Determination of oral tramadol pharmacokinetics in horses

The determination of the pharmacokinetic parameters of tramadol in plasma and a better characterization of its metabolites after oral administration to horses is necessary to design dosage regimens to achieve target plasma concentrations that are associated with analgesia. The purpose of this study was to determine the pharmacokinetics and elimination pattern in urine of tramadol and its metabolites after oral administration to horses. Tramadol was administered orally to six horses and its half-life, T_max and C_max in plasma were 10.1, 0.59 h, and 132.7 ng/mL, respectively. The half-life, T_max and C_max for M1 in plasma were 4.0, 0.59 h, and 28.0 ng/mL, respectively. Tramadol and its metabolites were detectable in urine between 1 and 24 h after the administration. In conclusion, the PK data reported in this study provides information for the design of future studies of tramadol in horses.     

Pharmacokinetics of tramadol in horses after intravenous, intramuscular and oral administration

Tramadol is a centrally acting analgesic drug that has been used clinically for the last two decades to treat moderate to moderately severe pain in humans. The present study investigated tramadol administration in horses by intravenous, intramuscular, oral as immediate-release and oral as sustained-release dosage-form routes. Seven horses were used in a four-way crossover study design in which racemic tramadol was administered at 2 mg/kg by each route of administration. Altogether, 23 blood samples were collected between 0 and 2880 min. The concentration of tramadol and its M1 metabolite were determined in the obtained plasma samples by use of an LC/MS/MS method and were used for pharmacokinetic calculations. Tramadol clearance, apparent volume of distribution at steady-state, mean residence time (MRT) and half-life after intravenous administration were 26+/-3 mL/min/kg, 2.17+/-0.52 L/kg, 83+/-10 min, and 82+/-10 min, respectively. The MRT and half-life after intramuscular administration were 155+/-23 and 92+/-14 min. The mean absorption time was 72+/-22 min and the bioavailability 111+/-39%. Tramadol was poorly absorbed after oral administration and only 3% of the administered dose was found in systemic circulation. The fate of the tramadol M1 metabolite was also investigated. M1 appeared to be a minor metabolite in horses, which could hardly be detected in plasma samples. The poor bioavailability after oral administration and the short half-life of tramadol may restrict its usefulness in clinical applications.     

Pharmacokinetics and pharmacodynamics of tramadol in horses following oral administration

Tramadol is a synthetic opioid used in human medicine, and to a lesser extent in veterinary medicine, for the treatment of both acute and chronic pain. In humans, the analgesic effects are owing to the actions of both the parent compound and an active metabolite (M1). The goal of the current study was to extend current knowledge of the pharmacokinetics of tramadol and M1 following oral administration of three doses of tramadol to horses. A total of nine healthy adult horses received a single oral administration of 3, 6, and 9 mg/kg of tramadol via nasogastric tube. Blood samples were collected at time 0 and at various times up to 96 h after drug administration. Urine samples were collected until 120 h after administration. Plasma and urine samples were analyzed using liquid chromatography–mass spectrometry, and the resulting data analyzed using noncompartmental analysis. For the 3, 6, and 9 mg/kg dose groups, C_max, T_max, and the t_1/2λ were 43.1, 90.7, and 218 ng/mL, 0.750, 2.0, and 1.5 h and 2.14, 2.25, and 2.39 h, respectively. While tramadol and M1 plasma concentrations within the analgesic range for humans were attained in the 3 and 6 mg/kg dose group, these concentrations were at the lower end of the analgesic range and were only transiently maintained. Furthermore, until effective analgesic plasma concentrations have been established in horses, tramadol should be cautiously recommended for control of pain in horses. No significant undesirable behavioral or physiologic effects were noted at any of the doses administered.     

