Preliminary pharmacokinetics of tramadol hydrochloride after administration via different routes in male and female B6 mice

Objective

1) To determine the pharmacokinetics of tramadol hydrochloride and its active metabolite, O-desmethyltramadol (M1), after administration through different routes in female and male C57Bl/6 mice; 2) to evaluate the stability of tramadol solutions; and 3) to identify a suitable dose regimen for prospective clinical analgesia in B6 mice.

Pharmacokinetics of single-dose oral pregabalin administration in normal dogs

ObjectiveTo describe the pharmacokinetics of pregabalin in normal dogs after a single oral dose.Study designProspective experiment.AnimalsSix adult Labrador/Greyhound dogs (four females and two males) aged 2.6 (2.6–5.6) years old (median and range) weighing 33.4 (26.8–42.1) kg.MethodsAfter jugular vein catheterization, the dogs received a single oral dose of pregabalin (～4 mg kg^?1). Blood samples were collected at: 0 (before drug administration), 15 and 30 minutes and at 1, 1.5, 2, 3, 4, 6, 8, 12, 24 and 36 hours after drug administration. Plasma pregabalin concentration was measured by HPLC. Noncompartmental analysis was used to estimate pharmacokinetic variables.ResultsNo adverse effects were observed. The median (range) pharmacokinetic parameters were: Area under the curve from time 0 to 36 hours = 81.8 (56.5–92.1) μg hour mL^?1; absorption half-life = 0.38 (0.25–1.11) hours; elimination half-life = 6.90 (6.21–7.40) hours; time over 2.8 μg mL^?1 (the presumed minimal effective concentration) = 11.11 (6.97–14.47) hours; maximal plasma concentration (C_max) = 7.15 (4.6–7.9) μg mL^?1; time for C_max to occur = 1.5 (1.0–4.0) hours. Assuming an 8-hour dosing interval, predicted minimal, average, and maximal steady state plasma concentrations were 6.5 (4.8–8.1), 8.8 (7.3–10.9), and 13.0 (8.8–15.2) μg mL^?1. The corresponding values assuming a 12-hour interval were 3.8 (2.4–4.8), 6.8 (4.9–7.9), and 10.1 (6.6–11.6) μg mL^?1.Conclusions and clinical relevancePregabalin 4 mg kg^?1 PO produces plasma concentrations within the extrapolated therapeutic range from humans for sufficient time to suggest that a twice daily dosing regime would be adequate. Further study of the drug's safety and efficacy for the treatment of neuropathic pain and seizures in dogs is warranted.     

The post-operative analgesic effects of epidurally administered morphine and transdermal fentanyl patch after ovariohysterectomy in dogs

ObjectiveTo investigate the analgesic and side effects of epidural morphine or a fentanyl patch after ovariohysterectomy in dogs.Study designProspective, randomized clinical study.AnimalsTwenty female mongrel dogs undergoing ovariohysterectomy.MethodsThe dogs were allocated to one of two groups: epidural morphine or transdermal fentanyl patch. Anaesthesia was induced with propofol and maintained with isoflurane. Morphine (0.1 mg kg^?1) was administered epidurally in the epidural morphine group and a transdermal fentanyl patch was applied 24 hours before the operation in the fentanyl patch group.The heart rate, respiratory rate, body temperature, plasma cortisol concentration, and sedation and analgesia scores were recorded during the 24 hour post-operative period. Adverse effects such as vomiting, anorexia, skin reactions, urinary retention, and time to start licking the surgical site were also recorded. p < 0.05 was considered significant. Statistical analyses utilized anova for repeated measures, Friedman tests, Mann-Whitney U-tests and independent sample t-tests as relevant.ResultsPain scores were lower in the epidural group than in the fentanyl group at all post-operative times. The dogs in the epidural morphine group were calm and relaxed, whereas discomfort and vocalization were recorded in the fentanyl patch group. The sedation scores were higher in the fentanyl patch group throughout the 12 hour period. Salivation and anorexia lasted longer in the fentanyl patch group than in the epidural morphine group. Plasma cortisol concentrations were high in the early post-operative period in both groups. The fentanyl patch group had higher cortisol concentrations than the epidural morphine group. Slight erythema was recorded in two dogs when the patches were removed.Conclusion and clinical relevanceEpidurally administered morphine provided better analgesia and caused fewer adverse effects than the fentanyl patch after ovariohysterectomy in dogs.     

