Characterisation of tramadol,morphine and tapentadol in an acute pain model in Beagle dogs

ObjectiveTo evaluate the analgesic potential of the centrally acting analgesics tramadol, morphine and the novel analgesic tapentadol in a pre-clinical research model of acute nociceptive pain, the tail-flick model in dogs.Study designProspective part-randomized pre-clinical research trial.AnimalsFifteen male Beagle dogs (HsdCpb:DOBE), aged 12–15 months.MethodsOn different occasions separated by at least 1 week, dogs received intravenous (IV) administrations of tramadol (6.81, 10.0 mg kg^?1), tapentadol (2.15, 4.64, 6.81 mg kg^?1) or morphine (0.464, 0.681, 1.0 mg kg^?1) with subsequent measurement of tail withdrawal latencies from a thermal stimulus (for each treatment n = 5). Blood samples were collected immediately after the pharmacodynamic measurements of tramadol to determine pharmacokinetics and the active metabolite O-demethyltramadol (M1).ResultsTapentadol and morphine induced dose-dependent antinociception with ED50-values of 4.3 mg kg^?1 and 0.71 mg kg^?1, respectively. In contrast, tramadol did not induce antinociception at any dose tested. Measurements of the serum levels of tramadol and the M1 metabolite revealed only marginal amounts of the M1 metabolite, which explains the absence of the antinociptive effect of tramadol in this experimental pain model in dogs.Conclusions and clinical relevanceDifferent breeds of dogs might not or only poorly respond to treatment with tramadol due to low metabolism of the drug. Tapentadol and morphine which act directly on μ-opioid receptors without the need for metabolic activation are demonstrated to induce potent antinociception in the experimental model used and should also provide a reliable pain management in the clinical situation. The non-opioid mechanisms of tramadol do not provide antinociception in this experimental setting. This contrasts to many clinical situations described in the literature, where tramadol appears to provide useful analgesia in dogs for post-operative pain relief and in more chronically pain states.     

Intra‐articular opioid analgesia is effective in reducing pain and inflammation in an equine LPS induced synovitis model

Reasons for performing study: Intra‐articular administration of morphine as a local analgesic and anti‐inflammatory drug is widely used in human medicine. In equids, little is known about its clinical analgesic and anti‐inflammatory efficacy. Objectives: To use an inflammatory orthopaedic pain model to investigate the analgesic and anti‐inflammatory effects of intra‐articularly administered morphine as a new treatment modality in horses with acute arthritis. Methods: In a crossover study design, synovitis was induced in the left or right talocrural joint by means of intra‐articular injection of 0.5 ng lipopolyssacharide (LPS). The effect of 120 mg morphine, intra‐articularly administered at 1 h after induction of synovitis, was evaluated using both physiological and behavioural pain variables. Synovial fluid was sampled at 0, 4, 8, 28 and 52 h after induction of synovitis and analysed for total protein concentration, leucocyte count and for prostaglandin E₂, bradykinin and substance P concentrations by ELISA. Ranges of motion of metatarsophalangeal and talocrural joints were measured as kinematic variables with the horses walking and trotting on a treadmill under sound and lame conditions. Clinical lameness scores and several behavioural variables related to the perception of pain were obtained. Results: LPS injection caused marked transient synovitis, resulting in increased concentrations of inflammatory synovial fluid markers, clinical lameness, joint effusion and several behavioural changes, such as increased time spent recumbent, decreased limb loading at rest and decreased time spent eating silage. Intra‐articular morphine resulted in a significant decrease in synovial white blood cell count, prostaglandin E₂ and bradykinin levels and improvement in clinical lameness, kinematic and behavioural parameters, compared to placebo treatment. Conclusions: Intra‐articular morphine offers potent analgesic and anti‐inflammatory effects in horses suffering from acute synovitis. Potential relevance: Local administration of opioids may be useful for horses with acute inflammatory joint pain and offers possibilities for multimodal analgesic therapies without opioid‐related systemic side effects.     

吗啡对不同来源KM小鼠的镇痛、耐受和身体依赖性的比较

用吗啡对A、B、C3家实验动物繁育生产专业单位KM小鼠进行镇痛、耐受性和身体依赖性的比较实验。结果显示,A、B、C3家单位KM小鼠的利用率分别为70%、77%和81%,吗啡热板法镇痛ED50分别为3.611mg/kg、3.635mg/kg和5.096mg/kg,A单位KM小鼠吗啡镇痛起效最快,作用维持时间最长,C单位KM小鼠镇痛作用最弱。吗啡的耐受性实验结果表明,3家单位的KM小鼠之间没有差异,但是吗啡的身体依赖性实验结果表明,B、C单位KM小鼠与A单位小鼠之间有显著性差异(p<0.01)。结果提示,用吗啡对KM小鼠进行镇痛实验时,必须使用同一来源的动物,此外,加速我国KM小鼠的标准化研究迫在眉睫。     

Analgesic efficacy of intra‐articular morphine in experimentally induced radiocarpal synovitis in horses