Pharmacokinetic and urine profile of tramadol and its major metabolites following oral immediate release capsules administration in dogs

The aim of the present paper was to test the oral administration of oral immediate release capsules of tramadol in dogs, to asses both its pharmacokinetic properties and its urine profile. After capsules administration of tramadol (4 mg/kg), involving eight male Beagle dogs, the concentration of tramadol and its main metabolites, M1, M2 and M5, were determined in plasma and urine using an HPLC method. The plasma concentrations of tramadol and metabolites were fitted on the basis of mono- and non-compartmental models, respectively. Tramadol was detected in plasma from 5 min up to 10 h in lesser amounts than M5 and M2, detected at similar concentrations, while M1 was detected in negligible amounts. In the urine, M5 and M1 showed the highest and smallest amount, respectively; M1 and M5 resulted widely conjugate with glucuronic acid. In conclusion, after oral administration of tramadol immediate release capsules, the absorption of the active ingredient was rapid, but its rapid metabolism quickly transformed the parental drug to high levels of M5 and M2, showing an extensive elimination via the kidney. Hence, in the dog, the oral immediate release pharmaceutical formulation of tramadol would have different pharmacokinetic behaviour than in humans.     

Intravenous Tramadol Injection has no Antinociceptive Effect in Horses Undergoing Electrical and Thermal Stimuli

Tramadol combines an μ opiate and nonopiate analgesic mechanism and might be a useful opioid in horses. This study evaluated the effect of IV tramadol on spontaneous locomotor activity (SLA), head height, and hoof withdrawal reflex (HWR) after thermal or electrical nociceptive stimuli in horses. Doses of 2 and 3 mg/kg tramadol did not affect HWR after electrical and thermal nociception, respectively. Head height and SLA were not modified by 2, 3, or 5 mg/kg tramadol. All horses treated with 5 mg/kg tramadol developed trembling in pectoral triceps, and gluteal muscles and adopted a base-wide stance. In conclusion, 2 and 3 mg/kg tramadol IV neither induced sedation nor prolonged HWR after thermal or electrical stimuli in conscious horses. The dose of 5 mg/kg tramadol IV produced excitement, and it is apparently unsuitable for clinical use.     

Pharmacokinetics of intravenous and intramuscular tramadol in llamas

The purpose of this study was to determine the pharmacokinetics of tramadol and its metabolite M1 after intravenous and intramuscular administration to llamas. Tramadol, a centrally acting analgesic whose efficacy is a result of complex interactions between opiate, adrenergic and serotonin receptor systems, has been used clinically to treat moderate to severe pain in humans. The pharmacokinetic parameters of tramadol and M1 in plasma were examined following intravenous and intramuscular administration to six healthy male llamas. Tramadol half-life, volume of distribution at steady-state and clearance after intravenous administration were 2.12 ± 0.37 h, 4.02 ± 1.16 L/kg and 1728.73 ± 152.82 mL/h/kg, respectively. The bioavailability was 110 ± 21% and half-life 2.54 ± 0.31 h following intramuscular administration of tramadol. M1 had a half-life of 10.40 ± 2.90 h and 7.71 ± 0.54 h following intravenous and intramuscular administration of tramadol.     

The effects of ketoconazole and cimetidine on the pharmacokinetics of oral tramadol in greyhound dogs

Tramadol is administered to dogs for analgesia but has variability in its extent of absorption, which may hinder its efficacy. Additionally, the active opioid metabolite (M1) occurs in low concentrations. The purpose of this study was to determine if administration of oral tramadol with suspected metabolism inhibitors (ketoconazole, cimetidine) would lead to improved bioavailability of tramadol and M1. Six healthy Greyhounds were included. They were administered tramadol orally and intravenously, M1 intravenously, oral tramadol with oral ketoconazole and oral tramadol with oral cimetidine. Oral tramadol bioavailability was low (2.6%). Ketoconazole and cimetidine significantly increased tramadol bioavailability to 18.2% and 20.3%, respectively. The mean maximum plasma concentration of tramadol alone was 22.9 ng/ml, and increased to 109.9 and 143.2 ng/ml with ketoconazole and cimetidine, respectively. However, measured tramadol plasma concentrations were below the minimum concentration considered effective in humans (228 μg/ml). In all treatment groups, measured M1 concentrations (<7 μg/ml) were below concentrations associated with efficacy in humans. To conclude, tramadol and M1 concentrations were low and variable in dogs after oral dosing of tramadol, even in combination with cimetidine or ketoconazole, but effective concentrations in dogs have not been defined.     

