Rimadyl Inject Peri-Op TB - draft 7 11/7/2014 11:56 AM Page 1 TECHNICAL BULLETIN November 2014 Peri-Operative Use of Key Points ® Injectable Rimadyl • Since inflammation is a driving factor in the develop ment of surgical pain, the anti-inflammatory (carprofen) properties of Rimadyl® (carprofen) make this drug an important component of a post-operative pain management protocol. • Preemptive pain management, followed by appro- priate intra-operative and post-operative analgesia, Sharon L. Campbell, DVM, MS, DACVIM can circumvent central sensitization and prevent Randi Brannan, DVM, FAVD, DAVDC the onset of chronic, intractable pain. Dennis Caywood, DVM, MS, DACVS, CCRT • Rimadyl is the only NSAID developed in the US Dennis J. Chmiel Jr., DVM, MBA specifically for canine use and is available as oral David Martin, DVM, DACVAA caplet, chewable tablet, and sterile injectable (SC) Paul Q Mitchell, DVM, DAVDC formulations. All formulations have the same indications: – relief of pain and inflammation associated with osteoarthritis; Zoetis Inc. – control of post-operative pain associated 100 Campus Drive with soft tissue and orthopedic procedures. Florham Park, NJ 07932 • Rimadyl is the only injectable NSAID approved by the FDA for controlling post-operative pain in the dog that is supported by greater than 10 years of research. • Rimadyl Injectable can be administered at 4.4 mg/kg (2.0 mg/lb) SC before surgery as part of a balanced, multimodal anesthesia/analgesia protocol, providing 24 hours of analgesia. After surgery, patients can be easily transitioned to oral Rimadyl since no wash-out period is required between use of the injectable and oral Rimadyl. • Clinical and pharmacokinetic studies support the benefits of administering Rimadyl Injectable pre- operatively to control post-operative pain in dogs, as dogs that received Rimadyl prior to surgery had better immediate post-operative analgesia than dogs that received Rimadyl after surgery. • The mechanism of action that allows NSAIDs to provide effective analgesia may also be responsible for adverse reactions in some patients. Although adverse events associated with Rimadyl Injectable are rare, patient selection is essential to ensure favorable outcomes. In stable canine patients, the benefits of administering Rimadyl Injectable pre- operatively outweigh the risks and will provide up to 24 hours of analgesia. Rimadyl Inject Peri-Op TB - draft 7 11/7/2014 11:56 AM Page 2 INTRODUCTION AND RATIONALE Although extensive studies have not been conducted to evaluate consecutive use of The effects of non-steroidal anti-inflammatory different NSAIDs, a wash-out period is drugs (NSAIDs) are exerted through the recommended when changing from one inhibition of cyclooxygenase (COX) enzymes NSAID to another.2 By using Rimadyl and the subsequent synthesis of prosta - Injectable pre-operatively, followed by oral glandins. As key components of inflammation, Rimadyl post-operatively, continuous and prostaglandins contribute to the generation of uninterrupted analgesia can be provided pain by synergistically interacting with other throughout surgery and recovery, including inflammatory mediators. Thus, the analgesic the convalescent period after the patient is effects of NSAIDs are mediated through released from the hospital. inhibition of COX enzymes and prostaglandin synthesis. With proper patient selection, preparation, and monitoring, the anti-inflammatory and analgesic Rimadyl® (carprofen) was the first NSAID benefits associated with pre-operative adminis- developed in the US specifically for use in the tration of an NSAID such as Rimadyl Injectable dog. The original oral tablet formulation was can outweigh potential risks. Evidence evalu- approved by the FDA in 1996, followed by ating the use of approval of the highly palatable chewable tablet Rimadyl Injectable in 1999. Rimadyl Injectable sterile solution was for control of post- approved in 2003 and is labeled for subcuta- opera tive pain, Since inflammation is a driving neous (SC) injection. Both formulations can be including a review of administered as a single daily dose of 4.4 relevant pharma- factor in the development of surgical mg/kg body weight (2.0 mg/lb) or divided into cology, efficacy, and pain, the anti-inflammatory twice-daily doses at 2.2 mg/kg (1.0 mg/lb).1 safety data, is properties of Rimadyl make this Both formulations have the same indications summarized in this for use: Bulletin to help drug an important component of a 1. Relief of pain and inflammation associated practitioners make post-operative pain-management with osteoarthritis informed decisions on protocol. 