ObjectiveTo compare the analgesic effect of intra-articular (IA) and intravenous (IV) morphine in horses with experimentally induced synovitis.AnimalsEight adult horses.Study designRandomized, observer blinded, double dummy trial with sequential crossover design.MethodsRadiocarpal synovitis was induced by IA injection of lipopolysaccharide on two occasions separated by a 3-week washout period. In one study period horses received treatment IA; morphine IA (0.05 mg kg^?1) plus saline IV and in the other study period they received treatment IV; saline IA plus morphine IV (0.05 mg kg^?1). Lameness and pain were evaluated repeatedly by two observers throughout each of the two 168-hour study periods. Pain was evaluated by use of a visual analogue scale of pain intensity (VAS) and a composite measure pain scale (CMPS). Comparison of treatments was performed by analysis of variance with repeated measurements. Significance level was set to p ≤ 0.05. Inter-observer agreement and agreement between the VAS and CMPS was assessed by use of the Bland–Altman method.ResultsIntra-articular injection of LPS elicited a marked synovitis resulting in lameness and pain. IA morphine resulted in significantly less lameness than IV morphine (p = 0.03). CMPS (p = 0.09) and VAS (p = 0.10) pain scores did not differ significantly between treatments. Inter-observer agreement of the CMPS was classified as good, but only fair for the VAS. Agreement between the two pain scales was considered fair.Conclusions and clinical relevanceAn analgesic effect of IA morphine was demonstrated by significantly reduced lameness scores. The results support the common practice of including IA morphine in a multimodal analgesic protocol after arthroscopic surgery, although further studies in clinical cases are needed. The employed CMPS had good reproducibility, and was easy to use, but may have limited sensitivity at mild intensity pain.     

Effect of metoclopramide on nausea and emesis in dogs premedicated with morphine and dexmedetomidine

Objective

To evaluate whether subcutaneous (SC) metoclopramide (0.2 mg kg^?1) administered 30 minutes prior to (T30) or simultaneously with (T0) intramuscular (IM) morphine (0.2 mg kg^?1) and dexmedetomidine (0.003 mg kg^?1) reduces the incidence of nausea and emesis in healthy dogs.

A comparison of epidural analgesia provided by bupivacaine alone,bupivacaine + morphine,or bupivacaine + dexmedetomidine for pelvic orthopedic surgery in dogs

ObjectiveTo compare the analgesic efficacy of bupivacaine, bupivacaine + morphine, or bupivacaine + dexmedetomidine administered epidurally in dogs undergoing pelvic limb orthopedic surgery.Study designProspective, randomized, double blinded clinical trial.AnimalsSixty dogs weighing (mean ± SD) 35 ± 15.7 kg, aged 5 ± 3 years.MethodsDogs were assigned to receive a lumbosacral epidural containing bupivacaine (B) 0.5%, 1 mg kg^?1; B, bupivacaine 0.5%, 1 mg kg^?1 + morphine 1%, 0.1 mg kg^?1; B + M, or bupivacaine 0.5%, 1 mg kg^?1 + dexmedetomidine 0.05%, 4 μg kg^?1; B + D. The anesthetic protocol was standardized. The median expired isoflurane concentration (E′Iso) and requirement for additional induction agent preventing purposeful movement were recorded. Pain was scored using visual analog (VAS) and modified University of Melbourne (UMPS) pain scales. Sedation was assessed using a 0–4 scale. All parameters were recorded preoperatively, and at extubation (t = 0), then at 1, 2, 4, 8, 12, 16, and 20–24 hours. Hydromorphone was administered postoperatively to patients with a VAS ≥ 35 and/or UMPS ≥ 9. Time to first voluntary urination and first motor activity were recorded.ResultsPostoperatively, B + D had a lower UMPS pain score than B at t = 1 hour (p = 0.013), but not compared to B + M. The B + D group had a shorter time to urination (p = 0.0131) and a longer time for return of motor function (p = 0.0068). There were no other differences between the treatments.Conclusion and clinical relevanceEpidurally administered B, B + M, or B + D in dogs all provided acceptable analgesia to manage post–operative orthopedic pelvic limb pain. Epidural administration of B + D is an effective alternative to the analgesia provided by B or B + M, but is associated with increased time to return of motor function. The direct neurotoxic effects of epidural dexmedetomidine have not been fully tested.     

Analgesic and gastrointestinal effects of epidural morphine in horses after laparoscopic cryptorchidectomy under general anesthesia

ObjectiveTo evaluate the hypothesis that epidural morphine (0.1 mg kg^?1) decreases pain in horses after laparoscopic surgery without adversely affecting gastrointestinal (GI) motility.Study designRandomized clinical trial.AnimalsEighteen horses undergoing laparoscopic cryptorchidectomy under general anesthesia.MethodsHorses were randomly assigned to receive either epidural morphine (0.1 mg kg^?1) or no epidural before the start of surgery. Pain behaviors were assessed during the first two post-operative days using a numerical rating scale. Barium-filled spheres were administered through a nasogastric tube before anesthesia. GI motility was assessed by recording manure production, by quantitating the spheres in the manure, and by abdominal auscultation of intestinal sounds. Heart rates and cortisol concentrations were also measured during the post-operative period.ResultsPain scores increased for 12 hours after surgery in the control group and were significantly higher than in the morphine group for the first 6 hours. Pain scores remained unaltered in the morphine group throughout the observation period. Heart rate and plasma cortisol concentrations did not differ between groups or with time. No signs of colic were observed in any horse.Conclusion and clinical relevanceEpidural morphine (0.1 mg kg^?1) did not adversely affect GI motility in horses after laparoscopic surgery under general anesthesia.     

