Nonsteroid Anti-inflammatory Drugs, Opioids, and Combinations

Transcription

1 CLINICAL ANESTHESIA /99 $ NEWER ANALGESICS Nonsteroid Anti-inflammatory Drugs, Opioids, and Combinations Polly M. Taylor, MA, VetMB, PhD, DVA, MRCVS Analgesia is an essential part of anesthesia, providing pre- and postoperative therapy as well as contributing to anesthesia itself. The role of analgesia as one of the three components of "balanced anesthesia" has long been recognized, with unconsciousness and relaxation being the other two. During unconsciousness, although pain is not experienced, nociception and autonomic responses still occur; thus, the analgesic component of anesthesia benefits the patient. In addition, prevention of nociceptive input to the central nervous system (CNS) during surgery contributes to post-operative analgesia by preventing sensitization of the CNS (see article on analgesics and pain in this issue). Opioids have traditionally been the most widely used analgesics in anesthetic practice, and their use continues, particularly as new, bettersuited, individual opioid drugs are developed. More recently, however, nonsteroidal anti-inflammatory drugs (NSAIDs) have become more prominent in providing perioperative analgesia; in many respects, veterinary use has led human medical experience in this field. Other agents such as ketamine and the alpha2-adrenoceptor agonists have been in veterinary anesthetic use for many years. They have not yet been fully exploited purely as analgesics. This article describes progress in development and clinical perioperative use of NSAIDs, revisits opioids in anesthesia, and draws attention to the potential analgesic value of a few other agents. From the Department of Clinical Veterinary Medicine, University of Cambridge, Cambridge, United Kingdom VETERINARY CLINICS OF NORTH AMERICA: SMALL ANIMAL PRACTICE VOLUME 29 NUMBER 3 MAY

2 720 TAYLOR NONSTEROIDAL ANTI-INFLAMMATORY DRUGS NSAIDs have been used in medical and veterinary treatment for many years. They have often been regarded as mild analgesics, whereas opioids are potent. Major advances in our understanding of the body's enzyme systems as they are affected by the NSAIDs have led to opportunities for the development of safer and more potent NSAIDs for the treatment of pain and inflammation. In some circumstances, NSAIDs are now able to provide better analgesia than the opioids. NSAIDs are used in the treatment of fever, inflammation, and pain. Extracts of willow bark (Salix alba) were used centuries ago to treat fever. In the early nineteenth century, active ingredients were isolated from the willow, leading to therapeutical use of the salicylate derivatives and the quest for new and better NSAIDs. Since then, a wide range of compounds derived from a number of different molecules have been developed. All NSAIDs have the potential to cause toxic side effects, and modern drugs have been developed in an attempt to improve safety and efficacy. Aspirin (acetylsalicylic acid) and the pyrazolone derivative phenylbutazone are typical of the older generation of NSAIDs and are still widely used today, although both may cause toxic side effects. The modern-generation NSAIDs used in veterinary medicine are potent, and toxicity is less of a hazard, but none are entirely safe. Introduction of lower toxicity injectable formulations has led to the perioperative use of NSAIDs largely for their analgesic activity. Mode of Action The NSAIDs act by blocking the action of cyclooxygenase (COX). 61 COX is the enzyme responsible for the conversion of arachidonic acid, released from normal cell membrane turnover, to the eicosanoids (Fig. 1). The eicosanoids so produced include the prostanoids, prostacyclin (PGI 2), and prostaglandin E2 (PGE2) as well as the thromboxanes (TXs). A second enzyme, 5-lipoxygenase, catalyzes the production of additional eicosanoids, the leukotrienes, from arachidonic acid. Leukotrienes also mediate some inflammatory processes, and a few NSAIDs block lipoxygenase in addition to COX. Role of Cyc/ooxygenase in Homeostasis The prostaglandins and TXs are responsible for a range of homeostatic and protective mechanisms throughout the body. Normal preservation of gastric mucosa, renal blood flow, and platelet function are of particular importance; toxic side effects of NSAIDs are usually a result of disruption of at least one of these homeostatic mechanisms. In the stomach, prostanoids thicken the mucous layer and increase bicarbonate secretion, both of which are essential in preventing acid erosion of the

