Methadone is an opioid analgesic used in veterinary medicine for pain management in horses. It acts on the central nervous system to alleviate moderate to severe pain by binding to opioid receptors. Methadone is sometimes employed in equine practice for its analgesic properties, particularly in cases of colic or after surgical procedures. The pharmacokinetics and pharmacodynamics of methadone in horses are subjects of study to understand its efficacy, dosage, and potential side effects. Research in this area explores the drug's metabolism, duration of action, and impact on equine physiology. This page gathers peer-reviewed research studies and scholarly articles focusing on the application, effects, and safety of methadone in equine medicine.
Haralambus R, Juri M, Mokry A, Jenner F.Effective management of postoperative pain is essential to ensure patient welfare, reduce morbidity and optimize recovery. Opioids are effective in managing moderate to severe pain in horses but concerns over their adverse effects on gastrointestinal (GI) motility and associated increased colic risk limit their widespread use. Studies investigating the impact of systemic opioids on both GI motility and colic incidence in horses have yielded inconclusive outcomes. Therefore, this retrospective study aims to assess the influence of systemic administration of butorphanol, morphine, and methadone ...
Parra Martínez C, Rico Pérez B, Kaartinen J.To evaluate the agreement between noninvasive arterial blood pressure (NIBP) measured from the tongue and thoracic limb with invasive blood pressure (IBP), and to compare NIBP measured from the tongue and thoracic limb in anaesthetized horses. Methods: Prospective clinical study. Methods: A group of eight client-owned healthy horses anaesthetized for scheduled procedures, American Society of Anesthesiologists classification I-II, weighing (mean ± standard deviation) 498 ± 91 kg and aged 7.8 ± 6.75 years. Methods: Animals were premedicated with intravenous (IV) romifidine (0.04-0.08 mg kg-1)...
Nannarone S, Giannettoni G, Laurenza C, Giontella A, Moretti G.While butorphanol is the most commonly used opioid in horses, methadone is not licensed in most countries. Our aim was to compare the effects of both drugs, combined with romifidine, regarding the quality of sedation and induction in horses undergoing elective surgery. Results indicate the suitability of both methadone and butorphanol in this patient population. Animals were scored 10 min after intravenous injection of sedatives. Despite lower overall sedation (OS) score in horses receiving methadone (p = 0.002), the quality and time of induction and intubation remained unchanged. None of the ...
de Oliveira AR, Gozalo-Marcilla M, Ringer SK, Schauvliege S, Fonseca MW, Esteves Trindade PH, Prospero Puoli Filho JN, Luna SPL.Although facial characteristics are used to estimate horse sedation, there are no studies measuring their reliability and validity. This randomised controlled, prospective, horizontal study aimed to validate a facial sedation scale for horses (FaceSed). Seven horses received detomidine infusion i.v. in low or high doses/rates alone (DL 2.5 μg/kg+6.25 μg/kg/h; DH 5 μg/kg+12.5 μg/kg/h) or combined with methadone (DLM and DHM, 0.2 mg/kg+0.05 mg/kg/h) for 120 min, or acepromazine boli i.v. in low (ACPL 0.02 mg/kg) or high doses (ACPH 0.09 mg/kg). Horses' faces were photographed at i) baseline,...
Sandbaumhüter FA, Gittel C, Larenza-Menzies MP, Theurillat R, Thormann W, Braun C.The enantioselectivity of the pharmacokinetics of methadone was investigated in anesthetized Shetland ponies after a single intravenous (0.5 mg/kg methadone hydrochloride; n = 6) or constant rate infusion (0.25 mg/kg bolus followed by 0.25 mg/kg/h methadone hydrochloride; n = 3) administration of racemic methadone. Plasma concentrations of l-methadone and d-methadone and their major metabolites, l- and d-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), respectively, were analyzed by CE with highly sulfated γ-cyclodextrin as chiral selector and electrokinetic analyte injection from...
de Oliveira AR, Gozalo-Marcilla M, Ringer SK, Schauvliege S, Fonseca MW, Trindade PHE, Puoli Filho JNP, Luna SPL.The lack of standardization of sedation scales in horses limits the reproducibility between different studies. This prospective, randomized, blinded, horizontal and controlled trial aimed to validate a scale for sedation in horses (EquiSed). Seven horses were treated with intravenous detomidine in low/high doses alone (DL 2.5 μg/kg + 6.25 μg/kg/h; DH 5 μg/kg +12.5 μg/kg/h) or associated with methadone (DLM and DHM, 0.2 mg/kg + 0.05 mg/kg/h) and with low (ACPL 0.02 mg/kg) or high (ACPH 0.09 mg/kg) doses of acepromazine alone. Horses were filmed at (i) baseline (ii) peak, (iii) intermediate,...