Pharmacokinetics of tramadol and metabolites after injective administrations in dogs

The aim of this study was to determine the pharmacokinetics of tramadol and its main metabolites after i.v. and i.m. injections. The pharmacokinetic cross-over study was carried out on 6 healthy male beagle dogs. Tramadol was administered by intravenous (i.v.) and intramuscular (i.m.) injection at 4 mg/kg. Tramadol and its main metabolites O-desmethyl-tramadol (M1), N-,N-didesmethyl-tramadol (M2) and N-,O-didesmethyl-tramadol (M5) concentrations were measured in plasma samples by a HPLC coupled with fluorimetric detection; pharmacokinetic evaluations were carried out with a compartmental and non-compartmental model for tramadol and its metabolites, respectively. The bioavailability of the drug, ranging between 84-102% (mean 92%), was within the generally accepted values for a positive bioequivalence decision of (80-125%). After the i.m. injection the mean plasma drug concentration peak was reached after a T(max) of 0.34 h with a C(max) of 2.52 microg/mL. No therapeutic relevant differences were observed between i.m. and i.v. administration. The minimal effective plasma concentration was reached after a few minutes and maintained for about 6-7 h in both administrations. M1 plasma concentration was low and the amounts of the other metabolites produced were analogous in both routes of administration. In conclusion, tramadol was rapidly and almost completely absorbed after i.m. administration and its systemic availability was equivalent to the i.v. injection. The different onset time and duration of action observed were very small and probably therapeutically irrelevant. The i.m. injection is a useful alternative to i.v. injection in the dog.     

Systemic and Local Effects Associated With Long-Term Epidural Catheterization and Morphine-Detomidine Administration in Horses

Objective — The purpose of this study was to determine the systemic and local effects associated with long-term epidural catheterization and epidural morphine-detomidine administration in horses. Study Design — Development of systemic or local effects was assessed by placing caudal epidural catheters in study horses and administering injections through the catheters every 12 hours for 14 days. Animals — Ten horses with epidural catheters that received daily injections; six uncatheterized horses presented for euthanasia. Methods — Horses received either 0.2 mg/kg morphine sulfate and 30 μg/kg detomidine hydrochloride or an equivalent volume of physiologic saline solution through epidural catheters. Systemic effects were compared between control and treatment horses by measuring physical parameters and hay and water consumption, as well as by evaluating major organs after euthanasia. Local effects were studied by examining cerebrospinal fluid and by grading representative samples of the spinal cord and surrounding tissues histologically for inflammation and fibrosis. Local effects were compared between control and treatment horses, as well as between catheter-ized (control plus treatment) horses and uncatheterized horses. Results — No significant difference was identified in daily variables or hay and water consumption between control and treatment horses. No growth was obtained from cerebrospinal fluid cultures. No significant difference in cerebrospinal fluid values or spinal tissue inflammation or fibrosis grades was shown between control and treatment horses. However, when compared with uncatheterized horses, cerebrospinal fluid red blood cell values were marginally higher and protein concentrations were significantly higher in the catheterized group. Lumbosacral and sacral spinal tissue segment inflammation grades, and sacral segment fibrosis grades were significantly higher in catheterized horses. Conclusions — Long-term epidural administration of a morphine-detomidine combination is not associated with apparent adverse systemic effects in horses. Localized inflammation and fibrosis seem to be catheter-related. Clinical Relevance — Potential systemic and local effects are important considerations with long-term administration of a morphine-detomidine combination through indwelling epidural catheters for alleviation of chronic musculoskeletal pain in horses.     

