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Methadone is an effective and long-lasting analgesic drug that is also used in medication-assisted treatment for people with opioid use disorders. Although there is evidence that methadone activates µ-opioid and Toll-like-4 receptors (TLR-4s), its effects on distinct immune cells, including mast cells (MCs), are not well characterized. MCs express µ-opioid and Toll-like receptors (TLRs) and constitute an important cell lineage involved in allergy and effective innate immunity responses. In the present study, murine bone-marrow-derived mast cells (BMMCs) were treated with methadone to evaluate cell viability by flow cytometry, cell morphology with immunofluorescence and scanning electron microscopy, reactive oxygen species (ROS) production, and intracellular calcium concentration ([Ca2+]i) increase. We found that exposure of BMMCs to 0.5 mM or 1 mM methadone rapidly induced cell death by forming extracellular DNA traps (ETosis). Methadone-induced cell death depended on ROS formation and [Ca2+]i. Using pharmacological approaches and TLR4-defective BMMC cultures, we found that µ-opioid receptors were necessary for both methadone-induced ROS production and intracellular calcium increase. Remarkably, TLR4 receptors were also involved in methadone-induced ROS production as it did not occur in BMMCs obtained from TLR4-deficient mice. Finally, confocal microscopy images showed a significant co-localization of µ-opioid and TLR4 receptors that increased after methadone treatment. Our results suggest that methadone produces MCETosis by a mechanism requiring a novel crosstalk pathway between µ-opioid and TLR4 receptors.

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OBJECTIVE: To determine the effective dosage of the combination tiletamine-zolazepam-ketamine-xylazine (TKX), with or without methadone, in dogs. STUDY DESIGN: Prospective, randomized, experimental study. ANIMALS: A total of 29 dogs. METHODS: Dogs were randomly administered TKX (group TKX, n = 13) or combined with 0.3 mg kg-1 of methadone (group TKXM, n = 16) intramuscularly. The TKX solution contained tiletamine (50 mg mL-1), zolazepam (50 mg mL-1), ketamine (80 mg mL-1) and xylazine (20 mg mL-1). The effective dosages for immobility in 50% and 95% of the population (ED50 and ED95) were estimated using the up-and-down method. Approximately 20 minutes after drug administration, a skin incision was performed and the response was judged as positive or negative if the dogs moved or did not move, respectively. The TKX volume for the subsequent dog in the same group was increased or decreased by 0.005 mL kg-1 if the response of the previous dog was positive or negative, respectively. Heart and respiratory rates, and sedation/anesthesia scores (range 0-21) were recorded before and 15 minutes after drug administration. RESULTS: Estimated ED50 and ED95 (95% confidence intervals) were: TKX, 0.025 (0.020-0.029) and 0.026 (0.010-0.042) mL kg-1; TKXM, 0.022 (0.018-0.025) and 0.033 (0.017-0.049) mL kg-1. Median (interquartile range) scores for sedation/anesthesia were 17 (16-18) and 17 (15-20), and times until lateral recumbency were 5 (4-6) and 6 (4-10) minutes in TKX and TKXM, respectively (p > 0.05). In both groups heart and respiratory rates decreased, but values remained acceptable for anesthetized dogs. CONCLUSIONS AND CLINICAL RELEVANCE: The results provide a guide for volumes of TKX and TKXM in dogs requiring restraint for minimally invasive procedures. Inclusion of methadone in the TKX combination did not influence ED50.

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Pain management associated with surgery is a constant concern of the health team as well as the patient. Multiple proposals for analgesia have been made in the perioperative context. The use of opioids with rapid effect and easy titration in the intraoperative period are currently frequent; to then perform a postoperative analgesic control with drugs with a longer half-life, usually achieving adequate pain management. However, sometimes the standard analgesic scheme is not enough. The problems associated with this situation have led to the need for high doses of opioids in the postoperative period, with the requirement for monitoring, health personnel, and the adverse effects that these involve. Methadone is a long-acting, rapid-onset opioid, the latter secondary to its long elimination half-life. It is presumed that these characteristics have led patients to report adequate pain management, which has been related to a decrease in the need and dose of rescue opioids, in addition to delaying the requirement of these if necessary during the postoperative. These properties allow methadone to be a potential solution to perioperative pain management.

