with 0.6 mg/kg of meloxicam. 2.3. Electrocardiography Electrocardiography was performed at 25 mm/s and adjusted to 1 mv per 10 mm using an electrocardiograph machine (BTL cardio point-Holter h600-BTL, United Kingdom). To take the ECG, after applying alcohol to each site of electrodes, the first electrode (L) was placed at the apex of the heart behind the elbow joint (in the space between the fifth and sixth ribs), the second electrode was placed at the top of the heart and the lower third of the neck (R), and the third electrode was placed on the left leg (F) with crocodile clips. 2.4. Evaluation of muscle relaxation, and vital signs To evaluate the effects of analgesia and muscle relaxation, head and neck muscle relaxation, head lowering, and motor ataxia were observed and recorded up to two hours after injections in each group. Vital signs such as body temperature, heart rate, and respiration rate were evaluated in each group at intervals of 15 minutes up to 2 hours post injections. 2.5. Statistical Analysis Data were reported as mean ± SD, and the graphs were plotted using Graph Pad Prism 5.04 software. Data were statistically analyzed using analysis of variances (Two-way ANOVA) followed by a post-Tukey test, and a p-value less than 0.05 was considered a significant difference. 3. Results The results of this study, after dividing the horses into 4 groups with different treatments. 3.1 Electrocardiography The number of heartbeats in the horses of all four groups was examined through electrocardiography. Electrocardiography was examined in healthy control group, in group treated with 3.5 µg/kg of medetomidine + 0.6 mg/kg of meloxicam at 0 min and 30 min, 5 µg/kg of medetomidine + 0.6 mg/kg of meloxicam, and 7 µg/kg of medetomidine + 0.6 mg/kg of meloxicam. 3.2. Comparison of the Effect of Medetomidine-Meloxicam on Horse Heart Rate The effect of the injection of 3 different drug doses of medetomidine-meloxicam drug combination and the control group on the heart rate of the studied horses is shown in Fig. 1 . The heart rate of horses treated with groups I, II, III and control group on the first day showed a significant increase compared to the control ( p < 0.0001 ****). A decrease was observed on days 15, 60, and 120 in horses treated with groups I and II ( p < 0.0001 ****). Comparing the heart rate changes of horses in different treatment groups showed that group III had a statistically significant increase in heart rate after 1 and 120 minutes compared to group I and group II ( p < 0.0001 ****). In contrast, this group showed a significant decrease in 15, 30, and 60 minutes after injection compared to the first and second samples ( p < 0.0001 ****). 3.3. Comparison of the Effect of Medetomidine-Meloxicam on Horse Respiratory Rate The effect of the injection of 3 different drug doses of medetomidine-meloxicam and the control group on the respiratory rate of the studied horses is shown in Fig. 2 . The respiratory rate in group I significantly increased compared to the control in the first and 120 days ( p < 0.0001 ****). A sharp increase in the respiratory rate in group 3 was observed after 15, 30, and 60 days compared to the control ( p < 0.0001 ****). On days 15, 30, and 60, a decrease in respirations was observed compared to the control in group II ( p < 0.0001 ****). Comparing the changes in the respiratory rate of horses in different treatment groups showed that group III had a statistically significant decrease compared to group I and group II after 1 and 120 minutes ( p < 0.0001 ****). In contrast, this group showed a significant increase in 15, 30, and 60 minutes after injection compared to the first and second groups ( p < 0.0001 ****). 3.4. Comparison of the Effect of Medetomidine-Meloxicam on Horse Body Temperature The effect of the injection of 3 different drug doses of medetomidine-meloxicam drug combination and the control group on the heart rate of the studied horses is shown in Fig. 3 . An increase in body temperature was observed in horses treated with groups I, II, and III ( p < 0.0001 ****). A decrease in temperature was observed on the 30th, 60th, and 120th minutes of group I ( p < 0.0001 ****), while an increase in body temperature was observed in groups II and III ( p < 0.0001 ****). Comparing the temperature changes of horses in different treatment groups showed that the body temperature in group III increased after 1, 30, and 120 minutes compared to group I ( p < 0.0001 ****). Also, compared with group II, it showed a decrease in body temperature at 15, 30, 60, and 120 minutes after injection ( p < 0.0001 ****). 3. Discussion Medetomdine is a potent, selective, and specific alpha-2 adrenoceptor agonist (Yamashita et al. 2000 ). Meloxicam is one of the first groups of drugs in the family of non-steroidal anti-inflammatory medications that selectively inhibit cyclooxygenase one and cyclooxygenase two enzymes (Charlier and Michaux 2003). The results of this study showed that the use of medetomidine-meloxicam led to the induction of appropriate relaxation and reduction of side effects caused by opioid drugs, such as respiratory depression and bradycardia in horses. Therefore, these drugs can be a more suitable alternative than opioid medications. The injection of 0.6 mg/kg body weight meloxicam for five days had significant sedative, analgesic, and anti-inflammatory effects in the postoperative period in horses suffering from fractured bones and lameness (Walliser et al. 2015 ). In another study on six horses, the cardiovascular and sedative effects of dexmedetomidine at doses of 3.5 and 5 µk/kg were observed as head and neck drop (HHAG), ataxia up to 15 minutes, and a decrease in response to external stimuli up to 30 minutes after injection, decreased heart rate and cardiac output and increased atrioventricular block (Isiordia-Espinoza et al. 2012 ). All groups' average arterial blood pressure dropped, although blood pressure increased initially in the group receiving medetomidine at a dose of 0.02 µk/kg. In this study, comparing the heart rate changes of horses in different treatment groups showed that group III had a statistically significant increase in heart rate after 1 and 120 minutes compared to group I and group II. In contrast, this group showed a significant decrease in 15, 30, and 60 minutes after injection compared to the first and second samples. The analgesic effect of