Guidelines for safe and effective use of NSAIDs in dogs

NSAIDs are the most widely used analgesics in veterinary medicine, and all have some toxic potential. The most common adverse class effects are gastrointestinal, renal, hepatic, and coagulation disorders. When treating chronic pain associated with osteoarthritis, the effectiveness of NSAIDs can be enhanced by physical therapy, use of chondroprotective agents, certain adjunctive drugs, and diet and exercise to control weight. To treat acute perioperative pain, NSAIDs are more effective when used preemptively, in the context of balanced (multimodal) analgesia, and in well-hydrated patients with normal blood pressure and renal function. Screening and monitoring to identify high-risk candidates for NSAID treatment should include a physical examination and patient history, identification of preexisting diseases or conditions, obtaining baseline and periodic hematologic and clinical chemistry values, and ensuring that other NSAIDs or contraindicated drugs are not used concurrently. When switching a patient from one NSAID to another (when no side effects have been seen), a washout period of 5 to 7 days minimizes chances for adverse drug interactions. Informing clients of the potential adverse effects of NSAID therapy and signs of NSAID toxicity greatly increases the likelihood of safe use of this class of drugs.     

Assessment and management of acute pain in cats

Abstract: Cats are popular pets, but until recently, their peri-operative and traumatic pain had been seriously underestimated and under-treated. The lack of treatment stems from difficulty in recognizing pain, lack of licensed analgesic drugs, fear of toxic side effects, and lack of information specific to cats. Fortunately, in the last decade, many advances have been made in feline analgesia. It is now obvious that because of the cat's unique metabolism, species-specific studies are essential. Opioids are the mainstay of any analgesic protocol for acute pain and can be used with few side effects. Other drugs that can be utilized include the α₂-agonists, local anesthetics, and non-steroidal anti-inflammatory drugs. Pain assessment in cats is challenging and developing, and validating pain scoring systems remains an important goal. The information in this article will help the critical care and emergency clinician formulate a safe and effective analgesic plan for feline patients.     

Clinical pharmacology of nonsteroidal anti-inflammatory drugs in dogs

OBJECTIVES: To discuss the clinical pharmacology of currently licensed veterinary NSAIDs and to review gastrointestinal and renal adverse effects as well as drug-drug interactions that have been reported with these drugs. To review the use of NSAIDs in the peri-operative setting and their use in patients with osteoarthritis. To further review the reported effects of NSAIDs on canine articular cartilage and liver as well as the clinical relevance of a washout period. DATABASES USED: PubMed, CAB abstracts and Google Scholar using dog, dogs, nonsteroidal anti-inflammatory drugs and NSAID(s) as keywords. CONCLUSIONS: A good understanding of the mechanisms by which NSAIDs elicit their analgesic effect is essential in order to minimize adverse effects and drug-drug interactions. Cyclooxygenase (COX) is present in at least two active isoforms in the body and is the primary pharmacologic target of NSAIDs. Inhibition of COX is associated with the analgesic effects of NSAIDs. COX is present in the gastrointestinal tract and kidneys, along with other areas of the body, and is also the likely reason for many adverse effects including gastrointestinal and renal adverse effects. The newer veterinary approved NSAIDs have a lower frequency of gastrointestinal adverse effects in dogs compared to drugs such as aspirin, ketoprofen and flunixin, which may be due to differential effects on the COX isoforms. There are currently no published reports demonstrating that the newer NSAIDs are associated with fewer renal or hepatic adverse effects in dogs. NSAIDs remain the cornerstone of oral therapy for osteoarthritis unless contraindicated by intolerance, concurrent therapies or underlying medical conditions. NSAIDs are also effective and frequently used for the management of post-operative pain.     

Gastrointestinal perforation in five dogs associated with the administration of meloxicam

Objective: Five canine cases of gastrointestinal (GI) perforation and septic peritonitis associated with the routine use of meloxicam are reviewed. Series summary: Selective cyclooxygenase‐2 (COX‐2) non‐steroidal anti‐inflammatory drugs (NSAIDs) are being used more extensively and routinely for acute and chronic pain as well as for perioperative management of pain. These medications are safe and effective but can be associated with known GI and renal side effects. The patients in this case series had no significant concurrent illness, were not on any concurrent medication known to potentiate the ulcerogenic effects of NSAIDs, and in most cases did not display clinical signs that were apparent to the owners until the time of perforation. New or unique information provided: Despite the preferential selectivity for COX‐2, newer NSAIDs still carry the risk of GI performation. The incidence of GI perforation may be increased with inappropriate dosing regimens, with use of non‐veterinary products and in animals that are at high risk for toxicity. Early signs of toxicity may include alteration in appetite, and subtle signs of nausea during treatment. Warning owners to monitor their pet for vomiting, melena, and hematemesis may not be sufficient to avoid the potential disastrous consequences of GI ulceration.     