2. Control of post-operative pain associated when to include with soft tissue and orthopedic procedures Rimadyl Injectable as part of a multimodal Rimadyl is the first injectable NSAID, and anesthetic/analgesic protocol. First, however, carprofen is the only injectable NSAID that is the role of COX enzymes in pain and inflam- FDA approved for controlling post-operative matory responses is briefly reviewed. pain in the dog, and is backed by over 10 years of research. Since inflammation is a driving COX ENZYMES AND EARLY NSAIDs factor in the development of surgical pain, the anti-inflammatory properties of Rimadyl make By inhibiting COX enzymes, NSAIDs are anti- this drug an important component of a post- inflammatory, analgesic, and antipyretic. The operative pain-management protocol: two primary COX enzymes are identified as COX-1 and COX-2, and differences between • Rimadyl Injectable can be administered SC these enzymes are summarized below. before surgery as part of a balanced, multimodal anesthesia/analgesia protocol. COX-1: The injectable Rimadyl formulation provides an alternative to use of an oral pre- • Is constitutively expressed (i.e., is detect - operative NSAID, especially when the able at relatively constant levels during animal is sedated or unresponsive, normal physiological conditions) and intractable, or at risk of emesis (e.g., due to responsible for maintaining normal an anesthetic drug), or for other situations homeostasis in a number of organ systems where oral medications are not an option. including: 3 • After surgery, patients can be easily – gastrointestinal (GI) tract integrity; transitioned to oral Rimadyl since no wash- – renal sodium and water absorption;4 out period is required between use of the – platelet aggregation.5 injectable and oral Rimadyl formulations. 2 Rimadyl Inject Peri-Op TB - draft 7 11/7/2014 11:56 AM Page 3 Zoetis NSAID Technical Bulletin COX-2: Results of these assays have been variable and the clinical relevance has not been established. • Is an inducible enzyme (i.e., only present Therefore, in vitro assays evaluating COX during pathological conditions such as inhibition by an NSAID are not reliably predictive inflammation) which is up-regulated after of efficacy or safety. Rather, the efficacy and arachidonic acid is released as a result of safety of an NSAID can only be determined by cell injury and initiates a cascade of events robust clinical studies.16 that results in synthesis of pro-inflammatory prostaglandins such as prostaglandin E2 Studies that have investigated the efficacy (PGE ) and prostacyclin (PGI ). 2 2 and safety of canine NSAIDs, combined with • Is constitutively expressed in the kidney their clinical history, have demonstrated that and, through PGE2 production, regulates all approved veterinary NSAIDs are safe and sodium and water absorption. effective when used according to label • Is up-regulated during renal ischemia, recommendations. Clear-cut distinctions in the performance of these NSAIDs have not been leading to synthesis of PGE2 and PGI2, both potent vasodilators that maintain renal observed in the general population of dogs, but individual patients may better tolerate one blood flow of the proximal renal artery to 17 preserve glomerular filtration rate in NSAID over another. Maximizing the benefits hypovolemic or hypotensive patients.6-8 and minimizing the risks of any NSAID used in an anesthesia protocol should involve appro- • May play a role in renal development priate patient selection, assessing the level of (COX-2-deficient mice have been shown analgesia required, supporting the patient to develop severe renal dysplasia).9 during surgery to maintain vital organ function, • Plays a cytoprotective role in the GI tract. monitoring the patient’s response, and Although not involved in maintaining GI accordingly adjusting the patient’s environment. homeostasis in the normal healthy GI tract, COX-2 enzymes are up-regulated in gastric ‘PAIN’ OVERVIEW inflammation and play an important role in healing gastric ulcerations.10 As potent anti-inflammatory drugs, NSAIDs are routinely used in human and veterinary When the first NSAIDs such as aspirin and medicine to control post-operative pain. The indomethacin were developed, the roles of the following graphics and discussion summarizes two COX enzymes were unknown. These key concepts that need to be considered for drugs indiscriminately inhibited both COX-1 managing the pain of a surgical patient. An and COX-2 enzymes, and although effective as overview of the pain pathway (Figure 1), the analgesics, the drugs had significant adverse- various types of pain, and the role that event profiles which limited their use. As it inflammation plays in initiating surgical pain became clear that COX-1 was constitutive and (Figure 2) is helpful to better understand the COX-2 was primarily involved in inflammation, analgesic effects of NSAIDs. newer