Carregaro AB, Ueda GI, Censoni JB, Bisetto SP, Alonso BB, Reginato GM.The aim of this study was to compare the effects of methadone combined with detomidine or acepromazine on the quality of sedation and its influence over dissociative anesthesia in healthy horses. In a crossover design, seven horses were administered with 0.1 mg/kg methadone and 0.02 mg/kg detomidine intravenously (group MD) or 0.1 mg/kg methadone and 0.05 mg/kg acepromazine intravenously (group MA). Subsequently, anesthesia was induced with a combination of 2.2 mg/kg ketamine and 0.1 mg/kg midazolam intravenously. Descriptive scales and footages were used to evaluate the quality of sedat...
Gozalo-Marcilla M, Moreira da Silva R, Pacca Loureiro Luna S, Rodrigues de Oliveira A, Werneck Fonseca M, Peporine Lopes N, Taylor PM, Pelligand L.The alpha(α) -agonist detomidine is used for equine sedation with opioids such as methadone. We retrieved the data from two randomized, crossover studies where detomidine and methadone were given intravenously alone or combined as boli (STUDY 1) (Gozalo-Marcilla et al., 2017, Veterinary Anaesthesia and Analgesia, 2017, 44, 1116) or as 2-hr constant rate infusions (STUDY 2) (Gozalo-Marcilla et al., 2019, Equine Veterinary Journal, 51, 530). Plasma drug concentrations were measured with a validated tandem Mass Spectrometry assay. We used nonlinear mixed effect modelling and took pharmacokinetic...
Theurillat R, Sandbaumhüter FA, Gittel C, Larenza Menzies MP, Braun C, Thormann W.An enantioselective assay for the determination of methadone and its main metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine in equine plasma based on capillary electrophoresis with highly sulfated γ-cyclodextrin as chiral selector and electrokinetic analyte injection is described. The assay is based on liquid/liquid extraction of the analytes at alkaline pH from 0.1 mL plasma followed by electrokinetic sample injection of the analytes from the extract across a buffer plug without chiral selector. Separation occurs cationically at normal polarity in a pH 3 phosphate buffer containin...
Schwarzbach SV, Melo CF, Xavier PLP, Roballo KC, Cordeiro YG, Ambrósio CE, Fukumasu H, Carregaro AB.Osteoarthritis (OA) is one of the main locomotor disorders in horses. Although nonsteroidal anti-inflammatory drugs are the first-line treatment for OA, opioids could also be used. In previous studies, opioids showed promising anti-inflammatory and analgesic effects. In this study, we aimed to investigate the effects of two opioids (morphine and methadone) against inflammation in lipopolysaccharide (LPS)-stimulated synoviocytes by analyzing microsomal prostaglandin E synthase-1 (mPGES-1) and prostaglandin-endoperoxide synthase 2 (PTGS2) expression. Synoviocytes were obtained from the joints at...
Gozalo-Marcilla M, Luna SP, Gasthuys F, Pollaris E, Vlaminck L, Martens A, Haspeslagh M, Schauvliege S.To determine the required rate of a detomidine infusion (loading dose 5 μg kg; initial rate 12.5 μg kg hour) added to a constant infusion of methadone (0.2 mg kg; 0.05 mg kg hour) for sedation in standing horses and ponies undergoing elective surgeries with appropriate local anaesthetic techniques. Methods: Prospective, clinical study. Methods: Adult, healthy, client-owned, non-food-producing horses or ponies sedated for elective standing surgeries longer than 45 minutes. Methods: At baseline (in the stables before administration of sedative agents), at 10 minutes after sedation and every 5 ...
Gozalo-Marcilla M, de Oliveira AR, Fonseca MW, Possebon FS, Pelligand L, Taylor PM, Luna SPL.Standing surgery avoids the risks of general anaesthesia in horses. Objective: To assess sedation, antinociception and gastrointestinal motility in standing horses after a detomidine loading dose and 2-h constant rate intravenous (i.v.) infusion, with or without methadone. Methods: Blinded, randomised, crossover with seven healthy adult cross-bred horses, three geldings and four females (404 ± 22 kg). Methods: Five i.v. treatments were administered to all horses with 1-week washout period: saline (SAL), detomidine low (2.5 μg/kg bwt + 6.25 μg/kg bwt/h) (DL) and high doses (5 μg/kg ...
Gozalo-Marcilla M, Luna SPL, Moreira da Silva R, Crosignani N, Lopes NP, Taylor PM, Pelligand L.Pharmacokinetic (PK)/pharmacodynamic (PD) modelling offers new insights to design protocols for sedation and analgesia in standing horses. Objective: To evaluate the parameters and interactions between detomidine and methadone when given alone or combined in standing horses. Methods: Randomised, placebo-controlled, blinded, crossover. Methods: Eight adult healthy horses were given six treatments intravenously: saline (SAL); detomidine (5 μg/kg bwt; DET); methadone (0.2 mg/kg bwt; MET) alone or combined with detomidine (2.5 [MLD], 5 [MMD] or 10 [MHD] μg/kg bwt). Venous blood samples were ob...