Cardiopulmonary effects of epidurally administered xylazine in the horse

This study was designed to determine whether the epidural administration of an alpha2 agonist, xylazine, would produce measurable changes in arterial blood pressure, electrocardiographic (ECG) activity and arterial blood gas values in horses. Six horses were given each of four treatments: epidural xylazine, intravenous xylazine, epidural lidocaine and epidural saline. A carotid artery catheter was used to measure arterial blood pressure and to collect samples for blood gas analysis before treatment and at intervals post treatment. Heart rate, arterial pressures, ECG activity and respiratory rate were recorded at the same intervals. No significant changes were recorded between time intervals or between individual treatments. It was concluded that this method of xylazine administration to horses produced potent caudal analgesia without measurable cardiopulmonary effects.     

Pharmacokinetics of tramadol, and its metabolite O-desmethyl-tramadol, in cats

Tramadol is an analgesic agent and is used in dogs and cats. Tramadol exerts its action through interactions with opioid, serotonin and adrenergic receptors. The opioid effect of tramadol is believed to be, at least in part, related to its metabolite, O-desmethyl-tramadol. The pharmacokinetics of tramadol and O-desmethyl-tramadol were examined after intravenous (i.v.) and oral administration of tramadol to six cats. A two-compartment model (with first-order absorption in the central compartment for the oral administration) with elimination from the central compartment best described the disposition of tramadol in cats. After i.v. administration, the apparent volume of distribution of the central compartment, the apparent volume of distribution at steady-state, the clearance, and the terminal half-life (mean +/- SEM) were 1553+/-118 mL/kg, 3103+/-132 mL/kg, 20.8+/-3.2 mL/min/kg, and 134+/-18 min, respectively. Systemic availability and terminal half-life after oral administration were 93+/-7% and 204+/-8 min, respectively. O-desmethyl-tramadol rapidly appeared in plasma following tramadol administration and had terminal half-lives of 261+/-28 and 289+/-19 min after i.v. and oral tramadol administration, respectively. The rate of formation of O-desmethyl-tramadol estimated from a model including both tramadol and O-desmethyl-tramadol was 0.014+/-0.003/min and 0.004+/-0.0008/min after i.v. and oral tramadol administration, respectively.     

Pharmacokinetics after oral and intravenous administration of a single dose of tramadol hydrochloride to Hispaniolan Amazon parrots (Amazona ventralis)

Objective-To determine pharmacokinetics after IV and oral administration of a single dose of tramadol hydrochloride to Hispaniolan Amazon parrots (Amazona ventralis). Animals-9 healthy adult Hispaniolan Amazon parrots (3 males, 5 females, and 1 of unknown sex). Procedures-Tramadol (5 mg/kg, IV) was administered to the parrots. Blood samples were collected from -5 to 720 minutes after administration. After a 3-week washout period, tramadol (10 and 30 mg/kg) was orally administered to parrots. Blood samples were collected from -5 to 1,440 minutes after administration. Three formulations of oral suspension (crushed tablets in a commercially available suspension agent, crushed tablets in sterile water, and chemical-grade powder in sterile water) were evaluated. Plasma concentrations of tramadol and its major metabolites were measured via high-performance liquid chromatography. Results-Mean plasma tramadol concentrations were > 100 ng/mL for approximately 2 to 4 hours after IV administration of tramadol. Plasma concentrations after oral administration of tramadol at a dose of 10 mg/kg were < 40 ng/mL for the entire time period, but oral administration at a dose of 30 mg/kg resulted in mean plasma concentrations > 100 ng/mL for approximately 6 hours after administration. Oral administration of the suspension consisting of the chemical-grade powder resulted in higher plasma tramadol concentrations than concentrations obtained after oral administration of the other 2 formulations; however, concentrations differed significantly only at 120 and 240 minutes after administration. Conclusions and Clinical Relevance-Oral administration of tramadol at a dose of 30 mg/kg resulted in plasma concentrations (> 100 ng/mL) that have been associated with analgesia in Hispaniolan Amazon parrots.     