Post-operative analgesic effects of butorphanol or firocoxib administered to dogs undergoing elective ovariohysterectomy

ObjectiveTo compare the post-operative analgesic effects of butorphanol or firocoxib in dogs undergoing ovariohysterectomy.Study designProspective, randomized, blinded, clinical trial.AnimalsTwenty-five dogs >1 year of age.MethodsDogs received acepromazine intramuscularly (IM), 0.05 mg kg^?1 and either butorphanol IM, 0.2 mg kg^?1 (BG, n = 12) or firocoxib orally (PO), 5 mg kg^?1 (FG, n = 13), approximately 30 minutes before induction of anesthesia with propofol. Anesthesia was maintained with isoflurane. Ovariohysterectomy was performed by the same surgeon. Pain scores using the dynamic and interactive visual analog scale (DIVAS) were performed before and at 1, 2, 3, 4, 6, 8 and 20 hours after the end of surgery by one observer, blinded to the treatment. Rescue analgesia was provided with morphine (0.5 mg kg^?1) IM and firocoxib, 5 mg kg^?1 (BG only) PO if DIVAS > 50. Groups were compared using paired t-tests and Fisher’s exact test (p < 0.05). Data are presented as mean ± SD.ResultsThe BG required significantly less propofol (BG: 2.6 ± 0.59 mg kg^?1; FG: 5.39 ± 0.7 mg kg^?1) (p < 0.05) but the anesthesia time was longer (BG: 14 ± 6, FG: 10 ± 4 minutes). There were no differences for body weight (BG: 7.9 ± 5.0, FG: 11.5 ± 4.6 kg), sedation scores, and surgery and extubation times (BG: 10 ± 2, 8 ± 5 minutes; FG: 9 ± 3, 8 ± 4 minutes, respectively) (p > 0.05). The FG had significantly lower pain scores than the BG at 1, 2 and 3 hours following surgery (p < 0.05). Rescue analgesia was administered to 11/12 (92%) and 2/13 (15%) dogs in the BG and FG, respectively (p < 0.05).Conclusion and clinical relevanceFirocoxib produced better post-operative analgesia than butorphanol. Firocoxib may be used as part of a multimodal analgesia protocol but may not be effective as a sole analgesic.     

Effects of tramadol,morphine or their combination in dogs undergoing ovariohysterectomy on peri-operative electroencephalographic responses and post-operative pain

Abstract

AIM: To compare the peri-operative electroencephalogram (EEG) responses and post-operative analgesic efficacy of pre-operative morphine or tramadol with a combination of low-dose pre-operative morphine and post-operative tramadol, in dogs undergoing ovariohysterectomy.

METHODS: Dogs undergoing routine ovariohysterectomy were treated with either pre-operative morphine (0.5 mg/kg S/C, n=8), or tramadol (3 mg/kg S/C, n=8), or pre-operative low-dose morphine (0.1 mg/kg S/C) and post-operative tramadol (3 mg/kg I/V, n=8). All dogs received routine pre-anaesthetic medication, and anaesthesia was induced with I/V thiopentone to effect and maintained with halothane in oxygen. Respiratory rate, heart rate, end-tidal halothane tension (EtHal) and end-tidal CO₂ tension (EtCO₂) were monitored throughout surgery. The EEG was recorded continuously in a three electrode montage. Median frequency (F50), total power (Ptot) and 95% spectral edge frequency (F95) of the EEG power spectra were compared during different 100-second periods of surgery: prior to and during skin incision, ligation of each ovarian pedicle, ligation of uterine body and skin closure. Post-operatively, pain was assessed using the short form of the Glasgow composite measure pain scale (CMPS-SF).