tramadol and meloxicam combination in different doses (tramadol + meloxicam in the ratio of 1: 1, 1: 3, and 3: 1) and the role of nitric oxide, opioid, and serotonergic pathways due to this analgesic effect in mice was assessed. A combination of tramadol and meloxicam can be promising in pain control by inducing a synergistic interaction involving opioid and serotonin receptors (Abass et al. 2014 ). The results of Roşu et al. studies showed that the heart rate decreased significantly after intravenous injection of medetomidine, which is consistent with our results in this study (2021). The results of the study of Rosu et al. in connection with the administration of 30 mg of medetomidine in wild horses and the evaluation of their body muscle relaxation are in line with our current study. In both studies, an increase in muscle relaxation was observed in the body of horses (Santangelo et al. 2016 ). According to the Bettschart-Wolfensberger et al. study results, head drop was observed in horses after intravenous injection of medetomidine (5 µg/kg). The current study observed head drop after injecting 7 µg/kg of intravenous medetomidine (1999). According to another study results that aimed to evaluate the pharmacokinetic effects of dexmedetomidine, seven horses were studied with a plasma half-life of dexmedetomidine at a concentration of 8µk/kg /h intravenously 20.9 minutes, and the drug clearance was reported to be 0.3 L/min /kg. The results of this study are consistent with the present study in terms of the soothing effect of a dose of 7 µk/kg of medetomidine (Diao et al. 2017 ). After the injection of dexmedetomidine with midazolam and dexmedetomidine-midazolam-butorphanol on silver fox, cardiovascular effects and behavioral changes were investigated. Muscle relaxation and pain relief were suitable for clinical examination, and some simple surgical procedures were provided. This study is consistent with the present study and by Kaartinen et al ( 2014; Taylor, Browning, and Harris 1988 ). In line with the studies done, comparing the changes in the respiratory rate of horses in different treatment groups in our study showed that group III had a statistically significant decrease compared to group I and group II after 1 and 120 minutes. In contrast, this group showed a significant increase in 15, 30, and 60 minutes after injection compared to the first and second groups. Also, comparing the temperature changes of horses in different treatment groups showed that the body temperature in group III increased after 1, 30, and 120 minutes compared to group I. Also, compared with group II, it showed a decrease in body temperature at 15, 30, 60, and 120 minutes after injection. Also, Response to contact stimuli was examined, and the results showed that only sedation with 7 µg/kg medetomidine had no stimulation on horses. There were no significant changes in the position of the limbs, anal reflex, perineal reflex, ataxia, abdominal auscultation, and abnormal sounds. To conclude, the results of this study indicate that meloxicam at a dose of 0.6 mg/kg and medetomidine at a quantity of 7 µg/kg (0.007 µg/kg) provide suitable sedation in horses. Concomitant use of medetomidine with meloxicam reduces the side effects of other drugs by reducing the use of these drugs. Declarations Acknowledgments I appreciate everyone I have had the opportunity to collaborate with on this project. The members of my Dissertation Committee have offered valuable personal and professional advice, imparting significant lessons about scientific research and life in general. Experimental Animals and Ethical Aspects Fifteen thoroughbred breed male horses (2-8 years, 250-350 kg) used in this study (Yamashita et al. 2000) were purchased from the horse breeding animal sciences department, Islamic Azad University, Science and Research Branch, Tehran, Iran. All animals underwent complete physical examination, and healthy horses were randomly divided into three categories (n = 5 per group). The animals ate nothing by mouth (NPO) for 12 hours, but the water was available ad libitum. Animals were placed in the examination box for 20 minutes before the start of the experiment. All horses were treated according to guidelines for the care and use of laboratory animals (NIH Publications No. 8023, revised 1978) and kept under ethical considerations of the Institutional Animal Care and Use Committee (Ethical code: IR.IAU.SRB.REC.1397.454). Conflict of interests The authors declare that they have no conflicting of interests. Ethics approval and consent to participate There are no “human subjects” in this study Consent for publication Not applicable Availability of data and materials All data analyzed during this study are included in this published article. Funding This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. Authors' contributions A.J. developed the idea and designed the experiments. SH.B. conducted the experiments. SH.B., S.O., and A.A. analyzed the data. SH.B. wrote the manuscript. All authors confirmed the final manuscript before submission. References Abass M, Mosbah E, Rizk A, Karrouf G, and Adel Zaghloul (2014) Synergistic Efficacy of Tramadol and Meloxicam on Alleviation of Pain and Selected Immunological Variables after Sciatic Nerve Ligation in Rats. Int J Veterinary Sci Med 2(1):14–20. https://doi.org/10.1016/j.ijvsm.2013.12.004 Bettschart-Wolfensberger R, Clarke KW, Vainio O, Aliabadi F, Demuth D (1999) Pharmacokinetics of Medetomidine in Ponies and Elaboration of a Medetomidine Infusion Regime Which Provides a Constant Level of Sedation. Res Vet Sci 67(1):41–46. https://doi.org/10.1053/rvsc.1998.0274 Charlier C, and Catherine Michaux (2003) Dual Inhibition of Cyclooxygenase-2 (COX-2) and 5-Lipoxygenase (5-LOX) as a New Strategy to Provide Safer Non-Steroidal Anti-Inflammatory Drugs. Eur J Med Chem 38(7–8):645–659. https://doi.org/10.1016/S0223-5234(03)00115-6 Clark J, Owens, and Terrence P. Clark (1999) Analgesia. Veterinary Clin North America: Equine Pract 15(3):705–723. https://doi.org/10.1016/S0749-0739(17)30140-2 Diao H-X, Zhang S, Hu X-Y, Guan W, Luan L, Liu H-Y, Hong-Gang F (2017) Behavioral and Cardiopulmonary Effects of Dexmedetomidine–Midazolam and Dexmedetomidine–Midazolam–Butorphanol in the Silver Fox (Vulpes Vulpes). Veterinary Anaesth Analg 44(1):114–120. https://doi.org/10.1111/vaa.12406 Gleerup KB, Lindegaard C (2016) Recognition