Comparison of perioperative analgesic protocols for dogs undergoing tibial plateau leveling osteotomy

OBJECTIVE: To compare effects of 3 commonly used perioperative analgesic protocols (epidural injection, intra-articular injection, and intravenous [IV] injection) for management of postoperative pain in dogs after tibial plateau leveling osteotomy (TPLO). STUDY DESIGN: Prospective, randomized clinical trial. ANIMALS: Fifty-six healthy dogs with naturally occurring cranial cruciate ligament rupture. METHODS: Dogs were premedicated with IV hydromorphone and acepromazine and were randomly assigned to receive either E (preoperative epidural injection with morphine and bupivacaine), IA (pre- and postoperative intra-articular injections of bupivacaine), or C (neither epidural morphine and bupivacaine, nor intra-articular bupivacaine). All dogs were administered hydromorphone (0.05 mg/kg IV) at extubation and as needed to maintain comfort postoperatively. Patients were observed and monitored continuously for 24 hours and discomfort was assessed using visual analog pain scores (VASs), multifactorial pain scores (MPSs), and response to a pressure nociceptive threshold (PNT) measuring device. Time to 1st dose and the total doses of hydromorphone required to achieve adequate comfort for each dog were recorded. RESULTS: No differences in measured indices of postoperative pain were observed between dogs of each treatment group; VAS (P=.190), MPS (P=.371), and PNT (P=.160). Time to 1st analgesic intervention was longer for Group E compared with Group C (P=.005) and longer for Group IA compared with Group C (P=.032). Although time to 1st intervention between Groups E and IA were longer for Group E, differences were not significant. To provide an adequate level of comfort, more analgesic interventions were administered to dogs in Group C compared with dogs in group E (P=.015). On average, more hydromorphone was administered to Group C compared with Group IA (P=.072) and to Group IA compared with Group E (P=.168), but statistical significance was not reached for these data. CONCLUSIONS: In this study population, significant differences were seen in time to 1st hydromorphone dose between Groups E and IA compared with Group C. As well, more supplemental analgesia was administered to Group C compared with Group E to maintain the same level of postoperative comfort. Although differences between Groups E and IA tended to favor the epidural group, differences were minimal and not statistically significant. CLINICAL RELEVANCE: Our results suggest that regardless of analgesic protocol, measured indices of pain in dogs after TPLO can be minimized if dogs are continuously observed and appropriately supplemented with parenteral opioids. However, the frequency of postoperative opioid dosing can be minimized and may be a factor when contemplating supplementary use of epidural or intra-articular injections as part of a balanced analgesic approach.     

The effect of neuraxial morphine on postoperative pain in dogs after extrahepatic portosystemic shunt attenuation

ObjectiveTo investigate the analgesic effect of epidural morphine after surgical extrahepatic portosystemic shunt (EHPSS) attenuation.Study designRandomized clinical trial.AnimalsA total of 20 dogs with a congenital EHPSS.MethodsDogs were randomly allocated to be given either a single epidural dose of 0.2 mg kg^–1 preservative-free morphine (group M) or not (group C) before surgery. All dogs were administered 0.3 mg kg^–1 methadone intravenously (IV) as preanaesthetic medication. Pain scores were determined every 2 hours for the first 24 hours postoperatively using the short-form Glasgow Composite Measure Pain Scale (GCMPS-SF). Dogs with a GCMPS-SF pain score >4/20 or >5/24 received 0.1 mg kg^–1 methadone IV as rescue analgesia and were reassessed 30 minutes later. If more than three doses of methadone were administered in a 2 hour period, alternative pain relief was provided and a treatment failure recorded. The GCMPS-SF pain scores and number of rescue analgesia injections were analysed over 24 hours. The last observation carried forward method was applied in case of treatment failure. Food consumption and time to first urination were recorded. Data were analysed using a Mann–Whitney U test and presented as median (minimum–maximum range), with significance set at p < 0.05.ResultsGroup M showed lower GCMPS-SF pain scores [15 (11–41) versus 31 (11–86); p = 0.023] and lower postoperative methadone requirements [0 (0–0.2) versus 0.25 (0–0.5) mg kg^–1; p = 0.029] than group C. There were three treatment failures in group C only. Food consumption and time to first urination did not differ between groups.Conclusions and clinical relevanceEpidural morphine reduced the requirement for postoperative analgesia in this study population.