Sandbaumhüter FA, Vimercati S, Thormann W, Mevissen M.The anesthetic ketamine is often combined with analgesics and benzodiazepines in equine medicine. Therefore, drug-drug interactions are possible. Enzyme kinetics for ketamine N-demethylation were determined using equine CYP3A94, CYP3A95 and CYP3A97, and the effect of medetomidine, diazepam and methadone on the ketamine metabolism was studied in vitro. Ketamine was incubated with the CYPs or equine liver microsomes (ELM) alone or in presence of medetomidine, diazepam and/or methadone for different times. Norketamine levels were determined using enantioselective capillary electrophoresis (CE) wi...
Gozalo-Marcilla M, Luna SP, Crosignani N, Filho JNP, Possebon FS, Pelligand L, Taylor PM.To evaluate intravenous (IV) detomidine with methadone in horses to identify a combination which provides sedation and antinociception without adverse effects. Methods: Randomized, placebo-controlled, blinded, crossover. Methods: A group of eight adult healthy horses aged (mean ± standard deviation) 7 ± 2 years and 372 ± 27 kg. Methods: A total of six treatments were administered IV: saline (SAL); detomidine (5 μg kg; DET); methadone (0.2 mg kg; MET) alone or combined with detomidine [2.5 (MLD), 5 (MMD) or 10 (MHD) μg kg]. Thermal, mechanical and electrical nociceptive thresholds were mea...
Crosignani N, Luna SP, Dalla Costa T, Pimenta EL, Detoni CB, Guterres SS, Puoli Filho JN, Pantoja JC, Pigatto MC.We investigated the thermal, electrical and mechanical antinociceptive and physiological effects (heart rate, respiratory rate, arterial blood pressure, head height and abdominal auscultation score), and pharmacokinetics, of 0.5 mg/kg of the injectable formulation (ORAL) or nanoparticulated methadone (NANO) given orally, in six adult mares, using a crossover, blind and prospective design. Repeated-measure models were used to compare parametric data between and within treatments, followed by Tukey's test. Nonparametric data were analysed with Wilcoxon signed-rank, adjusted by Bonferroni tests....
Lopes C, Luna SP, Rosa AC, Quarterone C, Crosignani N, Taylor PM, Pantoja JC, Puoli JN.To investigate two protocols to provide antinociception in horses. Objective: To evaluate the antinociceptive effects of intravenous methadone combined with detomidine or acepromazine in adult horses. Methods: Randomised, blinded, crossover study. Methods: Mechanical, thermal and electrical stimuli were applied to the dorsal left and right metacarpus and coronary band of the left thoracic limb, respectively. A thermal stimulus was applied caudal to the withers. The horses were treated with saline (C), a combination of methadone (0.2 mg/kg bwt) and detomidine (10 μg/kg bwt) (MD) or methadone...
Carregaro AB, Freitas GC, Ribeiro MH, Xavier NV, Dória RG.Continuous-rate infusion (CRI) of drugs results in more stable plasma drug concentrations than administration of intermittent boluses, thus providing greater stability of physiological parameters. The aim of this study was to evaluate the physiologic and analgesic effects of the administration of morphine, butorphanol, tramadol or methadone by CRI in horses with induced synovitis of the radiocarpal joint. Results: Increased values of cardiorespiratory parameters and body temperature were observed in all groups after initiation of opioid administration, and these increases were sustained throug...
Gozalo-Marcilla M, Gasthuys F, Schauvliege S.To review the literature with regard to the use of different intravenous agents as supplements to inhalational anaesthesia in horses. The Part 2 of this review will focus in the use of opioids and α2 -agonists. Methods: Pubmed and Web of Science. Search terms: horse, inhalant anaesthesia, balanced anaesthesia, partial intravenous anaesthesia, opioids, morphine, pethidine, butorphanol, methadone, fentanyl, alfentanil, remifentanil, sufentanil, xylazine, romifidine, detomidine, medetomidine and dexmedetomidine. Conclusions: Different drugs and their combinations can be administered systemically...
Linardi RL, Stokes AM, Andrews FM.Methadone is an effective analgesic opioid that may have a place for the treatment of pain in horses. However, its absorption seems to be impaired by the presence of a transmembrane protein, P-glycoprotein, present in different tissues including the small intestine in other species. This study aims to determine the effect of the P-glycoprotein on methadone flux in the equine intestinal mucosa, as an indicator of in vivo drug absorption. Jejunum tissues from five horses were placed into the Ussing chambers and exposed to methadone solution in the presence or absence of Rhodamine 123 or verapami...
Linardi RL, Stokes AM, Keowen ML, Barker SA, Hosgood GL, Short CR.To characterize the bioavailability and pharmacokinetics of oral and injectable formulations of methadone after IV, oral, and intragastric administration in horses. Methods: 6 healthy adult horses. Methods: Horses received single doses (each 0.15 mg/kg) of an oral formulation of methadone hydrochloride orally or intragastrically or an injectable formulation of the drug orally, intragastrically, or IV (5 experimental treatments/horse; 2-week washout period between each experimental treatment). A blood sample was collected from each horse before and at predetermined time points over a 360-minute...
