Evaluation of opioid receptors in synovial membranes of horses

OBJECTIVE: To evaluate mu-opioid receptors in synovial membranes of horses and determine whether these receptors are up-regulated in nerve endings during inflammation. SAMPLE POPULATION: Synovial tissue obtained from 39 client-owned horses during arthroscopy and 14 research horses during necropsy; brain and synovial tissues were obtained during necropsy from 1 horse, and control tissues were obtained from a mouse. PROCEDURE: Horses were classified into 7 groups on the basis of histologically determined degree of inflammation. Binding of primary rabbit antibody developed against mu-opioid receptors in equine synovial tissue was studied, using western blot analysis. Synovial membranes were tested for mu-opioid receptors by immunohistochemical staining, using a diaminobenzidine-cobalt chloride chromogen. Homogenates of synovial membranes were evaluated by use of radioligand binding. RESULTS: Examination of western blots of equine thalamus revealed that rabbit antibody developed against mu-opioid receptors yielded a band (molecular weight, 55 kd) that corresponded with that of other opioid receptors. Use of immunohistochemical staining of synovial tissue revealed considerable staining in the proliferative lining layer and in regions surrounding vascular structures. Specific radioligand binding of tissue homogenates was found in all groups. We did not detect significant differences in binding between horses with inflammation and horses without inflammation. CONCLUSIONS AND CLINICAL RELEVANCE: Results of immunohistochemical analysis and radioligand binding of tissue homogenates suggest that there are opioid receptors in synovial membranes of horses. Our results support the practice of intra-articular administration of opioids to relieve pain after arthroscopic surgery in horses.     

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.     

Epidural anesthesia and analgesia in horses.

Intercoccygeal, or caudal, epidural injection of local anesthetics is a convenient method of producing analgesia and local anesthesia of the tail and perineal structures in conscious standing horses. This technique has been further developed to provide long duration analgesia and anesthesia by placement of catheters into the epidural space of horses. More recently, opioid, alpha-2 adrenergic agonists, ketamine and other analgesic agents have been administered by caudal epidural injection, providing pain relief in both conscious, standing and anesthetized, recumbent horses. This chapter describes the development of different anesthetic and analgesic epidural techniques in horses, methods for epidural injection and catheterization, and reviews the current literature related to epidural analgesia and pain control in horses.     

A comparison of the effects of local analgesic solution in the navicular bursa of horses with lameness caused by solar toe or solar heel pain

We hypothesised that analgesia of the navicular bursa is not selective for the navicular apparatus; and that solar pain in some horses can be temporarily abolished or attenuated by analgesia of the navicular bursa. To test this hypothesis, we caused lameness in horses by inducing pain in the dorsal margin or the angles of the sole and then evaluated the ability of a local analgesic solution administered into the navicular bursa to attenuate lameness. The response of horses with solar pain in the dorsal or palmar aspect of the foot to 3.5 ml local analgesic solution administered into the navicular bursa was examined. Lameness was induced in 6 horses by creating solar pain in the dorsal aspect of one forefoot and, at another time, the palmar aspect of the other forefoot, with set-screws inserted into a custom-made shoe. Horses were videotaped trotting before and after application of set-screws and after administering 3.5 ml local analgesic solution into the navicular bursa. Lameness scores were assigned by examining videotaped gaits. Scores were significantly lower (P<0.05) for all horses with set-screws applied to the dorsal margin of the sole after administration of local analgesic solution into the navicular bursa. In conclusion, analgesia of the navicular bursa was less effective in desensitising the angles of the sole than in desensitising the dorsal margin of the sole. Pain arising from the sole should not be excluded as a cause of lameness when lameness is attenuated by analgesia of the navicular bursa.     

Ileal impaction in 245 horses: 1995-2007

The objective of this study was to identify parameters that would assist in determining the probability of a successful outcome with medical management versus surgical intervention in horses with ileal impaction. Medical records of 245 horses admitted for ileal impaction were reviewed and placed into 2 groups: medical (med) and surgical (sx) treatment. Persistence of abdominal pain, gastric reflux, frequency of analgesic administration, and 1-year survival were evaluated. There were no differences in signalment, abdominal pain, or heart rate among groups; however, significantly more sx horses had peritoneal fluid abnormalities (51%) and produced gastric reflux (62%) than did med horses (38% and 15%, respectively). Eighty-nine percent of med horses required repeated analgesic administration for successful resolution. One-year survival was 91% for sx horses and 92% for med horses. Horses with ileal impaction responsive to analgesic therapy with minimal gastric reflux are likely to be managed successfully with medical treatment. Horses with persistent abdominal pain and gastric reflux are candidates for surgery.     