RESULTS: There was no difference in F50 or Ptot of the EEG between baseline and noxious surgical events within each treatment group, or between the three groups (p>0.05). The mean F95 was higher during the first three periods of surgery for dogs administered tramadol and low-dose morphine than those that received 0.5 mg/kg morphine (p=0.001). Dogs that received low-dose morphine and tramadol had lower CMPS-SF pain scores after ovariohysterectomy than those that received either tramadol or morphine alone (p=0.001). There was no difference in pain scores between dogs in the latter two groups.

CONCLUSION AND CLINICAL RELEVANCE: Tramadol and morphine administered pre-operatively provided an equal degree of post-operative analgesia in dogs after ovariohysterectomy. A combination of pre-operative low-dose morphine and post-operative tramadol produced better post-operative analgesia than either drug administered alone pre-operatively. Administration of analgesics pre- and post-operatively could result in improved post-operative well-being of ovariohysterectomised dogs.     

Glomerular filtration rate after tramadol, parecoxib and pindolol following anaesthesia and analgesia in comparison with morphine in dogs

ObjectiveTo compare the effects of morphine, parecoxib, tramadol and a combination of parecoxib, tramadol and pindolol on nociceptive thresholds in awake animals and their effect on glomerular filtration rate (GFR) in dogs subjected to 30 minutes of anesthesia.AnimalsEight adult mixed breed experimental dogs.Study designRandomized, controlled trial.MethodsDogs received 0.05 mg kg^?1 acepromazine subcutaneously (SC) as anaesthetic pre-medication. Thirty to sixty minutes later, they received either tramadol 3 mg kg^?1 intravenously, (IV), parecoxib (1 mg kg^?1 IV), a combination of tramadol 3 mg kg^?1 (IV), parecoxib 1 mg kg^?1 (IV) and pindolol 5 μg kg^?1 (SC), morphine (0.1 mg kg^?1 (IV) or 0.9% saline (2 mL). Anaesthesia was then induced with IV propofol to effect (2.9 ± 0.8 mg kg^?1) and maintained with halothane in oxygen for 30 minutes. Systolic arterial blood pressure was maintained above 90 mmHg with IV fluids and by adjusting the inspired halothane concentration. Post-treatment nociceptive thresholds to mechanical stimuli, expressed as percent of pre-treatment values, were compared between the treatments to assess the analgesic efficacy of the drugs. Plasma iohexol clearance (ICL), a measure of GFR, was estimated both before and 24 hours after induction of anaesthesia to study the drugs’ effects on renal perfusion. Nociceptive threshold and GFR data were compared using mixed model analysis in sas^®9.1.ResultsBoth tramadol and parecoxib produced similar analgesia, which was less than that of morphine. Their combination with pindolol produced analgesia comparable with morphine. None of the test drugs, either alone or in combination, reduced GFR.ConclusionTramadol and parecoxib (either alone or in combination) can increase nociceptive thresholds in awake dogs and have minimal effects on renal perfusion in normotensive dogs subjected to anaesthesia.     

Pharmacokinetics of levofloxacin after single intravenous,oral and subcutaneous administration to dogs