Devisscher L, Schauvliege S, Dewulf J, Gasthuys F.To evaluate the effects of a constant rate infusion (CRI) of romifidine on the requirement of isoflurane, cardiovascular performance and recovery in anaesthetized horses undergoing arthroscopic surgery. Methods: Randomized blinded prospective clinical trial. Methods: Thirty horses scheduled for routine arthroscopy. Methods: After premedication (acepromazine 0.02 mg kg(-1), romifidine 80 microg kg(-1), methadone 0.1 mg kg(-1)) and induction (midazolam 0.06 mg kg(-1) ketamine 2.2 mg kg(-1)), anaesthesia was maintained with isoflurane in oxygen. Horses were assigned randomly to receive a CRI of s...
Linardi RL, Stokes AM, Barker SA, Short C, Hosgood G, Natalini CC.Methadone hydrochloride is a synthetic mu-opioid receptor agonist with potent analgesic properties. Oral methadone has been successfully used in human medicine and may overcome some limitations of other analgesics in equine species for producing analgesia with minimal adverse effects. However, there are no studies describing the pharmacokinetics (PK) of oral opioids in horses. The aim of this study was to describe the PK of orally administered methadone (0.1, 0.2 and 0.4 mg/kg) and physical effects in 12 healthy adult horses. Serum methadone concentrations were measured by gas chromatography/m...
de Vries A, Brearley JC, Taylor PM.Volatile agent-induced hypotension may contribute to anaesthetic-related morbidity and mortality in horses. Dobutamine is commonly used to support arterial blood pressure (ABP) but little is known about its cardiovascular effects under clinical conditions. The aim of this clinical study was to elucidate the relationship between cardiovascular function and dobutamine infusion in isoflurane-anaesthetized horses. Forty-four horses anaesthetized for a variety of surgical procedures were studied. Premedication with acepromazine, methadone and detomidine was followed by induction of anaesthesia with...
Olbrich VH, Mosing M.To evaluate and compare the effects of caudal epidural administration of methadone (METH) and lidocaine (LIDO) on tolerance to thermal stimulation over the dermatomes of the perineal, sacral, lumbar and thoracic regions in the horse. Methods: A blinded, randomized, prospective, experimental cross-over study. Methods: Seven healthy horses, 15.7 +/- 4.9 years (mean +/- SD) of age, weighing 536 +/- 37 kg. Methods: The horses were randomly assigned to receive two treatments (group M: METH, 0.1 mg kg-1 or group L: LIDO, 0.35 mg kg-1) at intervals of at least 28 days. An 18-gauge 80-mm Tuohy epidura...
Hagedorn HW, Meiser H, Zankl H, Schulz R.The misuse of opiates in racehorses relates to their effect of increasing locomotor activity. Because methadone, a narcotic analgesic, has been suspected of use as a doping compound in the past, it was added to the list of banned drugs and should be considered in doping control. Because the literature fails to provide information on detection of methadone in blood or urine of horses, an enzyme-linked immunosorbent assay was developed to monitor this narcotic in equine body fluids. Combined with high-performance liquid chromatography, the immunoassay also served to confirm positives indicated b...
Nilsfors L, Kvart C, Kallings P, Carlsten J, Bondesson U.Cardiorespiratory and sedative effects of a combination of acepromazine, xylazine and methadone were studied in the horse. Acepromazine and xylazine produced cardiovascular effects whereas methadone mainly affected respiratory rate. Decreases in heart rate, arterial blood pressure and respiratory rate were seen. Sedation was superior to that of acepromazine, xylazine or a combination of these. No serious side effects were seen.
Fisher RJ.Ketamine was used on 80 occasions to induce anaesthesia in 77 animals. Xylazine premedication was used alone on 75 occasions, in conjunction with methadone once, in conjunction with methadone and acepromazine once and, on three occasions, methadone and acepromazine only were used. Anaesthesia was maintained in seven cases with halothane and oxygen. Premedication with xylazine 5 mins previously or concurrently with ketamine gave similar results but an interval of more than 5 mins between the drugs produced less deep anaesthesia and this protocol is, therefore, not advised. Induction and recover...
Nolan AM, Hall LW.The effects of four intravenous combinations, xylazine (0.7 mg/kg)/methadone (0.1 mg/kg), xylazine (0.7 mg/kg)/buprenorphine (0.004 and 0.006 mg/kg) and acepromazine (0.05 mg/kg)/buprenorphine (0.006 mg/kg) on arterial blood pressure, central venous pressure, heart rate, respiratory rate and blood gases were studied in four experimental ponies. With xylazine/buprenorphine and xylazine/methadone onset of sedation was rapid and obvious and although no surgical or diagnostic procedures were carried out, sedation was judged to be satisfactory for the next 30 to 40 minutes. Onset of sedation after ...
Pippi NL, Lumb WV.An equine model, subjected to three kinds of pain (superficial, deep, and visceral) was used to test effects of analgesic drugs. Two groups of ponies were used. In the first group of six ponies, six drugs (fentanyl, meperidine, methadone, oxymorphone, pentazocine, and xylazine) were given according to a Latin square experimental design, and tests were made at 30-minute intervals for 4 hours. Mean values (control) for the three kinds of pain were obtained before and after the tests and were compared with the mean values (drugs) obtained over 2- and 4-hour intervals (four and eight measurements ...