and Quantification of Pain in Horses: A Tutorial Review. Equine Veterinary Education 28(1):47–57. https://doi.org/10.1111/eve.12383 Goodrich F, Robertson, Warnick (1998) A Toxicity Study of Eltenac, a Nonsteroidal Anti-inflammatory Drug, in Horses. J Vet Pharmacol Ther 21(1):24–33. https://doi.org/10.1046/j.1365-2885.1998.00813.x Grimsrud KN, Ait-Oudhia S, Durbin‐Johnson BP, Rocke DM, Mama KR, Rezende ML, Stanley SD, Jusko WJ (2015) Pharmacokinetic and Pharmacodynamic Analysis Comparing Diverse Effects of Detomidine, Medetomidine, and Dexmedetomidine in the Horse: A Population Analysis. J Vet Pharmacol Ther 38(1):24–34. https://doi.org/10.1111/jvp.12139 Isiordia-Espinoza MA, Terán‐Rosales F, Reyes‐García G, Granados‐Soto V (2012) Synergism between Tramadol and Meloxicam in the Formalin Test Involves Both Opioidergic and Serotonergic Pathways. Drug Dev Res 73(1):43–50. https://doi.org/10.1002/ddr.20461 Kaartinen J, Jérôme RE, Del Castillo K, Salla E, Troncy MR, Raekallio, and Outi M. Vainio (2014) Haemodynamic Interactions of Medetomidine and the Peripheral Alpha-2 Antagonist MK-467 during Step Infusions in Isoflurane-Anaesthetised Dogs. Vet J 202(2):353–360. https://doi.org/10.1016/j.tvjl.2014.08.019 Michou J, and Elizabeth Leece (2012) Sedation and Analgesia in the Standing Horse 1. Drugs Used for Sedation and Systemic Analgesia. In Practice 34(9):524–531. https://doi.org/10.1136/inp.e6423 Ringer SK, Karin Kalchofner J, Boller A, Fürst, and Regula Bettschart-Wolfensberger (2007) A Clinical Comparison of Two Anaesthetic Protocols Using Lidocaine or Medetomidine in Horses. Veterinary Anaesth Analg 34(4):257–268. https://doi.org/10.1111/j.1467-2995.2006.00321.x Roşu O, Melega I, Evans AL, Arnemo JM, and Susanne Küker (2021) Evaluation of Medetomidine-Ketamine for Immobilization of Feral Horses in Romania. Front Veterinary Sci 8(June):655217. https://doi.org/10.3389/fvets.2021.655217 Sanchez LC, Robertson SA (2014) Pain Control in Horses: What Do We Really Know? Equine Vet J 46(4):517–523. https://doi.org/10.1111/evj.12265 Santangelo B, Micieli F, Marino F, Reynaud F, Cassandro P, Carfora A, Petrella R, Borriello R, Cataldi M, Vesce G (2016) Plasma Concentrations and Sedative Effects of a Dexmedetomidine, Midazolam, and Butorphanol Combination after Transnasal Administration in Healthy Rabbits. J Vet Pharmacol Ther 39(4):408–411. https://doi.org/10.1111/jvp.12282 Taylor P, Browning A, Harris C (1988) Detomidine-Butorphanol Sedation in Equine Clinical Practice. Vet Rec 123(15):388–390. https://doi.org/10.1136/vr.123.15.388 Busch U, Schmid J, Heinzel Günther, Schmaus H, Baierl Jürgen, Huber C, Roth W (1998) Pharmacokinetics of Meloxicam in Animals and The Relevance to Humans. Drug Metab Dispos 26(6):576 Gunes V, Cinar M, Onmaz AC, Atalan G, Yavuz U n.d. Effects of Meloxicam on Oxidative Deterioration Due to Exercise in Horses Walliser U, Fenner A, Mohren N, Keefe T, deVries F, Rundfeldt C (2015) Evaluation of the Efficacy of Meloxicam for Post-Operative Management of Pain and Inflammation in Horses after Orthopaedic Surgery in a Placebo Controlled Clinical Field Trial. BMC Vet Res 11(1):113. https://doi.org/10.1186/s12917-015-0427-4 Yamashita K, Tsubakishita S, Futaoka S, Ueda I, Hamaguchi H, Seno T, Katoh S, Izumisawa Y, Kotani T, Muir WW (2000) Cardiovascular Effects of Medetomidine, Detomidine and Xylazine in Horses. J Vet Med Sci 62(10):1025–1032. https://doi.org/10.1292/jvms.62.1025 Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-3878144","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Short Report","associatedPublications":[],"authors":[{"id":268600843,"identity":"05f4143a-1567-47c2-8edb-b30e8e0ea041","order_by":0,"name":"Shahrzad Babolmorad","email":"","orcid":"","institution":"Islamic Azad University","correspondingAuthor":false,"prefix":"","firstName":"Shahrzad","middleName":"","lastName":"Babolmorad","suffix":""},{"id":268600844,"identity":"cd4e0430-5102-4d24-91d5-69433d091782","order_by":1,"name":"Saeed Ozmaie","email":"","orcid":"","institution":"Islamic Azad University","correspondingAuthor":false,"prefix":"","firstName":"Saeed","middleName":"","lastName":"Ozmaie","suffix":""},{"id":268600845,"identity":"4443e22a-230e-4cfc-9bfb-893a36e33d6f","order_by":2,"name":"Alireza Jahandideh","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA+UlEQVRIiWNgGAWjYBACxgYeIMkmwdggwXwAyJOAihsQpYUtgTgtDAxgLSDFPAZAkgiHMbefPfi5oMxCtl+65/Pnyh0W8gYHmB9+YCi4h9thPXnJ0jPOSRjPnHN2m+TZMxKGGw6wGUswGBTj8UuOgTRvm0Tihhu52xgb2yQYNxxgMAP6JQG3lv43xr9BWvbfyHn8EajFfsMB9m/4tczIMYPYIpHDINkIYhzgIWDLjDdm1jxAv8y4kWYm2XhGInnmYZ5iiQQ8Wgz7c4xv85TVyfbPSAY6bEedbd/x9o0fPvzBo6UBQ4gZiHFrYGCQxyM3CkbBKBgFowACAAsAUxjy1CaQAAAAAElFTkSuQmCC","orcid":"","institution":"Islamic Azad University","correspondingAuthor":true,"prefix":"","firstName":"Alireza","middleName":"","lastName":"Jahandideh","suffix":""},{"id":268600846,"identity":"1b2f8649-d9ed-4e74-84bb-c4485a69f4b9","order_by":3,"name":"Ahmad Asghari","email":"","orcid":"","institution":"Islamic Azad University","correspondingAuthor":false,"prefix":"","firstName":"Ahmad","middleName":"","lastName":"Asghari","suffix":""}],"badges":[],"createdAt":"2024-01-19 08:32:58","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-3878144/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-3878144/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":50092149,"identity":"871a09dc-e906-4591-93f4-99e5644dd3df","added_by":"auto","created_at":"2024-01-24 12:06:59","extension":"jpeg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":74462,"visible":true,"origin":"","legend":"\u003cp\u003eThe effect of three different doses of medetomidine-meloxicam drug combination; control group, 3.5 µg/kg of medetomidine + 0.6 mg/kg of meloxicam (group I), 5 µg/kg of medetomidine + 0.6 mg/kg of meloxicam (group II), and 7 µg/kg of medetomidine + 0.6 mg/kg of meloxicam (group III) on the heart rate of the studied horses (after 1, 15, 30, 60, and 120 minutes). Data are shown as mean ± SD, n=5, (p\u0026lt;0.001 ***; p\u0026lt;0.0001 #).\u003c/p\u003e","description":"","filename":"floatimage1.