3 NEWER ANALGESICS 721 cell membrane phospholipids natural turnover J phospholipase A2 arachidonic acid \::xygenase prostanoids (prostaglandins and thromboxanes) leukotrienes Figure 1. Eicosanoid production from arachidonic acid. Most NSAIDs inhibit cyclooxygenase (COX), thus preventing production of prostaglandins and thromboxanes. Some NSAIDs, the so-called "dual action" type, also inhibit lipoxygenase, and prevent production of leucotrienes as well. Phospholipase A2 is inhibited by corticosteroids. mucosal lining. 67 Equally important in normal gastric function is the maintenance of adequate microcirculation, primarily through PGI2-mediated vasodilation. In the kidney, autoregulation of renal blood flow ensures normal perfusion in the face of variations in systemic blood pressure. Autoregulation is controlled by a number of processes, and prostanoids make a significant contribution There is some species variation in the relative importance of the prostanoid contribution to autoregulation. Dogs appear to be particularly susceptible to developing prerenal failure if COX inhibitors prevent renal autoregulation in the presence of systemic hypotension. Control of platelet function is complex, relying on a balance between the effects of TXA 2 and PGI 2 Platelet aggregation is dependent on the TXA 2 produced by COX located in the platelets. COX inhibition may thus lead to defective clotting. PGI 2 located in vascular epithelium down-regulates platelet activity and tends to counteract the TXA2 effect. In addition, PGI2 is a potent vasodilator, and TX is a less potent vasoconstrictor. Because clotting may be affected by small blood vessel dynamics, these characteristics of the two mediators also affect clotting. The overall effect of NSAID-induced COX inhibition on platelet activity depends on NSAID access to the COX at each location. Prolonged bleeding time is a potential hazard of NSAID use, but this is not normally a clinical problem that prevents perioperative use, even when extensive surgery is performed. Role of Cyclooxygenase in Inflammation Products of COX activity are responsible for many of the characteristics of inflammation. Large quantities of eicosanoids, particularly PGE 2,

4 722 TAYLOR are produced in inflammatory processes. PGE2 leads to vasodilatation and the erythema seen in acute inflammation. 52 Vasodilatation increases blood flow through the tissues and augments the extravasation of fluid caused by agents such as bradykinin, which increase vascular permeability; this leads to the development of edema. 66 PGE2 acts synergistically with other products of inflammation to produce inflammatory pain. PGE 2 does not itself cause pain but sensitizes nerve endings to the action of bradykinin and histamine. 15 PGE 2 also causes pyrexia; its production is stimulated by interleukin-1, which is released in bacterial and viral infections. 49 PGE 2 thus contributes to fever during systemic infection. Analgesic Actions of Nonsteroidal Anti-Inflammatory Drugs There is no doubt that NSAIDs exert an analgesic effect through local inhibition of prostaglandin production as described above. In addition, NSAIDs may exert analgesic effects through routes other than COX inhibition? Interference with G-protein-mediated signal transduction may form the basis of an analgesic mechanism. Some NSAIDs also disrupt the lipoxygenase pathway, which may contribute to analgesia. There is also growing evidence that NSAIDs produce a central analgesic action? 47 Central analgesia may result from inhibition of brain COX activity. For instance, a stereoisomer of ketoprofen has been shown to inhibit the activity of COX produced in rat brain. 6 A number of other central effects unrelated to COX inhibition have also been proposed. These include mediation through endogenous opioid peptides, blockade of serotonin release, and a mechanism involving inhibition of NMDAreceptor activation? Cyclooxygenase-1 and Cyc/ooxygenase-2 The primary therapeutical role of NSAIDs is in the treatment of inflammation and pain via inhibition of COX activity. Unfortunately, COX inhibition affects production of both the regulatory prostanoids and those responsible for the inflammatory process. The beneficial effects are undisputed, however, and undesirable side effects have not prevented the widespread clinical use of NSAIDs. This is, in part, because in inflammation, large quantities of mediators, particularly PGE2, are produced, and even partial reduction has a therapeutic effect. Within the last few years, an enormous step forward has been made in research on inflammation. In 1990, two research groups reported that COX activity was substantially increased by bacterial endotoxin in human monocytes and mouse peritoneal macrophages and that this increase was associated with a newly discovered COX enzyme Subsequently, this new enzyme has been identified as a distinct isoform of COX induced by factors such as bacterial toxin, which cause inflammation. It is now accepted that there is a normal constitutive COX, COX-1, produced continuously in small quantities and responsible for production of the homeostatic prostaglandin and TX mediators. A second