El manejo del dolor asociado a la cirugía es una preocupación constante del equipo de salud al igual que del paciente. Se han planteado múltiples propuestas de analgesia en el contexto perioperatorio, siendo actualmente frecuente el uso de opioides de rápido efecto y fácil titulación en el intraoperatorio; para luego realizar un control analgésico postoperatorio con fármacos de mayor vida media, logrando habitualmente un manejo adecuado del dolor. Sin embargo, a veces el esquema analgésico estándar no es suficiente. La problemática asociada a esta situación ha llevado a la necesidad de altas dosis de opioides en el posoperatorio, con el requerimiento de monitorización, personal de salud y efectos adversos que estos involucran. La metadona es un opioide de inicio de acción rápido y larga duración, este último secundario a su vida media de eliminación prolongada. Se presume que estas características han logrado que los pacientes reporten un adecuado manejo de su dolor, lo que se ha relacionado a una disminución en la necesidad y dosis de opioides de rescate, además de retrasar el requerimiento de éstos en el caso de ser necesarios durante el postoperatorio. Estas propiedades permiten que la metadona pueda ser una potencial solución al manejo del dolor perioperatorio.

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OBJECTIVE: To evaluate the effects of pharmacologic treatment of neonatal abstinence syndrome on neurodevelopmental outcome from a randomized, controlled trial. STUDY DESIGN: Eight sites enrolled 116 full-term newborn infants with neonatal abstinence syndrome born to mothers maintained on methadone or buprenorphine into a randomized trial of morphine vs methadone. Ninety-nine infants (85%) were evaluated at hospital discharge using the NICU Network Neurobehavioral Scale. At 18 months, 83 of 99 infants (83.8%) were evaluated with the Bayley Scales of Infant and Toddler Development-Third Edition and 77 of 99 (77.7%) with the Child Behavior Checklist (CBCL). RESULTS: Primary analyses showed no significant differences between treatment groups on the NICU Network Neurobehavioral Scale, Bayley Scales of Infant and Toddler Development-Third Edition, or CBCL. However in post hoc analyses, we found differences by atypical NICU Network Neurobehavioral Scale profile on the CBCL. Infants receiving adjunctive phenobarbital had lower Bayley Scales of Infant and Toddler Development-Third Edition scores and more behavior problems on the CBCL. In adjusted analyses, internalizing and total behavior problems were associated with use of phenobarbital (P = .03; P = .04), maternal psychological distress (measured by the Brief Symptom Inventory) (both P < .01), and infant medical problems (both P = .02). Externalizing problems were associated with maternal psychological distress (P < .01) and continued maternal substance use (P < .01). CONCLUSIONS: Infants treated with either morphine or methadone had similar short-term and longer term neurobehavioral outcomes. Neurodevelopmental outcome may be related to the need for phenobarbital, overall health of the infant, and postnatal caregiving environment. TRIAL REGISTRATION: ClinicalTrials.gov: NCT01958476.

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Through the analysis of behavioural changes, this study demonstrates that methadone has behavioural, but not analgesic, effects on Oreochromis niloticus. It provides information that suggests the drug has sedative abilities, as the recovery time was shorter in the fish receiving methadone. Future research, with different doses and stimuli, is required to provide more information about analgesia.

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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 the distal limbs of dead animals. The cytotoxic effects of LPS, morphine, and methadone were investigated by using a cell viability assay with crystal violet dye. Synoviocytes were treated with LPS, LPS plus morphine, or LPS plus methadone for 3, 6, and 12 h, and mPGES-1 and PTGS2 expression was measured using real-time polymerase chain reaction. LPS, and morphine did not affect the viability of synoviocytes, even at high concentrations. LPS treatment increased mPGES-1 and PTGS2 expression, whereas morphine inhibited the increase in mPGES-1 and PTGS2 expression in LPS-stimulated synoviocytes. Methadone did not inhibit mPGES-1 or PTGS2 expression. These results suggest that morphine may exhibit anti-inflammatory effect; therefore, it might be beneficial for the treatment of OA.

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BACKGROUND: Standing surgery avoids the risks of general anaesthesia in horses. OBJECTIVES: 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. STUDY DESIGN: 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 bwt + 12.5 µg/kg bwt/h) (DH) alone or combined with methadone (0.2 mg/kg bwt + 0.05 mg/kg bwt/h), (DLM) and (DHM), respectively. Height of head above the ground (HHAG), electrical (ET), thermal (TT) and mechanical (MT) nociceptive thresholds and gastrointestinal motility were evaluated at predetermined times between 5 and 240 min. A mixed effect model and Kruskal-Wallis test were used to analyse normally and non-normally distributed data, respectively. RESULTS: Sedation (<50% basal HHAG) was achieved for the duration of the infusion, and for an additional 15 min in DH and DHM groups. Nociceptive thresholds were higher than baseline, to the greatest degree and the longest duration, with DHM (ET and TT for 135 min and MT for 150 min). After DH, TT was significantly higher than baseline from 30 to 120 min and MT from 15 to 135 min. After DLM, ET was increased at 90 min, TT at 30 min and MT for 120 min. Gastrointestinal motility was reduced for up to 135 min after DL, 150 min after DLM and 210 min after DH and DHM. MAIN LIMITATIONS: Nociceptive thresholds are not equivalent to surgical stimuli. CONCLUSION: Methadone with the highest detomidine dose (DHM) may provide sufficient sedation and analgesia for standing surgical procedures and warrants further investigation.