Toxicology of nonsteroidal antiinflammatory drugs

Nonsteroidal antiinflammatory drugs (NSAIDs) constitute a class of pharmacologically active agents with similar therapeutic actions and side effects, despite diverse chemical structures. NSAIDs inhibit the enzyme cyclo-oxygenase and, thus, decrease inflammation mediated by prostaglandins. Toxicoses due to NSAIDs are manifested primarily by gastrointestinal upset and hemorrhage and by renal damage. Management consists of detoxification measures, in addition to supportive and symptomatic care. The article outlines the incidence, clinical toxicity, mode of action, and pharmacokinetics of nonsteroidal antiinflammatory drugs. The toxic effects of NSAIDs on individual organ systems are described, and general management recommendations for the treatment of NSAID toxicoses are presented.     

The coxib NSAIDs: potential clinical and pharmacologic importance in veterinary medicine

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used to control acute and chronic pain as well as to manage oncologic and neurologic diseases in human and veterinary patients. Despite ongoing research and efforts to improve the safety and efficacy of existing drugs, adverse effects such as gastrointestinal irritation, renal and hepatic toxicity, interference with hemostasis, and reproductive problems persist. The true incidence of NSAID-induced adverse effects in animals is unknown, but is likely underestimated, because cats and dogs may be more sensitive than humans to NSAIDs due to alterations in drug metabolism, absorption, and enterohepatic recirculation. NSAIDs produce both analgesia and toxic adverse effects primarily by inhibiting cyclooxygenase (COX), thereby decreasing the production of prostaglandins that signal inflammation and pain as well as mediate physiologic functions such as platelet aggregation, gastric protection, and electrolyte balance in the kidney. The presence of at least 2 COX isoforms may account for variability in NSAID efficacy and toxicity both within and among species. This paper reviews and evaluates the published literature on the safety, pharmacology, uses, and complications of a subclass of COX-1-sparing drugs, the coxibs, in veterinary medicine. Coxibs and other COX-1-sparing drugs provide a clinically useful improvement over traditional NSAIDs, but data are incomplete and more in vivo species-specific, target-tissue, and clinical studies are needed.     

Sparing the gut: COX-2 inhibitors herald a new era for treatment of horses with surgical colic

Nonsteroidal anti-inflammatory drugs (NSAIDs) are commonly used to manage a wide variety of conditions in horses, including management of colic. Flunixin meglumine is by far the most commonly used drug in the control of colic pain and inflammation and has become a go-to for not only veterinarians but also horse-owners and nonmedical equine professionals. NSAID use, however, has always been controversial in critical cases due to a high risk of adverse effects associated with their potent cyclo-oxygenase (COX) inhibition. There are two important COX isoenzymes: COX-1 is generally beneficial for normal renal and gastrointestinal functions and COX-2 is associated with the pain and inflammation of disease. Newer selective NSAIDs can target COX-2-driven pathology while sparing important COX-1-driven physiology, which is of critical importance in horses with severe gastrointestinal disease. Emerging research suggests that firocoxib, a COX-2-selective NSAID labelled for use in horses, may be preferable for use in colic cases in spite of the decades-long dogma that flunixin saves lives.     

The future of antiinflammatory therapy.

The cells and mediators that make up the inflammatory response have the potential to injure tissues and contribute to the pathophysiology of many inflammatory diseases. Strategies to reduce neutrophil migration into sites of inflammation and subsequent activation by inhibiting integrin-mediated adhesion hold promise for successful treatment of a variety of inflammatory diseases. New pharmacologic agents that specifically target prostanoid mediators of inflammation by specifically inhibiting the activity of cyclooxygenase 2 are potent antiinflammatory agents with fewer gastrointestinal side effects than nonspecific cyclooxygenase inhibitors. These areas of antiinflammatory research are rapidly yielding drugs with diverse future applications in equine medicine.     

Cyclooxygenase (COX) inhibitors and the intestine

Nonsteroidal anti-inflammatory drugs (NSAIDs) have long been used for the treatment of pain and inflammation because of their inhibitory effects on cyclooxygenase (COX). For almost as long as NSAIDs have been in use, multiple adverse effects have been noted. Assessment of many of these adverse effects have been complicated because of the discovery of multiple splice variants of the cox gene, and a greater array of COX inhibitors, especially the COX-2 selective inhibitors have become available. Some of these adverse effects cannot be readily explained by the effect of these drugs on COX. This has sparked a new field of investigation into the COX-independent effects of the COX inhibitors. The major noncyclooxygenase targets of the COX inhibitors of particular relevance to inflammation and the gastrointestinal tract are phosphatidylinositol 3'-kinase Akt signaling, uncoupling of oxidative phosphorylation, PPARgamma, nuclear factor KB, mitogen activated protein kinases, and heat shock proteins.     