Gozalo-Marcilla M, Gasthuys F, Schauvliege S.To review the literature with regard to the use of different intravenous agents as supplements to inhalational anaesthesia in horses. The Part 2 of this review will focus in the use of opioids and α2 -agonists. Methods: Pubmed and Web of Science. Search terms: horse, inhalant anaesthesia, balanced anaesthesia, partial intravenous anaesthesia, opioids, morphine, pethidine, butorphanol, methadone, fentanyl, alfentanil, remifentanil, sufentanil, xylazine, romifidine, detomidine, medetomidine and dexmedetomidine. Conclusions: Different drugs and their combinations can be administered systemically...
Gozalo-Marcilla M, Luna SP, Crosignani N, Filho JNP, Possebon FS, Pelligand L, Taylor PM.To evaluate intravenous (IV) detomidine with methadone in horses to identify a combination which provides sedation and antinociception without adverse effects. Methods: Randomized, placebo-controlled, blinded, crossover. Methods: A group of eight adult healthy horses aged (mean ± standard deviation) 7 ± 2 years and 372 ± 27 kg. Methods: A total of six treatments were administered IV: saline (SAL); detomidine (5 μg kg; DET); methadone (0.2 mg kg; MET) alone or combined with detomidine [2.5 (MLD), 5 (MMD) or 10 (MHD) μg kg]. Thermal, mechanical and electrical nociceptive thresholds were mea...
de Oliveira AR, Gozalo-Marcilla M, Ringer SK, Schauvliege S, Fonseca MW, Esteves Trindade PH, Prospero Puoli Filho JN, Luna SPL.Although facial characteristics are used to estimate horse sedation, there are no studies measuring their reliability and validity. This randomised controlled, prospective, horizontal study aimed to validate a facial sedation scale for horses (FaceSed). Seven horses received detomidine infusion i.v. in low or high doses/rates alone (DL 2.5 μg/kg+6.25 μg/kg/h; DH 5 μg/kg+12.5 μg/kg/h) or combined with methadone (DLM and DHM, 0.2 mg/kg+0.05 mg/kg/h) for 120 min, or acepromazine boli i.v. in low (ACPL 0.02 mg/kg) or high doses (ACPH 0.09 mg/kg). Horses' faces were photographed at i) baseline,...
Gozalo-Marcilla M, de Oliveira AR, Fonseca MW, Possebon FS, Pelligand L, Taylor PM, Luna SPL.Standing surgery avoids the risks of general anaesthesia in horses. Objective: To assess sedation, antinociception and gastrointestinal motility in standing horses after a detomidine loading dose and 2-h constant rate intravenous (i.v.) infusion, with or without methadone. Methods: Blinded, randomised, crossover with seven healthy adult cross-bred horses, three geldings and four females (404 ± 22 kg). Methods: Five i.v. treatments were administered to all horses with 1-week washout period: saline (SAL), detomidine low (2.5 μg/kg bwt + 6.25 μg/kg bwt/h) (DL) and high doses (5 μg/kg ...
Devisscher L, Schauvliege S, Dewulf J, Gasthuys F.To evaluate the effects of a constant rate infusion (CRI) of romifidine on the requirement of isoflurane, cardiovascular performance and recovery in anaesthetized horses undergoing arthroscopic surgery. Methods: Randomized blinded prospective clinical trial. Methods: Thirty horses scheduled for routine arthroscopy. Methods: After premedication (acepromazine 0.02 mg kg(-1), romifidine 80 microg kg(-1), methadone 0.1 mg kg(-1)) and induction (midazolam 0.06 mg kg(-1) ketamine 2.2 mg kg(-1)), anaesthesia was maintained with isoflurane in oxygen. Horses were assigned randomly to receive a CRI of s...
Lopes C, Luna SP, Rosa AC, Quarterone C, Crosignani N, Taylor PM, Pantoja JC, Puoli JN.To investigate two protocols to provide antinociception in horses. Objective: To evaluate the antinociceptive effects of intravenous methadone combined with detomidine or acepromazine in adult horses. Methods: Randomised, blinded, crossover study. Methods: Mechanical, thermal and electrical stimuli were applied to the dorsal left and right metacarpus and coronary band of the left thoracic limb, respectively. A thermal stimulus was applied caudal to the withers. The horses were treated with saline (C), a combination of methadone (0.2 mg/kg bwt) and detomidine (10 μg/kg bwt) (MD) or methadone...