Salmonella Brandenburg — emergence of a variant strain on a sheep farm in the South Island of New Zealand

AIM: To compare the rectal and I/V administration of tramadol in dogs, to assess both its pharmacokinetic properties and absolute bioavailability.

METHODS: After rectal administration via suppositories and I/V injection of tramadol (4 mg/kg), the concentration of tramadol and its main metabolites, O-desmethyl-tramadol (M1), N-desmethyl-tramadol (M2) and N,O-didesmethyl-tramadol (M5), were determined in plasma, using high-performance liquid chromatography (HPLC). A balanced cross-over study was used, involving six male Beagle dogs.

RESULTS: Plasma concentrations after rectal and I/V administration were fitted on the basis of mono- and bi-compartmental models, respectively. Following rectal administration tramadol was detected from 5 minutes up to 10 hours, in lesser amounts than M5 and M2, while M1 was detected in negligible amounts. Following I/V administration tramadol was detected up to 10 hours, M2 and M5 were detected at similar concentrations, and M1 was present at low concentrations. The area under the curve (AUC) of the three metabolites did not differ significantly after either route of administration of tramadol. The absolute bioavailability of tramadol via rectal administration was 10 (SD 4)%.

CONCLUSIONS: After rectal administration of tramadol suppositories, absorption of the active ingredient was rapid, but its metabolism quickly transformed the parent drug to high levels of M2 and M5.

CLINICAL RELEVANCE: In the dog, rectal pharmaceutical formulation of tramadol would have a different pharmacokinetic behaviour than in humans.     

A comparison of the analgesic effects of caudal epidural methadone and lidocaine in the horse

Objective 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. Study design A blinded, randomized, prospective, experimental cross‐over study. Animals 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 epidural needle was placed in the first intercoccygeal space (Co1–Co2) in awake standing horses restrained in stocks. Analgesia was assessed by use of a probe maintained at a constant 62 °C by circulating hot water. The maximum stimulation time was 30 seconds. Bilateral stimulation was performed at five defined points. Before drug administration, baseline values of response time to thermal stimuli were obtained. Time to response was then measured 15 and 60 minutes after METH or LIDO administration and then hourly until the response returned to baseline at all stimulation points on two further assessments. Development of any ataxia and/or sedation was recorded. Positive pain responses were defined as purposeful avoidance movements of the head, neck, trunk, limbs and tail. Absence of attempts to kick, bite and turning of the head toward the stimulation site were used to indicate analgesia. Results Caudal epidural administration of METH and LIDO significantly increased reaction time to thermal stimulation (one‐sample t‐test; p = 0.05). Analgesia in the perineal region was present 15 minutes after both METH and LIDO administration and progressed from caudal to cranial dermatones with time. The duration of a significant increase in reaction time was 5 hours after METH injection compared to 3 hours following LIDO. All horses defaecated and urinated normally, and no excitement, sedation or ataxia were observed after METH administration. The horses were unable to defaecate normally and were moderately to severely ataxic with hindlimb weakness after LIDO. Conclusions Caudal epidural administration of methadone has considerable potential in the management of perineal, lumbo‐sacral and thoracic pain in horses. Regional differences exist in the onset, duration and intensity of the pain relief. Clinical relevance Epidural methadone administration provides analgesia with no measured side effects in these healthy adult horses.     

Effects of epidural opioid analgesics on heart rate, arterial blood pressure, respiratory rate, body temperature, and behavior in horses

Heart rate, arterial blood pressures, respiratory rate, body temperature, and central nervous system excitement were compared before and after epidural administration of morphine (0.1 mg/kg), butorphanol (0.08 mg/kg), alfentanil (0.02 mg/kg), tramadol (1.0 mg/kg), the k-opioid agonist U50488H (0.08 mg/kg), or sterile water using an incomplete Latin square crossover design in five conscious adult horses. Treatments were administered into the first intercoccygeal epidural space. Significant (P <.05) reductions in respiratory rate were detected after epidural administration of morphine, alfentanil, U50488H, and sterile water. Additionally, significant (P <.05) head ptosis was observed within the first hour after administration of morphine, U50488H, and tramadol, but neither of these changes appeared to be of clinical significance. No treatment-related changes in motor activity or behavior were observed.     