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3878144/v1/b3e4a6d0eaf6e95a93598259.jpeg"},{"id":50092151,"identity":"c5cc0d49-adb9-410a-acd7-7bb37821f515","added_by":"auto","created_at":"2024-01-24 12:06:59","extension":"jpeg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":66818,"visible":true,"origin":"","legend":"\u003cp\u003eThe effect of three different doses of medetomidine-meloxicam drug combination; control group, 3.5 µg/kg of medetomidine + 0.6 mg/kg of meloxicam (group I), 5 µg/kg of medetomidine + 0.6 mg/kg of meloxicam (group II), 7 µg/kg of medetomidine + 0.6 mg/kg of meloxicam (group III) on the respiratory rate of the studied horses (after 1, 15, 30, 60, and 120 minutes). Data are shown as mean ± SD, n=5, (\u003cem\u003ep\u003c/em\u003e\u0026lt;0.0001 #).\u003c/p\u003e","description":"","filename":"floatimage2.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3878144/v1/de0b6c78dbf67c4be59220f9.jpeg"},{"id":50092150,"identity":"a79aefb7-d13d-4bff-a6d6-843342b0a0f1","added_by":"auto","created_at":"2024-01-24 12:06:59","extension":"jpeg","order_by":3,"title":"Figure 3","display":"","copyAsset":false,"role":"figure","size":69827,"visible":true,"origin":"","legend":"\u003cp\u003eThe effect of three different doses of medetomidine-meloxicam drug combination; control group, 3.5 µg/kg of medetomidine + 0.6 mg/kg of meloxicam (group I), 5 µg/kg of medetomidine + 0.6 mg/kg of meloxicam (group II), and 7 µg/kg of medetomidine + 0.6 mg/kg of meloxicam (group III) on the body-temperature of the studied horses (after 1, 15, 30, 60, and 120 minutes). Data are shown as mean ± SD, n=5, (\u003cem\u003ep\u0026lt;\u003c/em\u003e0.0001 #).\u003c/p\u003e","description":"","filename":"floatimage3.jpeg","url":"https://assets-eu.researchsquare.com/files/rs-3878144/v1/27cffc0b12628c224b235dcd.jpeg"},{"id":52356789,"identity":"845c28ce-ac20-41fe-be3b-23a05d932a21","added_by":"auto","created_at":"2024-03-09 23:08:31","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":453971,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-3878144/v1/350665eb-4d03-413f-b457-8fc3946dfe5b.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"Assessing the Synergistic Effects of Medetomidine and Meloxicam in Adult Horses: A Comprehensive Study on Clinical, Analgesic, and Sedative Outcome","fulltext":[{"header":"1. Introduction","content":"\u003cp\u003eAn \u0026ldquo;irritating sensory and emotional experience related to authentic or possible damages to the tissues\u0026rdquo; is described as pain (Clark and Clark \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e1999\u003c/span\u003e). Pain is a helpful mechanism that protects horses. Inducing withdrawal or struggling to escape is a consequence of acute pain, although subacute pain promotes the safeguarding of the injured region to facilitate the recovery process (Gleerup and Lindegaard \u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). Horses have obvious pain behaviors such as rolling, kicking the belly, looking sideways, limping, or blepharospasm, which is essential to recognize and diagnose these reactions. Pain in these animals can be identified by alterations in facial expressions, head positioning, stall location, and reactions to touch or human engagement (Sanchez and Robertson \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e2014\u003c/span\u003e).\u003c/p\u003e \u003cp\u003ePharmaceutical substances used for pain control in horses fall into categories including opioids, nonsteroidal anti-inflammatory agents (NSAIDs), and alpha-2 agonists (Clark and Clark \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e1999\u003c/span\u003e). The objective of combining sedation and analgesia is to render the horse unreactive to painful procedures and external stimuli, allowing it to remain standing with minimal loss of coordination while avoiding excessive or insufficient sedation. Sedative and analgesic medications are typically delivered via intravenous administration, as this offers the highest bioavailability and the quickest onset of action. (Michou and Leece 2012).\u003c/p\u003e \u003cp\u003eThe introduction of alpha2-adrenoceptor agonists in the field of veterinary medicine was initially documented by Clark and Hall in the 1960s, as they evaluated the sedative effects of xylazine in horses and cattle. Additional alpha-2 agonists such as detomidine, medetomidine, and dexmedetomidine have been introduced and become essential resources for veterinarians in both small and large animal practices (Grimsrud et al. \u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e2015\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eMedetomidine is the most powerful and specific alpha-2 adrenoreceptor agonist used in veterinary sedation and provides potent analgesia in horses. With medetomidine, adjustment of anesthesia depth is more accessible, and fewer additional drugs are needed to deepen anesthesia (Ringer et al. \u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e2007\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eThe use of non-steroidal inflammatory drugs (NSAIDs) is extremely common due to their beneficial anti-inflammatory, analgesia, and antipyretic effects (Goodrich et al. \u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e1998\u003c/span\u003e). The therapeutic index of meloxicam is higher than that of other NSAIDs, including piroxicam, diclofenac, and indomethacin (Ulrich Busch et al. \u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e1998\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAs far as the author is aware, concomitant use of medetomidine and meloxicam on horses has not been conducted until this date. The importance of conducting this research lies in the fact that, unlike opioids, medetomidine and meloxicam did not induce bradycardia, ataxia, and respiratory depression. This research can be conducted using dexmedetomidine in higher doses and the results can be compared to the current article.\u003c/p\u003e"},{"header":"2. Materials and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003e2.1. Materials\u003c/h2\u003e \u003cp\u003eDorbene vet 1mg/ml medetomidine hydrochloride (Cat No: 5160, United Kingdom); meloxicam (Cat No: 92-197-S, L.99BI0005); Phosphate-Buffered Saline (PBS) (Gibco, Germany) was purchased.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003e2.2. Experimental Animals Study Design\u003c/h2\u003e \u003cp\u003eAfter aseptic preparation of the jugular vein site of each horse, an 18th gauge polyvinyl chloride catheter was placed in the jugular vein for drug administration. Intravenous (IV) injections of medetomidine and meloxicam were performed for one week to evaluate the clinical, analgesic, and sedative effects.