Gozalo-Marcilla M, Luna SP, Gasthuys F, Pollaris E, Vlaminck L, Martens A, Haspeslagh M, Schauvliege S.To determine the required rate of a detomidine infusion (loading dose 5 μg kg; initial rate 12.5 μg kg hour) added to a constant infusion of methadone (0.2 mg kg; 0.05 mg kg hour) for sedation in standing horses and ponies undergoing elective surgeries with appropriate local anaesthetic techniques. Methods: Prospective, clinical study. Methods: Adult, healthy, client-owned, non-food-producing horses or ponies sedated for elective standing surgeries longer than 45 minutes. Methods: At baseline (in the stables before administration of sedative agents), at 10 minutes after sedation and every 5 ...
de Vries A, Brearley JC, Taylor PM.Volatile agent-induced hypotension may contribute to anaesthetic-related morbidity and mortality in horses. Dobutamine is commonly used to support arterial blood pressure (ABP) but little is known about its cardiovascular effects under clinical conditions. The aim of this clinical study was to elucidate the relationship between cardiovascular function and dobutamine infusion in isoflurane-anaesthetized horses. Forty-four horses anaesthetized for a variety of surgical procedures were studied. Premedication with acepromazine, methadone and detomidine was followed by induction of anaesthesia with...
Muir WW, Skarda RT, Sheehan WC.The cardiopulmonary effects of the narcotic agonists morphine, meperidine, oxymorphone, and methadone and of the partial agonist pentazocine were examined in the pain-free adult horse. The drugs produced dysphoric followed by euphoric effects. Increases in heart rate, arterial blood pressure, and cardiac output were observed in all horses with all drugs. Arterial blood pressure remained increased even after heart rate and cardiac output had returned to base-line values. Respiratory rate generally remained unchanged or increased shortly after drug administration and then decreased insignificant...
Carregaro AB, Freitas GC, Ribeiro MH, Xavier NV, Dória RG.Continuous-rate infusion (CRI) of drugs results in more stable plasma drug concentrations than administration of intermittent boluses, thus providing greater stability of physiological parameters. The aim of this study was to evaluate the physiologic and analgesic effects of the administration of morphine, butorphanol, tramadol or methadone by CRI in horses with induced synovitis of the radiocarpal joint. Results: Increased values of cardiorespiratory parameters and body temperature were observed in all groups after initiation of opioid administration, and these increases were sustained throug...
Gozalo-Marcilla M, Luna SPL, Moreira da Silva R, Crosignani N, Lopes NP, Taylor PM, Pelligand L.Pharmacokinetic (PK)/pharmacodynamic (PD) modelling offers new insights to design protocols for sedation and analgesia in standing horses. Objective: To evaluate the parameters and interactions between detomidine and methadone when given alone or combined in standing horses. Methods: Randomised, placebo-controlled, blinded, crossover. Methods: Eight adult healthy horses were given six treatments intravenously: saline (SAL); detomidine (5 μg/kg bwt; DET); methadone (0.2 mg/kg bwt; MET) alone or combined with detomidine (2.5 [MLD], 5 [MMD] or 10 [MHD] μg/kg bwt). Venous blood samples were ob...
Fisher RJ.Ketamine was used on 80 occasions to induce anaesthesia in 77 animals. Xylazine premedication was used alone on 75 occasions, in conjunction with methadone once, in conjunction with methadone and acepromazine once and, on three occasions, methadone and acepromazine only were used. Anaesthesia was maintained in seven cases with halothane and oxygen. Premedication with xylazine 5 mins previously or concurrently with ketamine gave similar results but an interval of more than 5 mins between the drugs produced less deep anaesthesia and this protocol is, therefore, not advised. Induction and recover...
Pippi NL, Lumb WV.An equine model, subjected to three kinds of pain (superficial, deep, and visceral) was used to test effects of analgesic drugs. Two groups of ponies were used. In the first group of six ponies, six drugs (fentanyl, meperidine, methadone, oxymorphone, pentazocine, and xylazine) were given according to a Latin square experimental design, and tests were made at 30-minute intervals for 4 hours. Mean values (control) for the three kinds of pain were obtained before and after the tests and were compared with the mean values (drugs) obtained over 2- and 4-hour intervals (four and eight measurements ...
Carregaro AB, Ueda GI, Censoni JB, Bisetto SP, Alonso BB, Reginato GM.The aim of this study was to compare the effects of methadone combined with detomidine or acepromazine on the quality of sedation and its influence over dissociative anesthesia in healthy horses. In a crossover design, seven horses were administered with 0.1 mg/kg methadone and 0.02 mg/kg detomidine intravenously (group MD) or 0.1 mg/kg methadone and 0.05 mg/kg acepromazine intravenously (group MA). Subsequently, anesthesia was induced with a combination of 2.2 mg/kg ketamine and 0.1 mg/kg midazolam intravenously. Descriptive scales and footages were used to evaluate the quality of sedat...
Olbrich VH, Mosing M.To evaluate and compare the effects of caudal epidural administration of methadone (METH) and lidocaine (LIDO) on tolerance to thermal stimulation over the dermatomes of the perineal, sacral, lumbar and thoracic regions in the horse. Methods: A blinded, randomized, prospective, experimental cross-over study. Methods: Seven healthy horses, 15.7 +/- 4.9 years (mean +/- SD) of age, weighing 536 +/- 37 kg. Methods: The horses were randomly assigned to receive two treatments (group M: METH, 0.1 mg kg-1 or group L: LIDO, 0.35 mg kg-1) at intervals of at least 28 days. An 18-gauge 80-mm Tuohy epidura...