5 NEWER ANALGESICS 723 similar but structurally distinct inducible form, COX-2, is produced in large quantities in response to stimuli such as bacterial infection. The products of COX-2 are thought to be responsible for the inflammatory process. COX-1 and COX-2 are encoded by separate genes 68 ; although they are similar, they have some structural differences. It should be emphasized that COX-1 and COX-2 catalyze the same reactions and produce the same mediators. The major significance of the difference between COX-1 and COX-2 is, first, how production of the enzyme itself is controlled and, second, the amount of enzyme that is manufactured. Since the discovery of COX-2 and its prime role in inflammation, development of an NSAID that blocks COX-2 without affecting COX-1 has become a major quest. In this way, inflammation and pain could theoretically be treated without affecting the homeostatic protective roles of the prostanoids. Considerable effort has gone into assessing currently available and potential new NSAIDs for their relative COX-1 and COX-2 inhibitory action. This can be performed in vitro using purified enzymes or wholecell systems; inevitably, results from different techniques do not always agree. Nevertheless, many NSAIDs have now been studied in this way, and the relative activity against COX-1 and COX-2 is expressed as a ratio of COX-2-to-COX-1 activity. A high value indicates more COX-1 activity, because the ratios are calculated on the concentrations of the drug at which the COX-1 and COX-2 activity is equivalent. Tables of activity ratios of a range of drugs have been drawn up (Table 1). 38 The differential effect of NSAIDs on COX-1 and COX-2 activity is a result of the slight difference in structure of the two enzyme isoforms. 30 The active site on the COX complex where arachidonic acid is oxygenated is located down a long hydrophobic channel (Fig. 2). 43 Most NSAIDs are thought to inhibit COX activity by binding reversibly to the COX complex near the apex, thus preventing arachidonate access to the active site and causing competitive inhibition (Fig. 3). 21 Aspirin is unique in binding irreversibly to the COX complex in this area of the channel but otherwise prevents arachidonate access to the active site in the same Table 1. SOME EXAMPLES OF NONSTEROIDAL ANTI-INFLAMMATORY DRUG CYCLOOXYGENASE-1 AND CYCLOOXYGENASE-2 RATIOS Drug Meloxicam Carprofen Ibuprofen Tolfenamic acid Indomethacin Aspirin Piroxicam Ratio Data from Mitchell JA, Akarasereenont P, Thiemerman C, et a!: Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooygenase. Proc Nat! Acad Sci USA 90:11693, 1993.