\u003c/p\u003e \u003cp\u003eGroup Ӏ: Healthy control.\u003c/p\u003e \u003cp\u003eGroup II: 3.5 \u0026micro;g/kg of medetomidine was diluted with 8 ml of normal saline and was injected with 0.6 mg/kg of meloxicam (V Gunes, M Cinar, AC Onmaz, G Atalan, U Yavuz, n.d.; Yamashita et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2000\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eGroup III: 5 \u0026micro;g/kg of medetomidine was diluted with 8 ml of normal saline and was injected with 0.6 mg/kg of meloxicam.\u003c/p\u003e \u003cp\u003eGroup IV: 7 \u0026micro;g/kg of medetomidine was diluted with 8 ml of normal saline and was injected with 0.6 mg/kg of meloxicam.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec5\" class=\"Section2\"\u003e \u003ch2\u003e2.3. Electrocardiography\u003c/h2\u003e \u003cp\u003eElectrocardiography was performed at 25 mm/s and adjusted to 1 mv per 10 mm using an electrocardiograph machine (BTL cardio point-Holter h600-BTL, United Kingdom). To take the ECG, after applying alcohol to each site of electrodes, the first electrode (L) was placed at the apex of the heart behind the elbow joint (in the space between the fifth and sixth ribs), the second electrode was placed at the top of the heart and the lower third of the neck (R), and the third electrode was placed on the left leg (F) with crocodile clips.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec6\" class=\"Section2\"\u003e \u003ch2\u003e2.4. Evaluation of muscle relaxation, and vital signs\u003c/h2\u003e \u003cp\u003eTo evaluate the effects of analgesia and muscle relaxation, head and neck muscle relaxation, head lowering, and motor ataxia were observed and recorded up to two hours after injections in each group. Vital signs such as body temperature, heart rate, and respiration rate were evaluated in each group at intervals of 15 minutes up to 2 hours post injections.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec7\" class=\"Section2\"\u003e \u003ch2\u003e2.5. Statistical Analysis\u003c/h2\u003e \u003cp\u003eData were reported as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD, and the graphs were plotted using Graph Pad Prism 5.04 software. Data were statistically analyzed using analysis of variances (Two-way ANOVA) followed by a post-Tukey test, and a p-value less than 0.05 was considered a significant difference.\u003c/p\u003e \u003c/div\u003e"},{"header":"3. Results","content":"\u003cp\u003eThe results of this study, after dividing the horses into 4 groups with different treatments.\u003c/p\u003e \u003cdiv id=\"Sec9\" class=\"Section2\"\u003e \u003ch2\u003e3.1 Electrocardiography\u003c/h2\u003e \u003cp\u003eThe number of heartbeats in the horses of all four groups was examined through electrocardiography. Electrocardiography was examined in healthy control group, in group treated with 3.5 \u0026micro;g/kg of medetomidine\u0026thinsp;+\u0026thinsp;0.6 mg/kg of meloxicam at 0 min and 30 min, 5 \u0026micro;g/kg of medetomidine\u0026thinsp;+\u0026thinsp;0.6 mg/kg of meloxicam, and 7 \u0026micro;g/kg of medetomidine\u0026thinsp;+\u0026thinsp;0.6 mg/kg of meloxicam.\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec10\" class=\"Section2\"\u003e \u003ch2\u003e3.2. Comparison of the Effect of Medetomidine-Meloxicam on Horse Heart Rate\u003c/h2\u003e \u003cp\u003eThe effect of the injection of 3 different drug doses of medetomidine-meloxicam drug combination and the control group on the heart rate of the studied horses is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e. The heart rate of horses treated with groups I, II, III and control group on the first day showed a significant increase compared to the control (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 ****). A decrease was observed on days 15, 60, and 120 in horses treated with groups I and II (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 ****). Comparing the heart rate changes of horses in different treatment groups showed that group III had a statistically significant increase in heart rate after 1 and 120 minutes compared to group I and group II (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 ****). In contrast, this group showed a significant decrease in 15, 30, and 60 minutes after injection compared to the first and second samples (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 ****).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec11\" class=\"Section2\"\u003e \u003ch2\u003e3.3. Comparison of the Effect of Medetomidine-Meloxicam on Horse Respiratory Rate\u003c/h2\u003e \u003cp\u003eThe effect of the injection of 3 different drug doses of medetomidine-meloxicam and the control group on the respiratory rate of the studied horses is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e. The respiratory rate in group I significantly increased compared to the control in the first and 120 days (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 ****). A sharp increase in the respiratory rate in group 3 was observed after 15, 30, and 60 days compared to the control (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 ****). On days 15, 30, and 60, a decrease in respirations was observed compared to the control in group II (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 ****). Comparing the changes in the respiratory rate of horses in different treatment groups showed that group III had a statistically significant decrease compared to group I and group II after 1 and 120 minutes (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 ****). In contrast, this group showed a significant increase in 15, 30, and 60 minutes after injection compared to the first and second groups (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 ****).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec12\" class=\"Section2\"\u003e \u003ch2\u003e3.4. Comparison of the Effect of Medetomidine-Meloxicam on Horse Body Temperature\u003c/h2\u003e \u003cp\u003eThe effect of the injection of 3 different drug doses of medetomidine-meloxicam drug combination and the control group on the heart rate of the studied horses is shown in Fig.