Linardi RL, Stokes AM, Andrews FM.Methadone is an effective analgesic opioid that may have a place for the treatment of pain in horses. However, its absorption seems to be impaired by the presence of a transmembrane protein, P-glycoprotein, present in different tissues including the small intestine in other species. This study aims to determine the effect of the P-glycoprotein on methadone flux in the equine intestinal mucosa, as an indicator of in vivo drug absorption. Jejunum tissues from five horses were placed into the Ussing chambers and exposed to methadone solution in the presence or absence of Rhodamine 123 or verapami...
Nilsfors L, Kvart C, Kallings P, Carlsten J, Bondesson U.Cardiorespiratory and sedative effects of a combination of acepromazine, xylazine and methadone were studied in the horse. Acepromazine and xylazine produced cardiovascular effects whereas methadone mainly affected respiratory rate. Decreases in heart rate, arterial blood pressure and respiratory rate were seen. Sedation was superior to that of acepromazine, xylazine or a combination of these. No serious side effects were seen.
Linardi RL, Stokes AM, Keowen ML, Barker SA, Hosgood GL, Short CR.To characterize the bioavailability and pharmacokinetics of oral and injectable formulations of methadone after IV, oral, and intragastric administration in horses. Methods: 6 healthy adult horses. Methods: Horses received single doses (each 0.15 mg/kg) of an oral formulation of methadone hydrochloride orally or intragastrically or an injectable formulation of the drug orally, intragastrically, or IV (5 experimental treatments/horse; 2-week washout period between each experimental treatment). A blood sample was collected from each horse before and at predetermined time points over a 360-minute...
Nannarone S, Giannettoni G, Laurenza C, Giontella A, Moretti G.While butorphanol is the most commonly used opioid in horses, methadone is not licensed in most countries. Our aim was to compare the effects of both drugs, combined with romifidine, regarding the quality of sedation and induction in horses undergoing elective surgery. Results indicate the suitability of both methadone and butorphanol in this patient population. Animals were scored 10 min after intravenous injection of sedatives. Despite lower overall sedation (OS) score in horses receiving methadone (p = 0.002), the quality and time of induction and intubation remained unchanged. None of the ...
Nolan AM, Hall LW.The effects of four intravenous combinations, xylazine (0.7 mg/kg)/methadone (0.1 mg/kg), xylazine (0.7 mg/kg)/buprenorphine (0.004 and 0.006 mg/kg) and acepromazine (0.05 mg/kg)/buprenorphine (0.006 mg/kg) on arterial blood pressure, central venous pressure, heart rate, respiratory rate and blood gases were studied in four experimental ponies. With xylazine/buprenorphine and xylazine/methadone onset of sedation was rapid and obvious and although no surgical or diagnostic procedures were carried out, sedation was judged to be satisfactory for the next 30 to 40 minutes. Onset of sedation after ...
Gozalo-Marcilla M, Moreira da Silva R, Pacca Loureiro Luna S, Rodrigues de Oliveira A, Werneck Fonseca M, Peporine Lopes N, Taylor PM, Pelligand L.The alpha(α) -agonist detomidine is used for equine sedation with opioids such as methadone. We retrieved the data from two randomized, crossover studies where detomidine and methadone were given intravenously alone or combined as boli (STUDY 1) (Gozalo-Marcilla et al., 2017, Veterinary Anaesthesia and Analgesia, 2017, 44, 1116) or as 2-hr constant rate infusions (STUDY 2) (Gozalo-Marcilla et al., 2019, Equine Veterinary Journal, 51, 530). Plasma drug concentrations were measured with a validated tandem Mass Spectrometry assay. We used nonlinear mixed effect modelling and took pharmacokinetic...
Theurillat R, Sandbaumhüter FA, Gittel C, Larenza Menzies MP, Braun C, Thormann W.An enantioselective assay for the determination of methadone and its main metabolite 2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine in equine plasma based on capillary electrophoresis with highly sulfated γ-cyclodextrin as chiral selector and electrokinetic analyte injection is described. The assay is based on liquid/liquid extraction of the analytes at alkaline pH from 0.1 mL plasma followed by electrokinetic sample injection of the analytes from the extract across a buffer plug without chiral selector. Separation occurs cationically at normal polarity in a pH 3 phosphate buffer containin...
Crosignani N, Luna SP, Dalla Costa T, Pimenta EL, Detoni CB, Guterres SS, Puoli Filho JN, Pantoja JC, Pigatto MC.We investigated the thermal, electrical and mechanical antinociceptive and physiological effects (heart rate, respiratory rate, arterial blood pressure, head height and abdominal auscultation score), and pharmacokinetics, of 0.5 mg/kg of the injectable formulation (ORAL) or nanoparticulated methadone (NANO) given orally, in six adult mares, using a crossover, blind and prospective design. Repeated-measure models were used to compare parametric data between and within treatments, followed by Tukey's test. Nonparametric data were analysed with Wilcoxon signed-rank, adjusted by Bonferroni tests....