Opioid dysphoria in three dogs

Objective: To describe the clinical manifestations and response to management of opioid dysphoria in 3 dogs. Case summary: Three dogs being managed for post‐operative pain were evaluated. All 3 dogs had been managed with various opioids including morphine, hydromorphone, and fentanyl following the surgical procedure. The 3 dogs exhibited vocalization that did not respond to interaction and did not change with administration of analgesic and anxiolytic agents. The dogs were treated with naloxone and, within 5 minutes of its administration, ceased vocalizing, and became aware and interactive with their environment. Further pain management consisted of non‐steroidal anti‐inflammatory medications, alpha‐2 (α₂) receptor agonists or the partial μ‐receptor opioid agonist, buprenorphine. New and unique information provided: Vocalization and lack of response to interaction with humans are clinical signs which can be seen in dogs with opioid dysphoria, and generally are not responsive to analgesics or sedation. Reversal with naloxone results in rapid resolution of vocalization and opioid‐induced dysphoria.     

A comparison of the effects of two volumes of local analgesic solution in the distal interphalangeal joint of horses with lameness caused by solar toe or solar heel pain

The response of horses, with solar pain in the dorsal or palmar aspect of the foot, to 6 or 10 ml local analgesic solution administered into the distal interphalangeal (DIP) joint was examined. Lameness was induced in 7 horses by creating solar pain in the dorsal aspect of one forefoot and, at another time, the palmar aspect of the other forefoot with set-screws inserted into a custom-made shoe. Horses were videotaped trotting before and after application of set-screws and, in separate trials, after 6 or 10 ml local analgesic solution was administered into the DIP joint. Lameness scores were assigned by examining videotaped gaits. Scores were significantly lower (P < 0.05) for horses with set-screws applied to the angles of the sole and receiving 10 ml, but not 6 ml, local analgesic solution into the DIP joint. Scores were significantly lower (P < 0.05) for all horses with set-screws in the dorsal margin of the sole receiving either volume of local analgesic solution. Analgesia of the DIP joint was less effective in desensitising the angles of the sole than in desensitising the dorsal margin of the sole, and 10 ml local analgesic solution was more effective than 6 ml in desensitising these regions. The response of horses with solar pain to local analgesic solution in the DIP joint was influenced by the volume administered and the region of sole affected.     

Lack of local anaesthetic efficacy of fentanyl in the abaxial sesamoid block model

Fentanyl and other opioid drugs have their effect in the central nervous system; however, activity at peripheral sites has also been demonstrated. Pain-suppression activity at peripheral sites raises the possibility of skilled individuals producing local anaesthetic effects with small doses of opioid drugs that would be difficult to detect forensically and could be used to affect the outcome of a race. Therefore, the local pain-suppression effect (peripheral nerve inhibition) of fentanyl was tested using an abaxial sesamoid block/hoof withdrawal model. With this model, fentanyl did not produce significant anaesthesia when tested in eight Thoroughbred horses. This suggests that fentanyl at this or lower doses is unlikely to reduce pain perception when applied directly to sensory neurons. However, the effect of fentanyl and other opioids on joint pain perception of horses, especially inflamed joints, is unknown.     

Analgesia.

Critical to reducing patient morbidity as well as heightened ethical awareness, alleviation of pain in animals has become integral to medical case management and surgical procedures. Pharmacotherapy is directed at peripheral nociceptors, primary and secondary spinal neurons, and pain-processing areas in the CNS. Accordingly, three primary pharmacologic strategies have evolved: drugs that bind to and activate opioid receptors, drugs that bind to and activate alpha 2 receptors, and drugs that reduce de novo prostaglandin synthesis. In horses, the two predominant types of pain encountered are musculoskeletal and visceral pain. Several factors must be considered when devising a therapeutic strategy, including the etiology of the painful event, desired duration of therapy (acute vs chronic), desire for sedation, and potential side effects and toxicity. Opioids and alpha 2 agonists are particularly effective for visceral pain associated with colic. Butorphanol remains the only commercially available opioid and provides superior visceral analgesia compared with pentazocine or flunixin meglumine but not compared with the alpha 2 agonists. The behavioral changes such the sedative effects of alpha 2 agonists and the increased locomotion and CNS excitability seen with some opioids are important considerations when these agents are used as analgesics. NSAIDs may be considered for visceral pain therapy also, especially pain associated with an inflammatory component or endotoxemia. In particular, flunixin meglumine and ketoprofen provide prolonged analgesia and suppress the effects of endotoxin. Long-term therapy of musculoskeletal diseases usually necessitates chronic NSAID use. Although many NSAIDs are now available in approved equine formulations, there remain some important differences among NSAIDs for the practitioner to consider when choosing an analgesic. NSAIDs differ in their ability to ameliorate pyrexia, affect platelet function, alleviate pain, and reduce inflammation. For ease of administration, those available for oral use include phenylbutazone, meclofenamic acid, flunixin meglumine, and naproxen. All are potentially ulcerogenic, and poor tolerance to one may necessitate switching to another with a better toleration profile or to drug from a different analgesic class.     