\u0026nbsp;\u003cspan refid=\"Fig3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. An increase in body temperature was observed in horses treated with groups I, II, and III (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 ****). A decrease in temperature was observed on the 30th, 60th, and 120th minutes of group I (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 ****), while an increase in body temperature was observed in groups II and III (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 ****). Comparing the temperature changes of horses in different treatment groups showed that the body temperature in group III increased after 1, 30, and 120 minutes compared to group I (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 ****). Also, compared with group II, it showed a decrease in body temperature at 15, 30, 60, and 120 minutes after injection (\u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001 ****).\u003c/p\u003e \u003cp\u003e \u003c/p\u003e \u003c/div\u003e"},{"header":"3. Discussion","content":"\u003cp\u003eMedetomdine is a potent, selective, and specific alpha-2 adrenoceptor agonist (Yamashita et al. \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e2000\u003c/span\u003e). Meloxicam is one of the first groups of drugs in the family of non-steroidal anti-inflammatory medications that selectively inhibit cyclooxygenase one and cyclooxygenase two enzymes (Charlier and Michaux 2003). The results of this study showed that the use of medetomidine-meloxicam led to the induction of appropriate relaxation and reduction of side effects caused by opioid drugs, such as respiratory depression and bradycardia in horses. Therefore, these drugs can be a more suitable alternative than opioid medications. The injection of 0.6 mg/kg body weight meloxicam for five days had significant sedative, analgesic, and anti-inflammatory effects in the postoperative period in horses suffering from fractured bones and lameness (Walliser et al. \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e2015\u003c/span\u003e). In another study on six horses, the cardiovascular and sedative effects of dexmedetomidine at doses of 3.5 and 5 \u0026micro;k/kg were observed as head and neck drop (HHAG), ataxia up to 15 minutes, and a decrease in response to external stimuli up to 30 minutes after injection, decreased heart rate and cardiac output and increased atrioventricular block (Isiordia-Espinoza et al. \u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e2012\u003c/span\u003e). All groups' average arterial blood pressure dropped, although blood pressure increased initially in the group receiving medetomidine at a dose of 0.02 \u0026micro;k/kg. In this study, comparing the heart rate changes of horses in different treatment groups showed that group III had a statistically significant increase in heart rate after 1 and 120 minutes compared to group I and group II. In contrast, this group showed a significant decrease in 15, 30, and 60 minutes after injection compared to the first and second samples.\u003c/p\u003e \u003cp\u003eThe analgesic effect of tramadol and meloxicam combination in different doses (tramadol\u0026thinsp;+\u0026thinsp;meloxicam in the ratio of 1: 1, 1: 3, and 3: 1) and the role of nitric oxide, opioid, and serotonergic pathways due to this analgesic effect in mice was assessed. A combination of tramadol and meloxicam can be promising in pain control by inducing a synergistic interaction involving opioid and serotonin receptors (Abass et al. \u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e2014\u003c/span\u003e). The results of Roşu et al. studies showed that the heart rate decreased significantly after intravenous injection of medetomidine, which is consistent with our results in this study (2021). The results of the study of Rosu et al. in connection with the administration of 30 mg of medetomidine in wild horses and the evaluation of their body muscle relaxation are in line with our current study. In both studies, an increase in muscle relaxation was observed in the body of horses (Santangelo et al. \u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e2016\u003c/span\u003e). According to the Bettschart-Wolfensberger et al. study results, head drop was observed in horses after intravenous injection of medetomidine (5 \u0026micro;g/kg). The current study observed head drop after injecting 7 \u0026micro;g/kg of intravenous medetomidine (1999).\u003c/p\u003e \u003cp\u003eAccording to another study results that aimed to evaluate the pharmacokinetic effects of dexmedetomidine, seven horses were studied with a plasma half-life of dexmedetomidine at a concentration of 8\u0026micro;k/kg /h intravenously 20.9 minutes, and the drug clearance was reported to be 0.3 L/min /kg. The results of this study are consistent with the present study in terms of the soothing effect of a dose of 7 \u0026micro;k/kg of medetomidine (Diao et al. \u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e2017\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eAfter the injection of dexmedetomidine with midazolam and dexmedetomidine-midazolam-butorphanol on silver fox, cardiovascular effects and behavioral changes were investigated. Muscle relaxation and pain relief were suitable for clinical examination, and some simple surgical procedures were provided. This study is consistent with the present study and by Kaartinen et al ( 2014; Taylor, Browning, and Harris \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e1988\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eIn line with the studies done, comparing the changes in the respiratory rate of horses in different treatment groups in our study showed that group III had a statistically significant decrease compared to group I and group II after 1 and 120 minutes. In contrast, this group showed a significant increase in 15, 30, and 60 minutes after injection compared to the first and second groups. Also, comparing the temperature changes of horses in different treatment groups showed that the body temperature in group III increased after 1, 30, and 120 minutes compared to group I. Also, compared with group II, it showed a decrease in body temperature at 15, 30, 60, and 120 minutes after injection.\u003c/p\u003e \u003cp\u003eAlso, Response to contact stimuli was examined, and the results showed that only sedation with 7 \u0026micro;g/kg medetomidine had no stimulation on horses. There were no significant changes in the position of the limbs, anal reflex, perineal reflex, ataxia, abdominal auscultation, and abnormal sounds. To conclude, the results of this study indicate that meloxicam at a dose of 0.6 mg/kg and medetomidine at a quantity of 7 \u0026micro;g/kg (0.007 \u0026micro;g/kg) provide suitable sedation in horses. Concomitant use of medetomidine with meloxicam reduces the side effects of other drugs by reducing the use of these drugs.