Evaluation of the analgesic effects of epidurally administered morphine, alfentanil, butorphanol, tramadol, and U50488H in horses

OBJECTIVE: To evaluate and compare effects of epidurally administered morphine, alfentanil, butorphanol, tramadol, and U50488H on avoidance threshold to noxious electrical stimulation over the dermatomes of the perineal, sacral, lumbar, and thoracic regions in horses. ANIMALS: 5 healthy adult horses. PROCEDURE: Using a Latin square complete repeated-measures design, horses were randomly assigned to receive 1 of 6 treatments (morphine, alfentanil, butorphanol, tramadol, U50488H, or sterile water) at intervals of at least 7 days. Agents were injected epidurally at the first intercoccygeal epidural space, and electrical stimulation was applied at repeated intervals for 24 hours to the dermatomes of the perineal, sacral, lumbar, and thoracic regions. Avoidance threshold to electrical stimulation was recorded. RESULTS: Administration of butorphanol, U50488H, and sterile water did not induce change in avoidance threshold. Alfentanil increased avoidance threshold during the first 4 hours, but not significantly. Tramadol and morphine significantly increased threshold and analgesic effects. Complete analgesia (avoidance threshold, >40 V) in the perineal and sacral areas was achieved 30 minutes after tramadol injection, compared with 6 hours after morphine injection. Duration of complete analgesia was 4 hours and 5 hours after tramadol and morphine injections, respectively. CONCLUSIONS AND CLINICAL RELEVANCE: Epidural administration of tramadol and morphine induces long-lasting analgesia in healthy adult horses. Epidural administration of opioids may provide long-lasting analgesia in horses without excitation of the CNS.     

Pharmacokinetics of orally administered tramadol in Muscovy ducks (Cairina moschata domestica)

This study documents the pharmacokinetics of oral tramadol in Muscovy ducks. Six ducks received a single 30 mg/kg dose of tramadol, orally by stomach tube, with blood collection prior to and up to 24 hr after tramadol administration. Plasma tramadol, and metabolites O‐desmethyltramadol (M1), and N,O‐didesmethyltramadol (M5) concentrations were determined by high‐pressure liquid chromatography (HPLC) with fluorescence (FL) detection. Pharmacokinetic parameters were calculated using a one‐compartment model with first‐order input. No adverse effects were noted after oral administration. All ducks achieved plasma concentrations of tramadol above 0.10 μg/ml and maintained those concentrations for at least 12 hr. Elimination half‐life was 3.95 hr for tramadol in ducks, which is similar to other avian species. All ducks in this study produced the M1 metabolite and maintained plasma concentrations above 0.1 μg/ml for at least 24 hr.     

L-Bupivacaine 0.5% vs. racemic 0.5% bupivacaine for caudal epidural analgesia in horses