Caeco-caecal and caeco-colic intussusception in two half-sibling Standardbred horses

This report describes caecal intussusception in two young half-sibling Standardbred horses. Both horses presented showing signs of low-grade abdominal pain. The horses remained haemodynamically stable despite signs of abdominal pain and associated tachycardia. Exploratory celiotomy was undertaken in both horses due to persistent abdominal pain and a poor response to administration of analgesic medications. Exploration of the abdomen revealed caeco-caecal intussusception in one horse and caeco-colic intussusception in the other horse. An underlying cause for caecal dysfunction and subsequent intussusception was not identified in either patient. Manual reduction of the intussusception was successful in both cases. The horses recovered uneventfully from surgery.     

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.     

Pain management in cats--past, present and future. Part 2. Treatment of pain--clinical pharmacology

Opioids have an unjustified reputation for causing mania in cats, but with refinements in dosing they are now used successfully in this species. The mu-opioid agonists are generally considered the best analgesics. Morphine (0.1-0.3 mg/kg) is effective in a clinical setting. Methadone (up to 0.5 mg/kg) has a similar profile to morphine. Pethidine (Demerol, meperidine; 2-5 mg/kg) is a useful analgesic with a faster onset but shorter duration of action than morphine. Oxymorphone and hydromorphone (0.05-0.1 mg/kg) are widely used in the USA. These opioids are more potent (up to 10 times), and longer acting than morphine in cats. Butorphanol (0.1-0.4 mg/kg) is a mu-opioid antagonist that produces its analgesic actions through kappa agonist activity. It rapidly reaches a ceiling effect, is short acting and is a weaker analgesic than pure mu opioids. Buprenorphine (0.01-0.02 mg/kg), a partial mu-agonist, is the most popular opioid used in small animal practice in the UK, other parts of Europe, Australia and South Africa. In clinical studies it has produced better analgesia than several other opioids and appears to be highly suitable for perioperative pain management in cats. NSAIDs are also used in cats for pain management, although cats metabolise these differently from other species. With appropriate dosing, carprofen (1-4 mg/kg) and meloxicam (0.3 mg/kg) have proved highly effective with few side effects. The use of ketoprofen (2 mg/kg), tolfenamic acid (4 mg/kg) and vedaprofen (0.5 mg/kg) has been reported in cats. Other less traditional analgesics such as ketamine, medetomidine and local anaesthetics are also used for clinical pain management. The transmucosal, transdermal and epidural routes offer novel methods for administration of analgesic drugs and have considerable potential for improving techniques in feline pain management.     

Evaluation of electroacupuncture treatment of horses with signs of chronic thoracolumbar pain

OBJECTIVE: To evaluate use of electroacupuncture for treatment of horses with signs of chronic thoracolumbar pain. DESIGN: Prospective study. ANIMALS: 15 horses with signs of chronic thoracolumbar pain. PROCEDURE: Horses were randomly allocated to 1 of 3 treatment groups. Horses in group 1 received electroacupuncture stimulation (once every 3 days for 5 treatments), those in group 2 received phenylbutazone (2.2 mg/kg [1 mg/lb], PO, q 12 h, for 5 days), and those in group 3 received saline (0.9% NaCl) solution (20 mL, PO, q 12 h, for 5 days). Thoracolumbar pain scores (TPSs) were evaluated before (baseline) and after each treatment. RESULTS: Mean +/- SE TPSs in horses receiving phenylbutazone or saline solution did not change significantly during the study. After the third treatment, mean +/- SE TPS (2.1 +/- 0.6) in horses receiving electroacupuncture stimulation was significantly lower than baseline (6.0 +/- 0.6) TPS. Mean +/- SE TPSs in horses receiving electroacupuncture stimulation were significantly lower than baseline TPSs and TPSs in horses receiving phenylbutazone or saline solution after the third treatment to 14 days after the last treatment. CONCLUSIONS AND CLINICAL RELEVANCE: TPSs are useful for evaluating the efficacy of various analgesic methods used for treatment of thoracolumbar pain in horses. Electroacupuncture was effective for treatment of chronic thoracolumbar pain in horses. Results provided evidence that 3 sessions of electroacupuncture treatment can successfully alleviate signs of thoracolumbar pain in horses. The analgesic effect induced by electroacupuncture can last at least 2 weeks. Phenylbutazone administered PO did not effectively alleviate signs of thoracolumbar pain in horses in this study.     