Sandbaumhüter FA, Gittel C, Larenza-Menzies MP, Theurillat R, Thormann W, Braun C.The enantioselectivity of the pharmacokinetics of methadone was investigated in anesthetized Shetland ponies after a single intravenous (0.5 mg/kg methadone hydrochloride; n = 6) or constant rate infusion (0.25 mg/kg bolus followed by 0.25 mg/kg/h methadone hydrochloride; n = 3) administration of racemic methadone. Plasma concentrations of l-methadone and d-methadone and their major metabolites, l- and d-2-ethylidene-1,5-dimethyl-3,3-diphenylpyrrolidine (EDDP), respectively, were analyzed by CE with highly sulfated γ-cyclodextrin as chiral selector and electrokinetic analyte injection from...
Sandbaumhüter FA, Vimercati S, Thormann W, Mevissen M.The anesthetic ketamine is often combined with analgesics and benzodiazepines in equine medicine. Therefore, drug-drug interactions are possible. Enzyme kinetics for ketamine N-demethylation were determined using equine CYP3A94, CYP3A95 and CYP3A97, and the effect of medetomidine, diazepam and methadone on the ketamine metabolism was studied in vitro. Ketamine was incubated with the CYPs or equine liver microsomes (ELM) alone or in presence of medetomidine, diazepam and/or methadone for different times. Norketamine levels were determined using enantioselective capillary electrophoresis (CE) wi...
Linardi RL, Stokes AM, Barker SA, Short C, Hosgood G, Natalini CC.Methadone hydrochloride is a synthetic mu-opioid receptor agonist with potent analgesic properties. Oral methadone has been successfully used in human medicine and may overcome some limitations of other analgesics in equine species for producing analgesia with minimal adverse effects. However, there are no studies describing the pharmacokinetics (PK) of oral opioids in horses. The aim of this study was to describe the PK of orally administered methadone (0.1, 0.2 and 0.4 mg/kg) and physical effects in 12 healthy adult horses. Serum methadone concentrations were measured by gas chromatography/m...
de Oliveira AR, Gozalo-Marcilla M, Ringer SK, Schauvliege S, Fonseca MW, Trindade PHE, Puoli Filho JNP, Luna SPL.The lack of standardization of sedation scales in horses limits the reproducibility between different studies. This prospective, randomized, blinded, horizontal and controlled trial aimed to validate a scale for sedation in horses (EquiSed). Seven horses were treated with intravenous detomidine in low/high doses alone (DL 2.5 μg/kg + 6.25 μg/kg/h; DH 5 μg/kg +12.5 μg/kg/h) or associated with methadone (DLM and DHM, 0.2 mg/kg + 0.05 mg/kg/h) and with low (ACPL 0.02 mg/kg) or high (ACPH 0.09 mg/kg) doses of acepromazine alone. Horses were filmed at (i) baseline (ii) peak, (iii) intermediate,...
Hagedorn HW, Meiser H, Zankl H, Schulz R.The misuse of opiates in racehorses relates to their effect of increasing locomotor activity. Because methadone, a narcotic analgesic, has been suspected of use as a doping compound in the past, it was added to the list of banned drugs and should be considered in doping control. Because the literature fails to provide information on detection of methadone in blood or urine of horses, an enzyme-linked immunosorbent assay was developed to monitor this narcotic in equine body fluids. Combined with high-performance liquid chromatography, the immunoassay also served to confirm positives indicated b...
Schwarzbach SV, Melo CF, Xavier PLP, Roballo KC, Cordeiro YG, Ambrósio CE, Fukumasu H, Carregaro AB.Osteoarthritis (OA) is one of the main locomotor disorders in horses. Although nonsteroidal anti-inflammatory drugs are the first-line treatment for OA, opioids could also be used. In previous studies, opioids showed promising anti-inflammatory and analgesic effects. In this study, we aimed to investigate the effects of two opioids (morphine and methadone) against inflammation in lipopolysaccharide (LPS)-stimulated synoviocytes by analyzing microsomal prostaglandin E synthase-1 (mPGES-1) and prostaglandin-endoperoxide synthase 2 (PTGS2) expression. Synoviocytes were obtained from the joints at...
Parra Martínez C, Rico Pérez B, Kaartinen J.To evaluate the agreement between noninvasive arterial blood pressure (NIBP) measured from the tongue and thoracic limb with invasive blood pressure (IBP), and to compare NIBP measured from the tongue and thoracic limb in anaesthetized horses. Methods: Prospective clinical study. Methods: A group of eight client-owned healthy horses anaesthetized for scheduled procedures, American Society of Anesthesiologists classification I-II, weighing (mean ± standard deviation) 498 ± 91 kg and aged 7.8 ± 6.75 years. Methods: Animals were premedicated with intravenous (IV) romifidine (0.04-0.08 mg kg-1)...