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BACKGROUND: Pharmacokinetic (PK)/pharmacodynamic (PD) modelling offers new insights to design protocols for sedation and analgesia in standing horses. OBJECTIVES: To evaluate the parameters and interactions between detomidine and methadone when given alone or combined in standing horses. STUDY DESIGN: 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 obtained at predetermined times between 0 and 360 min after drug administration. Plasma detomidine and methadone were measured using a single, liquid/liquid extraction technique by liquid chromatography coupled with a triple quadrupole mass spectrometer (LC-MS/MS). Sequential PK/PD modelling compared rival models, with and without PK and PD interaction between drugs, to fit the PD data including height of the head above the ground (HHAG), a visual analogue scale for sedation (VAS), electrical (ET), thermal (TT) and mechanical (MT) nociceptive thresholds and gastrointestinal motility (GIM) [1]. RESULTS: Two and three compartment models best described the PK of detomidine and methadone, respectively. Detomidine decreased its own clearance as well as the clearance of methadone. The interaction of methadone on the effect of detomidine revealed an infra-additive (partial antagonism) effect for HHAG (α = -1.33), VAS (α = -0.98) and GIM (α = -1.05), a positive potentiation for ET (pot = 0.0041) and TT (pot = 0.133) and a synergistic to additive effect for MT (α = 0.78). MAIN LIMITATIONS: This is a small experimental study. CONCLUSIONS: Different PK/PD interactions were demonstrated for each PD parameter and could be modelled in vivo. The modelling of our data will allow us to simulate and predict the effect of constant rate infusions of both drugs for future investigations.

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Cardiopulmonary and sedative effects of intravenous or epidural methadone were compared. Six beagles were randomly assigned to group MIV (methadone 0.5 mg/kg IV + NaCl 0.9% epidurally) or MEP (methadone 0.5 mg/kg epidurally + NaCl 0.9% IV). Cardiopulmonary, blood gas and sedation were assessed at time (T) 0, 15, 30, 60, 120, 240 and 480 min after drug administration. Compared to T0, heart rate decreased at T15-T120 in MIV (p < .001) and T15-T240 in MEP (p < .05); mean arterial pressure was reduced at T15-T60 in MEP (p < .01); respiratory rate was higher at T15 and T30 in both groups (p < .05); pH was lower at T15-T120 in MIV (p < .01) and T15, T30 and T120 in MEP (p < .05); PaCO2 was higher at T15-T60 in MIV (p < .01) and T15, T30 and T120 in MEP (p < .01); sedation scores were higher at T15 and T30 in MIV and T15-T60 in MEP (p < .05). At T120 and T240, sedation score was higher in group MEP compared with group MIV (p < .01) In conclusion, cardiopulmonary and sedative effects of identical methadone doses are similar when administered IV or epidurally to conscious healthy dogs.

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OBJECTIVE: To evaluate the sedative and cardiopulmonary effects of three methadone doses, combined with acepromazine, in dogs. STUDY DESIGN: Prospective, randomized, complete block study. ANIMALS: Six healthy, adult, cross-bred dogs weighing 17.2±4.4 kg (mean±standard deviation). METHODS: Each dog was administered four treatments: acepromazine (0.05 mg kg-1) alone or acepromazine (same dose) in combination with methadone (0.25, 0.50 or 0.75 mg kg-1). All drugs were administered intramuscularly. Sedation was scored by a numeric descriptive scale (NDS, range 0-3) and a simple numerical scale (SNS, range 0-10). Heart rate, invasive blood pressure, arterial blood gases and rectal temperature were measured at 15 to 30 minute intervals for 120 minutes. RESULTS: According to NDS scores, mild to moderate sedation (NDS=1-2) was observed in most dogs in the acepromazine treatment, with only one out of six dogs scored as exhibiting intense sedation (NDS=3). All treatments with methadone resulted in significantly higher SNS scores compared with acepromazine alone. In these treatments, most dogs exhibited intense sedation (NDS=3). Increasing the dose of methadone from 0.25 to 0.50 or 0.75 mg kg-1 prolonged sedation in a dose-related manner, but did not influence the degree of sedation. The main adverse effects following administration of acepromazine-methadone treatments were decreased blood pressure, mild respiratory acidosis and decreased rectal temperature. These effects were well tolerated and resolved without treatment. CONCLUSIONS AND CLINICAL RELEVANCE: In this study in six dogs, acepromazine-methadone administration resulted in intense sedation in most dogs. The results are interpreted to indicate that a low dose of methadone (0.25 mg kg-1) administered in combination with acepromazine (0.05 mg kg-1) will induce short-term sedation in dogs, whereas higher doses of methadone should be administered when prolonged sedation is desired.

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