The use of analgesic drugs by South African veterinarians

According to a survey, non-steroidal anti-inflammatory agents were the most popular analgesic used in South Africa for management of peri-operative pain, acute post-operative pain and chronic pain. The most popular non-steroidal anti-inflammatory agents are flunixin meglumine and phenylbutazone. The most popular opioid type drug is buprenorphine, followed by morphine. In the peri-operative setting, analgesic agents were not actively administered to 86.3% of cats and 80.7% of dogs. Analgesic premedications were frequently administered, e.g. xylazine or ketamine, but no specific drug was administered for post-operative pain. Veterinarians need to critically review their anaesthetic and analgesic practices in order to achieve balanced anaesthesia.     

Pharmacokinetics of the opioid antagonist N-methylnaltrexone and evaluation of its effects on gastrointestinal tract function in horses treated or not treated with morphine

OBJECTIVE: To determine the pharmacokinetics and effects of the morphine antagonist N-methylnaltrexone (MNTX) on gastrointestinal tract function in horses when administered alone and in combination with morphine. ANIMALS: 5 healthy adult horses. PROCEDURES: Horses were treated with MNTX (1 mg/kg, IV), and serial blood samples were collected for determination of drug pharmacokinetics. For evaluation of effects on the gastrointestinal tract when administered alone, MNTX was administered at a dosage of 0.75 mg/kg, IV, twice daily for 4 days. For evaluation of effects when administered concurrently with morphine, MNTX (0.75 mg/kg, IV, q 12 hours) and morphine (0.5 mg/kg, IV, q 12 hours) were administered for 6 days. Gastrointestinal variables evaluated were defecation frequency, weight of feces produced, fecal moisture content, intestinal transit time, and borborygmus scores. RESULTS: The time-concentration data for MNTX disposition best fit a 2-compartment model with a steady-state volume of distribution of 244.6 +/- 21.8 mL/kg, t1/2 of 47.04 +/- 11.65 minutes, and clearance of 11.43 +/- 1.06 mL/min/kg. Adverse effects were not observed at doses 相似文献   

Pharmacokinetics of Tramadol after Epidural Administration in Horses

Tramadol is a centrally acting analgesic structurally related to codeine and morphine. The aim of the present study was to evaluate the pharmacokinetic of tramadol and its major metabolites after caudal epidural administration in the horse. Six gelding male adult horses were assigned to receive epidural administration of tramadol at 2 mg/kg. Plasma substances detection was achieved using a HPLC-FL method. Tramadol was detectable after 5 minutes up to 8 hours after epidural administration. Metabolites plasma concentrations were found under the limit of quantification of the method; however negligible amounts of M2 was detected from 30 min up to 1 hour in three subjects. In conclusion, this study shows that tramadol administered by caudal route in horses produces plasma concentrations within the extrapolated therapeutic range from humans for sufficient time to provide analgesia. Further study of the drug's safety and efficacy for the treatment of pain in horses is warranted.     

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 fentanyl following intravenous and transdermal administration in horses

REASONS FOR PERFORMING STUDY: Although fentanyl has been reported to cause CNS excitation in horses, a transdermal therapeutic system (TTS) containing this mu agonist has recently been used empirically in equine medicine to treat moderate to severe pain. A better understanding of the disposition of fentanyl following transdermal administration would facilitate the clinical use of TTS fentanyl to obtain analgesia in horses. OBJECTIVES: To determine the pharmacokinetics of fentanyl following i.v. and TTS patch administration in healthy, mature horses and to evaluate the tolerance of horses to TTS fentanyl administration. METHODS: The pharmacokinetics of fentanyl in serum were assessed following a single i.v. dose, a single TTS dose, and multiple TTS doses in 6 healthy horses. Physical examinations, haematology and serum biochemistry analyses during transdermal fentanyl application were then performed to determine tolerance of continuous fentanyl administration. RESULTS: Fentanyl was very rapidly and completely absorbed following a single TTS dose. Mean serum fentanyl concentrations consistent with analgesia in other species were reached by 1 h and maintained until 32 h after patch application. Similar steady state serum concentrations were obtained when multiple doses of TTS fentanyl were administered every 48 or 72 h over 8 or 9 days, with less fluctuation in serum concentrations during the 48 h dosing interval. Three horses exhibited brief (< 12 h) episodes of increased body temperature; however, transdermal fentanyl administrations were not associated with other significant changes in haematology and biochemistry panels or physical examination findings. CONCLUSIONS AND POTENTIAL RELEVANCE: Although the pharmacodynamics of fentanyl have not been investigated fully in horses, transdermally-administered fentanyl exhibited a favourable pharmacokinetic profile without clinically relevant side effects and may be a useful analgesic in equine patients.