The pharmacokinetic properties of the fluoroquinolone levofloxacin (LFX) were investigated in six dogs after single intravenous, oral and subcutaneous administration at a dose of 2.5, 5 and 5 mg/kg, respectively. After intravenous administration, distribution was rapid (T_½dist 0.127 ± 0.055 hr) and wide as reflected by the volume of distribution of 1.20 ± 0.13 L/kg. Drug elimination was relatively slow with a total body clearance of 0.11 ± 0.03 L kg^?1 hr^?1 and a T_½ for this process of 7.85 ± 2.30 hr. After oral and subcutaneous administration, absorption half‐life and T_max were 0.35 and 0.80 hr and 1.82 and 2.82 hr, respectively. The bioavailability was significantly higher (p ? 0.05) after subcutaneous than oral administration (79.90 vs. 60.94%). No statistically significant differences were observed between other pharmacokinetic parameters. Considering the AUC_24 hr/MIC and C_max/MIC ratios obtained, it can be concluded that LFX administered intravenously (2.5 mg/kg), subcutaneously (5 mg/kg) or orally (5 mg/kg) is efficacious against Gram‐negative bacteria with MIC values of 0.1 μg/ml. For Gram‐positive bacteria with MIC values of 0.5 μg/kg, only SC and PO administration at a dosage of 5 mg/kg showed to be efficacious. MIC‐based PK/PD analysis by Monte Carlo simulation indicates that the proposed dose regimens of LFX, 5 and 7.5 mg/kg/24 hr by SC route and 10 mg/kg/24 hr by oral route, in dogs may be adequate to recommend as an empirical therapy against S. aureus strains with MIC ≤ 0.5 μg/ml and E. coli strains with MIC values ≤0.125 μg/ml.     

Comparison of transdermal fentanyl and oral tramadol for lateral thoracotomy in dogs: cardiovascular and behavioural data

Objective

To compare the analgesic efficacy and suitability of an existing oral tramadol-based protocol with a transdermal fentanyl-based protocol following lateral thoracotomy in dogs.

Effects of tramadol alone,in combination with meloxicam or dipyrone,on postoperative pain and the analgesic requirement in dogs undergoing unilateral mastectomy with or without ovariohysterectomy

ObjectiveTo compare the effects of tramadol alone, or in combination with dipyrone or meloxicam, on postoperative pain and analgesia requirement after unilateral mastectomy with or without ovariohysterectomy in dogs.Study designProspective, randomized, clinical study.AnimalsTwenty seven bitches undergoing unilateral mastectomy with or without ovariohysterectomy.MethodsAnesthesia was induced with propofol and maintained with isoflurane and a constant rate infusion of morphine. Before the end of surgery, dogs were randomly assigned to receive intravenous tramadol alone (3 mg kg^?1, group T), combined with dipyrone (30 mg kg^?1, group TD) or meloxicam (0.2 mg kg^?1, group TM). Dogs received additional doses of tramadol (groups T and TM) or tramadol with dipyrone (group TD) at 8 and 16 hours after extubation. Postoperative pain was assessed by a blinded observer before anesthesia (baseline) and at 1, 2, 3, 4, 6, 8, 12, 16 and 24 hours after extubation using a visual analog scale (VAS) and a modified Glasgow scale. Rescue analgesia (morphine, 0.5 mg kg^?1) was administered if the Glasgow pain score was >3.5.ResultsThere were no significant differences among groups in pain scores evaluated by the VAS or the Glasgow scale. In groups T, TD and TM, pain scores were significantly higher than at baseline for 6, 8 and 2 hours, respectively. Rescue analgesia was administered to 3/9, 2/9 and 1/9 dogs in groups T, TD and TM, respectively (p > 0.05) [Correction added on 15 August 2013, after first online publication: ‘T, TM and TD’ was changed to ‘T, TD and TM’.].Conclusions and clinical relevanceUnder the conditions of this study, tramadol alone or in combination with dypyrone or meloxicam provided effective analgesia for 24 hours in most dogs after unilateral mastectomy with or without ovariohysterectomy. Further evaluation of combination therapies is needed in larger groups of dogs.     

Comparison of the postoperative analgesic effects of cimicoxib,buprenorphine and their combination in healthy dogs undergoing ovariohysterectomy

Objective

To determine the noninferior postoperative analgesic efficacy of cimicoxib compared to buprenorphine following elective ovariohysterectomy in healthy bitches.