Bupivacaine is available as a racemic mixture of its enantiomers, d -bupivacaine and l -bupivacaine (LB). The aim of this randomized, double-blind study was to investigate the clinical efficacy and safety of S(−)-bupivacaine compared with standard racemic bupivacaine (RB) in horses under caudal epidural analgesia. Two treatments were administered to each horse, with a 2-week interval between subsequent treatments. Treatment 1 consisted of 0.5% LB at a dose of 0.06 mg/kg of body weight, and treatment 2 consisted of 0.5% RB at a dose of 0.06 mg/kg of body weight. Epidural injections were given in all animals between the first and second coccygeal vertebra. Heart rate (HR), arterial pressures, respiratory rate (RR), rectal temperature (RT), analgesia, and motor blocking were determined before drug administration (basal) and 5, 10, 15 and 30 min after drug administration, and at 30 min intervals thereafter. There were no significant differences between the two treatments in the quality of sensory and motor block. The duration of analgesia was 320 ± 30 min (mean ± SD) for RB and 360 ± 42 min for LB. HRs and RRs, arterial pressures and RT did not change ( P  < 0.05) significantly from basal values after epidural administration of LB or RB. This study supports that 0.5% LB is an effective alternative to RB in caudal epidural analgesia in conscious, standing horses. The use of LB vs. RB warrants further investigation, particularly for long-lasting surgery in the perineal region.     

Pharmacokinetics of tramadol and the metabolite O-desmethyltramadol in dogs

Tramadol is an analgesic and antitussive agent that is metabolized to O-desmethyltramadol (M1), which is also active. Tramadol and M1 exert their mode of action through complex interactions between opiate, adrenergic, and serotonin receptors. The pharmacokinetics of tramadol and M1 were examined following intravenous and oral tramadol administration to six healthy dogs, as well as intravenous M1 to three healthy dogs. The calculated parameters for half-life, volume of distribution, and total body clearance were 0.80 +/- 0.12 h, 3.79 +/- 0.93 L/kg, and 54.63 +/- 8.19 mL/kg/min following 4.4 mg/kg tramadol HCl administered intravenously. The systemic availability was 65 +/- 38% and half-life 1.71 +/- 0.12 h following tramadol 11 mg/kg p.o. M1 had a half-life of 1.69 +/- 0.45 and 2.18 +/- 0.55 h following intravenous and oral administration of tramadol. Following intravenous M1 administration the half-life, volume of distribution, and clearance of M1 were 0.94 +/- 0.09 h, 2.80 +/- 0.15 L/kg, and 34.93 +/- 5.53 mL/kg/min respectively. Simulated oral dosing regimens at 5 mg/kg every 6 h and 2.5 mg/kg every 4 h predict tramadol and M1 plasma concentrations consistent with analgesia in humans; however, studies are needed to establish the safety and efficacy of these doses.     

Analgesic, hemodynamic, and respiratory effects induced by caudal epidural administration of meperidine hydrochloride in mares.

OBJECTIVE: To determine the analgesic, hemodynamic, and respiratory effects induced by caudal epidural administration of meperidine hydrochloride in mares. ANIMALS: 7 healthy mares. Procedure: Each mare received meperidine (5%; 0.8 mg/kg of body weight) or saline (0.9% NaCl) solution via caudal epidural injection on 2 occasions. At least 2 weeks elapsed between treatments. Degree of analgesia in response to noxious electrical, thermal, and skin and muscle prick stimuli was determined before and for 5 hours after treatment. In addition, cardiovascular and respiratory variables were measured and degree of sedation (head position) and ataxia (pelvic limb position) evaluated. RESULTS: Caudal epidural administration of meperidine induced bilateral analgesia extending from the. coccygeal to S1 dermatomes in standing mares; degree of sedation and ataxia was minimal. Mean (+/- SD) onset of analgesia was 12 +/- 4 minutes after meperidine administration, and duration of analgesia ranged from 240 minutes to the entire 300-minute testing period. Heart and respiratory rates, rectal temperature, arterial blood pressures, Hct, PaO2, PaCO2, pHa, total solids and bicarbonate concentrations, and base excess were not significantly different from baseline values after caudal epidural administration of either meperidine or saline solution. CONCLUSIONS AND CLINICAL RELEVANCE: Caudal epidural administration of meperidine induced prolonged perineal analgesia in healthy mares. Degree of sedation and ataxia was minimal, and adverse cardiorespiratory effects were not detected. Meperidine may be a useful agent for induction of caudal epidural analgesia in mares undergoing prolonged diagnostic, obstetric, or surgical procedures in the anal and perineal regions.