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eAcknowledgments\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eI appreciate everyone I have had the opportunity to collaborate with on this project. The members of my Dissertation Committee have offered valuable personal and professional advice, imparting significant lessons about scientific research and life in general.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eExperimental Animals and Ethical Aspects\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFifteen thoroughbred breed male horses (2-8 years, 250-350 kg) used in this study\u0026nbsp;(Yamashita et al. 2000)\u0026nbsp;were purchased from the horse breeding animal sciences department, Islamic Azad University, Science and Research Branch, Tehran, Iran. All animals underwent complete physical examination, and healthy horses were randomly divided into three categories (n = 5 per group). The animals ate nothing by mouth (NPO) for 12 hours, but the water was available ad libitum. Animals were placed in the examination box for 20 minutes before the start of the experiment. All horses were treated according to guidelines for the care and use of laboratory animals (NIH Publications No. 8023, revised 1978) and kept under ethical considerations of the Institutional Animal Care and Use Committee (Ethical code: IR.IAU.SRB.REC.1397.454).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConflict of interests \u0026nbsp; \u0026nbsp; \u0026nbsp; \u0026nbsp;\u0026nbsp;\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no conflicting of interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;There are no \u0026ldquo;human subjects\u0026rdquo; in this study\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;Not applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u0026nbsp;All data analyzed during this study are included in this published article.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThis research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026apos; contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eA.J. developed the idea and designed the experiments. SH.B. conducted the experiments. SH.B., S.O., and A.A. analyzed the data. SH.B. wrote the manuscript. All authors confirmed the final manuscript before submission.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\u003cli\u003e\u003cspan\u003eAbass M, Mosbah E, Rizk A, Karrouf G, and Adel Zaghloul (2014) Synergistic Efficacy of Tramadol and Meloxicam on Alleviation of Pain and Selected Immunological Variables after Sciatic Nerve Ligation in Rats. Int J Veterinary Sci Med 2(1):14\u0026ndash;20. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.ijvsm.2013.12.004\u003c/span\u003e\u003cspan address=\"10.1016/j.ijvsm.2013.12.004\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBettschart-Wolfensberger R, Clarke KW, Vainio O, Aliabadi F, Demuth D (1999) Pharmacokinetics of Medetomidine in Ponies and Elaboration of a Medetomidine Infusion Regime Which Provides a Constant Level of Sedation. Res Vet Sci 67(1):41\u0026ndash;46. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1053/rvsc.1998.0274\u003c/span\u003e\u003cspan address=\"10.1053/rvsc.1998.0274\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eCharlier C, and Catherine Michaux (2003) Dual Inhibition of Cyclooxygenase-2 (COX-2) and 5-Lipoxygenase (5-LOX) as a New Strategy to Provide Safer Non-Steroidal Anti-Inflammatory Drugs. Eur J Med Chem 38(7\u0026ndash;8):645\u0026ndash;659. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S0223-5234(03)00115-6\u003c/span\u003e\u003cspan address=\"10.1016/S0223-5234(03)00115-6\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eClark J, Owens, and Terrence P. Clark (1999) Analgesia. Veterinary Clin North America: Equine Pract 15(3):705\u0026ndash;723. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/S0749-0739(17)30140-2\u003c/span\u003e\u003cspan address=\"10.1016/S0749-0739(17)30140-2\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eDiao H-X, Zhang S, Hu X-Y, Guan W, Luan L, Liu H-Y, Hong-Gang F (2017) Behavioral and Cardiopulmonary Effects of Dexmedetomidine\u0026ndash;Midazolam and Dexmedetomidine\u0026ndash;Midazolam\u0026ndash;Butorphanol in the Silver Fox (Vulpes Vulpes). Veterinary Anaesth Analg 44(1):114\u0026ndash;120. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/vaa.12406\u003c/span\u003e\u003cspan address=\"10.1111/vaa.12406\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGleerup KB, Lindegaard C (2016) Recognition and Quantification of Pain in Horses: A Tutorial Review. Equine Veterinary Education 28(1):47\u0026ndash;57. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/eve.12383\u003c/span\u003e\u003cspan address=\"10.1111/eve.12383\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGoodrich F, Robertson, Warnick (1998) A Toxicity Study of Eltenac, a Nonsteroidal Anti-inflammatory Drug, in Horses. J Vet Pharmacol Ther 21(1):24\u0026ndash;33. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1046/j.1365-2885.1998.00813.x\u003c/span\u003e\u003cspan address=\"10.1046/j.1365-2885.1998.00813.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGrimsrud KN, Ait-Oudhia S, Durbin‐Johnson BP, Rocke DM, Mama KR, Rezende ML, Stanley SD, Jusko WJ (2015) Pharmacokinetic and Pharmacodynamic Analysis Comparing Diverse Effects of Detomidine, Medetomidine, and Dexmedetomidine in the Horse: A Population Analysis. J Vet Pharmacol Ther 38(1):24\u0026ndash;34. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/jvp.12139\u003c/span\u003e\u003cspan address=\"10.1111/jvp.12139\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eIsiordia-Espinoza MA, Ter\u0026aacute;n‐Rosales F, Reyes‐Garc\u0026iacute;a G, Granados‐Soto V (2012) Synergism between Tramadol and Meloxicam in the Formalin Test Involves Both Opioidergic and Serotonergic Pathways. Drug Dev Res 73(1):43\u0026ndash;50. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1002/ddr.20461\u003c/span\u003e\u003cspan address=\"10.1002/ddr.20461\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eKaartinen J, J\u0026eacute;r\u0026ocirc;me RE, Del Castillo K, Salla E, Troncy MR, Raekallio, and Outi M. Vainio (2014) Haemodynamic Interactions of Medetomidine and the Peripheral Alpha-2 Antagonist MK-467 during Step Infusions in Isoflurane-Anaesthetised Dogs. Vet J 202(2):353\u0026ndash;360. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1016/j.tvjl.2014.08.019\u003c/span\u003e\u003cspan address=\"10.1016/j.tvjl.2014.08.019\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eMichou J, and Elizabeth Leece (2012) Sedation and Analgesia in the Standing Horse 1. Drugs Used for Sedation and Systemic Analgesia. In Practice 34(9):524\u0026ndash;531. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1136/inp.e6423\u003c/span\u003e\u003cspan address=\"10.1136/inp.e6423\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRinger SK, Karin Kalchofner J, Boller A, F\u0026uuml;rst, and Regula Bettschart-Wolfensberger (2007) A Clinical Comparison of Two Anaesthetic Protocols Using Lidocaine or Medetomidine in Horses. Veterinary Anaesth Analg 34(4):257\u0026ndash;268. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/j.1467-2995.2006.00321.x\u003c/span\u003e\u003cspan address=\"10.1111/j.1467-2995.2006.00321.x\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eRoşu O, Melega I, Evans AL, Arnemo JM, and Susanne K\u0026uuml;ker (2021) Evaluation of Medetomidine-Ketamine for Immobilization of Feral Horses in Romania. Front Veterinary Sci 8(June):655217. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.3389/fvets.2021.655217\u003c/span\u003e\u003cspan address=\"10.3389/fvets.2021.655217\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSanchez LC, Robertson SA (2014) Pain Control in Horses: What Do We Really Know? Equine Vet J 46(4):517\u0026ndash;523. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/evj.12265\u003c/span\u003e\u003cspan address=\"10.1111/evj.12265\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eSantangelo B, Micieli F, Marino F, Reynaud F, Cassandro P, Carfora A, Petrella R, Borriello R, Cataldi M, Vesce G (2016) Plasma Concentrations and Sedative Effects of a Dexmedetomidine, Midazolam, and Butorphanol Combination after Transnasal Administration in Healthy Rabbits. J Vet Pharmacol Ther 39(4):408\u0026ndash;411. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1111/jvp.12282\u003c/span\u003e\u003cspan address=\"10.1111/jvp.12282\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eTaylor P, Browning A, Harris C (1988) Detomidine-Butorphanol Sedation in Equine Clinical Practice. Vet Rec 123(15):388\u0026ndash;390. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1136/vr.123.15.388\u003c/span\u003e\u003cspan address=\"10.1136/vr.123.15.388\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eBusch U, Schmid J, Heinzel G\u0026uuml;nther, Schmaus H, Baierl J\u0026uuml;rgen, Huber C, Roth W (1998) Pharmacokinetics of Meloxicam in Animals and The Relevance to Humans. Drug Metab Dispos 26(6):576\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eGunes V, Cinar M, Onmaz AC, Atalan G, Yavuz U n.d. Effects of Meloxicam on Oxidative Deterioration Due to Exercise in Horses\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eWalliser U, Fenner A, Mohren N, Keefe T, deVries F, Rundfeldt C (2015) Evaluation of the Efficacy of Meloxicam for Post-Operative Management of Pain and Inflammation in Horses after Orthopaedic Surgery in a Placebo Controlled Clinical Field Trial. BMC Vet Res 11(1):113. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1186/s12917-015-0427-4\u003c/span\u003e\u003cspan address=\"10.1186/s12917-015-0427-4\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e \u003cli\u003e\u003cspan\u003eYamashita K, Tsubakishita S, Futaoka S, Ueda I, Hamaguchi H, Seno T, Katoh S, Izumisawa Y, Kotani T, Muir WW (2000) Cardiovascular Effects of Medetomidine, Detomidine and Xylazine in Horses. J Vet Med Sci 62(10):1025\u0026ndash;1032. \u003cspan class=\"ExternalRef\"\u003e\u003cspan class=\"RefSource\"\u003ehttps://doi.org/10.1292/jvms.62.1025\u003c/span\u003e\u003cspan address=\"10.1292/jvms.62.1025\" targettype=\"DOI\" class=\"RefTarget\"\u003e\u003c/span\u003e\u003c/span\u003e\u003c/span\u003e\u003c/li\u003e\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Analgesia, Horses, Medetomidine, Meloxicam, Sedation","lastPublishedDoi":"10.21203/rs.3.rs-3878144/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-3878144/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eThis study investigated medetomidine's clinical, analgesic, and sedative effects with meloxicam in adult horses. 20 horses were divided into four groups; healthy control, received 3.5 \u0026micro;g/kg medetomidine and 0.6 mg/kg meloxicam intravenously, received 5 \u0026micro;g/kg and 0.6 mg/kg meloxicam, and received 7 \u0026micro;g/kg medetomidine and 0.6 mg/kg meloxicam. Heart rate, respiratory rate, temperature, electrocardiographs, and sedation scores were monitored before and after the injection. In the fourth group, the heart rate had a statistically significant decrease after (15, 30, and 60 minutes), and the respiratory rate decreased after (1 and 120 minutes) compared to other groups. The body temperature compared to the first group (1, 30, and 120 minutes) and the second group (15, 30, 60, and 120 minutes) after injection showed a decrease. Response to contact stimuli was examined, and only sedation with 7 \u0026micro;g/kg medetomidine had no stimulation. There were no significant changes in the position of the limbs, anal reflex, perineal reflex, ataxia, abdominal auscultation, and abnormal sounds. Meloxicam and medetomidine induced appropriate relaxation and reduced side effects (e.g., respiratory depression and bradycardia) in horses.\u003c/p\u003e","manuscriptTitle":"Assessing the Synergistic Effects of Medetomidine and Meloxicam in Adult Horses: A Comprehensive Study on Clinical, Analgesic, and Sedative Outcome","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-01-24 12:06:55","doi":"10.21203/rs.3.rs-3878144/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"fba6e325-a18f-4483-a96b-8693df61c7af","owner":[],"postedDate":"January 24th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-03-09T23:00:14+00:00","versionOfRecord":[],"versionCreatedAt":"2024-01-24 12:06:55","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-3878144","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-3878144","identity":"rs-3878144","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}