Drug therapy in cats: a systems approach

In the second part of this 4-part series, drug therapy in cats is discussed by use of a systems approach. Specifically, drugs that can be used safely for treatment of disorders affecting the feline gastrointestinal, central nervous, respiratory, cardiovascular, and urogenital systems are described. Many drugs that are used in dogs can be safely used in cats according to the same or similar dosing regimens. Several drugs that have traditionally been considered inappropriate (eg, morphine derivatives, primidone) can probably also be used, if cautiously, in cats. In contrast, use of several drugs that are safely used in other species should be avoided in cats (eg, selected emetics and antiemetics, phosphate salt enemas, and selected urinary antiseptics). Cats are more sensitive than dogs to the adverse side effects of a variety of drugs (eg, aspirin, digoxin, selected antiarrhythmics), and extra precautions must be taken when these drugs are used in cats. Finally, several drugs are used for the treatment of illnesses that tend to be unique to cats (eg, taurine and calcium-channel blockers in selected feline cardiovascular disorders).     

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.     

Effects of pharmacological agents on gastrointestinal motility

The control mechanisms of gastrointestinal motility are complex. Extrinsic neurohormonal effects modulate an intrinsic system, often called the "gut brain," composed of nervous and neuropeptide components. To exert pharmacologic influence on GI motility, use is made of agents that mimic the external control system. Agents that stimulate opioid receptors, block adrenoceptors, block or facilitate acetylcholine action, or antagonize the action of prostaglandins are used to effect changes in GI motility. The major indications for pharmacologic intervention are to increase motility in constipation, to reduce it in most cases of diarrhea, and to restore propulsive coordination in postoperative ileus. In cases of clinical colic the primary requirement is control of pain. Agents used for this purpose may adversely affect motility, and choice requires knowledge of their actions in this respect. In addition, drugs used for other purposes, anthelmintics for instance, may also influence gut motility. A synopsis of the actions of the agents commonly employed in GI motility control and some associated drugs are displayed in Table 3. Recent advances in the understanding of drug action on the gut should help in the selection of drugs for clinical use.     

A comparison of tepoxalin-buprenorphine combination and buprenorphine for postoperative analgesia in dogs: a clinical study

The present study compares the analgesic effect of a tepoxalin-buprenorphine combination to that of buprenorphine alone in the 24 h peri-operative period in 20 dogs undergoing cranial cruciate ligament repair, which were randomly assigned to the two treatment protocols (n = 10). Additionally, possible side effects induced by tepoxalin were investigated. Analgesia was compared using a visual analogue scale (VAS) and a multifactorial pain scale (MFPS), by an anaesthetist blinded from treatment. Analysis of the overall VAS-scores showed a significant decrease over time in both treatment groups. The decrease in the two groups was not significantly different from each other. No significant differences were found between the MFPS-scores of both protocols. Potential side effects of tepoxalin were investigated by venous blood sampling before premedication and 24 h after extubation, a buccal mucosal bleeding time test and recording of vomiting, diarrhoea and adverse effects at the surgical site. Analysis of the blood parameters showed that fibrinogen levels were overall higher 24 h after surgery in both protocols, but were significantly more elevated in the tepoxalin group. No significant differences were found for the other blood parameters. Statistically, tepoxalin failed to improve analgesia induced by buprenorphine. There was no convincing evidence that the administration of tepoxalin was not associated with gastrointestinal side effects. There were no significant adverse effects on renal function and primary haemostasis.     

Placebo-controlled blinded study of postoperative pain therapy with carprofen and levomethadone in dogs with fractures

It was the aim of this placebo-controlled study to evaluate the analgesic efficacy of the NASAID carprofen and the pure m-agonist levomthadone over a five-day postoperative evaluation period in dogs with fractures of the humerus or the femur (n = 30). Pain and sedation evaluation was carried out with a visual analogues system (VAS) and with the aid of a numerical estimation scale(NRS). The degree of lameness, the pain treshhold, the glucose and cortisol concentration curves as well as the respiration and heart rate and the systolic blood pressure were used as further pain indicators and to identify drug side effects. The levomethadon group displayed the lowest degree of pain on postoperative examination on the first day. On days 2 to 5, the carprofen group showed the lowest degree of pain in comparison to the placebo group. The levomethadon- and the carprofen group showed no statistically proven differences from day 2 on. Due to great variations in the pain scores and comparatively high median pain score especially on the first day of this study, the efficacy of all analgesics evaluated here must be regarded as insufficient in many cases. Only the parameter nociceptive pain treshhold showed a little, the degree of lameness, the glucose and cortisol levels showed no close correlation to the VAS and NRS pain scores and were therefore of little usefulness as postoperative pain indicators. No relevant clinical side effects caused by the used analgesics were detected in the kidney, the liver, the gastrointestinal tract and the circulatory system in this study. Rather, traumatically induced elevation of enzyme levels improves or normalised until the 5th day of the study. In addition, no negative effect on wound healing was noted, especially for carprofen. Therefore, the evaluated analgesics seems to be adequate for postoperative pain therapy also in fracture patients (trauma patients). However, the efficacy of all analgesics evaluated here must be regarded as insufficient in many cases.     