A comparison of preoperative tramadol and morphine for the control of early postoperative pain in canine ovariohysterectomy

Objective To compare morphine with tramadol for the management of early postoperative pain following ovariohysterectomy after pyometra in dogs. Study design Prospective randomized blinded clinical trial. Animals Thirty female dogs, 2–14 years old. Methods Animals were randomly divided into two equal groups. Group 1 received 0.2 mg kg^?1 of morphine IV and group 2 received 2 mg kg^?1 of tramadol IV after the induction of anesthesia. The dogs were premedicated with acepromazine, and anesthesia was induced with intravenous midazolam and ketamine. Isoflurane was used for the maintenance of anesthesia. The variables measured were: analgesia; sedation; cardiac and respiratory rates; arterial blood pressure; end‐tidal isoflurane and carbon dioxide (Pe ′CO₂); oxyhemoglobin saturation (SpO₂); plasma catecholamines; serum cortisol and glucose concentrations; pH and blood gases. The animals were monitored for 6 hours after the administration of the analgesic agent. Results There were no differences between the two groups with regard to analgesia, sedation, SpO₂, pH and blood gases, cardiovascular variables, glucose, catecholamine and cortisol concentrations. Forty minutes postopioid administration, the end‐tidal isoflurane concentration was significantly lower in the morphine‐treated group as compared to the tramadol group. At 30 minutes following opioid injection, Pe ′CO₂ was significantly higher in the morphine group than in the tramadol group. Two dogs in the tramadol group and one in the morphine group were given morphine postoperatively because of increasing pain scores. Conclusion and clinical relevance Morphine and tramadol, administered preemptively can be used safely in dogs to control early pain after ovariohysterectomy without significant adverse effects.     

Evaluation of analgesic,sympathetic and motor effects of 1% and 2% lidocaine administered epidurally in dogs undergoing ovariohysterectomy

ObjectiveTo compare, versus a control, the sensory, sympathetic and motor blockade of lidocaine 1% and 2% administered epidurally in bitches undergoing ovariohysterectomy.Study designRandomized, blinded, controlled clinical trial.AnimalsA total of 24 mixed-breed intact female dogs.MethodsAll dogs were administered dexmedetomidine, tramadol and meloxicam prior to general anesthesia with midazolam–propofol and isoflurane. Animals were randomly assigned for an epidural injection of lidocaine 1% (0.4 mL kg⁻¹; group L1), lidocaine 2% (0.4 mL kg⁻¹; group L2) or no injection (group CONTROL). Heart rate (HR), respiratory rate (f_R), end-tidal partial pressure of carbon dioxide (Pe′CO₂), and invasive systolic (SAP), mean (MAP) and diastolic (DAP) arterial pressures were recorded every 5 minutes. Increases in physiological variables were treated with fentanyl (3 μg kg⁻¹) intravenously (IV). Phenylephrine (1 μg kg⁻¹) was administered IV when MAP was <60 mmHg. Postoperative pain [Glasgow Composite Pain Score – Short Form (GCPS–SF)] and return of normal ambulation were recorded at 1, 2, 3, 4 and 6 hours after extubation.ResultsThere were no differences over time or among groups for HR, f_R, Pe′CO₂ and SAP. MAP and DAP were lower in epidural groups than in CONTROL (p = 0.0146 and 0.0047, respectively). There was no difference in the use of phenylephrine boluses. More fentanyl was administered in CONTROL than in L1 and L2 (p = 0.011). GCPS–SF was lower for L2 than for CONTROL, and lower in L1 than in both other groups (p = 0.001). Time to ambulation was 2 (1–2) hours in L1 and 3 (2–4) hours in L2 (p = 0.004).Conclusions and clinical relevanceEpidural administration of lidocaine (0.4 mL kg⁻¹) reduced fentanyl requirements and lowered MAP and DAP. Time to ambulation decreased and postoperative pain scores were improved by use of 1% lidocaine compared with 2% lidocaine.     