Opioid analgesics.

Opioids are useful and potent drugs for the management of pain in small animal patients. They have a wide therapeutic index and can be given by a number of different routes. Some of these techniques (e.g., epidural and intraarticular) allow for the production of profound analgesia in a localized area of the body while limiting the dose and the side effects, and others provide a noninvasive method for the delivery of continuous analgesia (e.g., transdermal administration).     

The pain-relieving effects of lactoferrin on oxaliplatin-induced neuropathic pain

Oxaliplatin (OXL) therapy often causes side effects including chronic peripheral neuropathy. We investigated the pain-relieving effects of recombinant human lactoferrin (rhLf) as well as a long-acting IgG-Fc fused rhLf (rhLf-Fc) on OXL-induced neuropathic pain. We used the hLf in this study, because the homology between mouse Lf and hLf is higher than that of bovine Lf. In addition, rhLf-Fc is expected to enhance the analgesic effect due to the life extension effect in the body. We administered OXL (2 mg/kg, i.v.) to mice twice weekly for 4 weeks. Phosphate buffered saline (PBS), rhLf (100 mg/kg, i.p.) or rhLf-Fc (100 mg/kg, i.p.) was administered once a week from day 15 to 32. We also assessed the continuous infusion of same drugs (10 mg/kg/day) into the external jugular vein by using an osmotic pump. Both of rhLf and rhLf-Fc significantly reduced the hypersensitivity to mechanical stimulation when they were administered intraperitoneally. The continuous infusion of rhLf resulted in a more pronounced effect. Histopathological analysis of sciatic nerve showed that both rhLf and rhLf-Fc tended to reduce nerve fiber damage, but no significant difference was observed in nerve fiber cross-sectional area. Therefore, it was suggested that rhLf or rhLf-Fc injection could be an option for controlling neuropathic pain, which are side effects of OXL.     

奶牛常用药物与循证用药

本文对近年来山东省临朐县奶牛场常用药物进行了统计分析,并结合临床实践经验,对奶牛养殖活动中常见的体温升高、疼痛、腹泻、休克、呼吸困难、胃肠迟缓、水肿等7大类症状的病因、治疗用药和注意事项,以及常见的"三炎"疾病的对因治疗进行了全面归纳,以期为广大奶牛养殖场户科学购置、使用药物,规范治疗提供参考.     

芩红乳房灌注液提取工艺研究

抗生素的药物残留和抗药性问题,正逐渐引起人民的关注,而中草药毒副作用较小,残留少,并且许多中草药还具有很好的免疫调节作用,因此被研究学者广泛关注。灌注剂,给药方式独特,局部用药起效更快,减少全身毒副作用,且对药物浪费比较少。芩红乳房灌注液主要用于治疗奶牛乳房炎,具有化瘀止痛、消肿通乳的功效。本研究通过正交试验,选择较适宜的溶媒、加水量、提取温度、提取时间、提取次数等,确定芩红乳房灌注液的最佳提取工艺,为芩红乳房灌注液的生产和临床应用奠定基础。     

Equine gastrointestinal motility--ileus and pharmacological modification

Colic is a common problem encountered in equine practice. Alteration of gastrointestinal motility is often the underlying cause for abdominal pain. Gastrointestinal motility can be measured as myoelectric activity, mechanical activity, and transit of intraluminal contents. Regulation of motility is based on a complex interaction between central innervation, autonomic innervation, and the enteric nervous system. Various humoral and neurochemical substances are required to interact flawlessly to allow propulsive motility. Ileus is defined as the absence of propulsive aboral movement of gastrointestinal contents, irrespective of its pathophysiology. Potential etiologies for ileus are described in this review. The prokinetic drugs available for clinical use are discussed. Choosing the appropriate prokinetic drug requires knowledge about the complex nature of gastrointestinal motility and its abnormalities.     

促胃肠动力药物研究现状

胃肠动力迟缓类疾病由于发病特征的不显著,在动物身上并未引起足够的重视,但随着近几年畜牧业的不断发展,其发病率不断升高,对国家已造成了不可估量的损失。从药物机制、临床研究等方面对比阐述了人用及兽用促胃肠动力药物的应用现状,旨在为兽用促胃肠动力药物的研发及兽医临床中的使用提供参考。