Sedative and analgesic effects of intravenous xylazine and tramadol on horses

This study was performed to evaluate the sedative and analgesic effects of xylazine (X) and tramadol (T) intravenously (IV) administered to horses. Six thoroughbred saddle horses each received X (1.0 mg/kg), T (2.0 mg/kg), and a combination of XT (1.0 and 2.0 mg/kg, respectively) IV. Heart rate (HR), respiratory rate (RR), rectal temperature (RT), indirect arterial pressure (IAP), capillary refill time (CRT), sedation, and analgesia (using electrical stimulation and pinprick) were measured before and after drug administration. HR and RR significantly decreased from basal values with X and XT treatments, and significantly increased with T treatment (p < 0.05). RT and IAP also significantly increased with T treatment (p < 0.05). CRT did not change significantly with any treatments. The onset of sedation and analgesia were approximately 5 min after both X and XT treatments; however, the XT combination produced a longer duration of sedation and analgesia than X alone. Two horses in the XT treatment group displayed excited transient behavior within 5 min of drug administration. The results suggest that the XT combination is useful for sedation and analgesia in horses. However, careful monitoring for excited behavior shortly after administration is recommended.     

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.     

Influence of tramadol on acute thermal and mechanical cutaneous nociception in dogs

Objective

The aim of the study was to evaluate the influence of tramadol on acute nociception in dogs.

Effects of tramadol on the minimum alveolar concentration of sevoflurane in dogs

ObjectiveTo evaluate the effect of tramadol on sevoflurane minimum alveolar concentration (MAC_SEVO) in dogs. It was hypothesized that tramadol would dose-dependently decrease MAC_SEVO.Study designRandomized crossover experimental study.AnimalsSix healthy, adult female mixed-breed dogs (24.2 ± 2.6 kg).MethodsEach dog was studied on two occasions with a 7-day washout period. Anesthesia was induced using sevoflurane delivered via a mask. Baseline MAC (MAC_B) was determined starting 45 minutes after tracheal intubation. A noxious stimulus (50 V, 50 Hz, 10 ms) was applied subcutaneously over the mid-humeral area. If purposeful movement occurred, the end-tidal sevoflurane was increased by 0.1%; otherwise, it was decreased by 0.1%, and the stimulus was re-applied after a 20-minute equilibration. After MAC_B determination, dogs randomly received a tramadol loading dose of either 1.5 mg kg^?1 followed by a continuous rate infusion (CRI) of 1.3 mg kg^?1 hour^?1 (T1) or 3 mg kg^?1 followed by a 2.6 mg kg^?1 hour^?1 CRI (T2). Post-treatment MAC determination (MAC_T) began 45 minutes after starting the CRI. Data were analyzed using a mixed model anova to determine the effect of treatment on percentage change in baseline MAC_SEVO (p < 0.05).ResultsThe MAC_B values were 1.80 ± 0.3 and 1.75 ± 0.2 for T1 and T2, respectively, and did not differ significantly. MAC_T decreased by 26 ± 8% for T1 and 36 ± 12% for T2. However, there was no statistically significant difference in the decrease between the two treatments.Conclusion and clinical relevanceTramadol significantly reduced MAC_SEVO but this was not dose dependent at the doses studied.     

Pharmacokinetics and bioavailability of carbetocin after intravenous and intramuscular administration in cows and gilts

The pharmacokinetics of carbetocin, which is used to control postpartum hemorrhage after giving birth, was studied in cows and gilts after a single intravenous (IV) or intramuscular (IM) injection. Blood samples from animals were assessed by oxytocin radioimmunoassay, and then the pharmacokinetic parameters were calculated using a noncompartmental model. For gilts, there was no significant difference between half-life (T_1/2λZ), mean residue time (MRT), and maximum concentration (C_max) between IM and IV administration. Conversely, the time to reach the C_max (T_max) and MRT were higher following administration of 350 μg/animal in cows via the IM administration compared with IV. The longest T_1/2λZ was 0.85 hr, indicating carbetocin was absorbed and eliminated rapidly in both animal species after administration. The T_max was similar between cows and gilts following IM administration. Moreover, the C_max after IM injection was about half that of IV administration in both animals. The bioavailability was more than 80% in cows, suggesting administration via the IM route is efficient. This is in agreement with the longer T_1/2λZ in cows after IM administration. However, the IV route is recommended for gilts due to a lower bioavailability (35%) and shorter T_1/2λZ after IM administration compared with IV.