6 724 TAYLOR hydrophobic channel cox._._. enzyme / oomple pox active site Figure 2. Conversion of arachidonic acid to prostanoids is a complex process involving a number of steps catalyzed by different sites on the enzyme complex. The COX site, where chemical oxygenation occurs, is located within the cell membrane, down a hydrophobic channel. An intermediary stage involving chemical reduction is catalyzed (by a peroxidase, POX) at an external site. NSAIDs act by binding at the entrance of the hydrophobic channel, thereby preventing arachidonic acid access to the COX site. NSAID blocks arachidonic acid access to COX I active site COX-1 NSAID (e.g. aspirin) still allows arachidonic acid access hydrophobic to active site channel NSAID ~ COX-1 cox active site COX-2 Figure 3. The hydrophobic channel on the COX-2 enzyme complex is wider than that of COX-1. COX-1 selective NSAIDs are unable to block the access completely to the COX site. COX-2 selective NSAIDs change the structure of the channel entrance and are still able to prevent arachidonic acid access. * = NSAID binding site.

7 NEWER ANALGESICS 725 way. 31 In contrast to other NSAIDs, COX activity is not restored after aspirin treatment until new enzyme is formed. The hydrophobic channel is slightly wider in the COX-2 isoform, and access is still available to the active site after aspirin has been bound; aspirin is thus a poor COX-2 inhibitor. Inhibition by the other NSAIDs probably relates to the different structure at the entrance to the channel and how it opens to let arachidonate iny Under most methods used to assess COX-2-to-COX-1 ratios, aspirin, piroxicam, and indomethacin have high ratios, or poor relative COX-2 inhibitory activity; carprofen has an intermediate ratio, and nimesulide, meloxicam, and eltenac have some of the lowest ratios. Agents with marked selective COX-2 activity are under development, but currently, meloxicam and eltenac are the most selective agents available for clinical use. Disadvantages of Cyclooxygenase-2 Inhibitors The search for a pure COX-2 inhibitor continues; however, data are now accumulating suggesting that this approach is not the perfect answer to prevention of toxic NSAID side effects. This is probably a result of the fact that in some areas, COX-2 also has a regulatory role in normal function. In addition, the role of COX-1 in inflammation is not clear, and, at least in chronic inflammation, it may be as important as COX-2. Carproten Carprofen is a unique modern NSAID in that it has limited COX inhibitory action but retains potent analgesic and anti-inflammatory properties. 54 The exact mode of action of carprofen is not understood; however, there is evidence from ex vivo canine studies that it is COX-2 selective. 23 Alternatively, carprofen may have a significant effect on CNS COX activity or perhaps on another putative isoenzyme; the latter suggestion is little more than pure speculation. Nitric Oxide-Releasing Nonsteroidal Anti-Inflammatory Drugs In human medicine at least, the side effect most likely to prevent long-term use of an NSAID is the effect on gastric mucosa, leading to gastric ulceration and bleeding. A promising approach to this has been the development of a novel class of nitric oxide (NO)-releasing NSAIDs. These drugs are taken orally and are cleaved on reaching the stomach, releasing the NSAID and a NO donor. 63 The NSAID acts as a normal COX inhibitor, and it appears that the NO donor supports the local microvascular circulation through its vasodilatory effect. In this way, NO protects the gastric mucosa in place of the usual PGI 2, whose production is decreased by the COX inhibitor. The importance of this range of compounds in veterinary medicine has yet to be determined.

8 726 TAYLOR Veterinary Perioperative Use of Nonsteroidal Anti-Inflammatory Drugs Drugs such as phenylbutazone and aspmn have been used for many years to treat chronic pain in conditions such as arthritis. More recently, however, the advent of potent and less toxic injectable NSAIDs such as carprofen, ketoprofen, keterolac, and tolfenamic acid have led to perioperative NSAID use in small animals A number of NSAIDs have now been shown to perform better than opioids in clinical trials investigating postoperative analgesia in small animals Carprofen In the United Kingdom, carprofen (Zenecarp) has transformed postoperative analgesia in dogs and cats Carprofen is a weak COX inhibitor in dogs and cats/ 6 56 resulting in less potential for adverse effects on the kidney, as renal autoregulation is still maintained even if hypotension occurs. Carprofen is the only NSAID that is licensed for preoperative use. In the last 4 to 5 years, given preoperatively, it has been widely used in the United Kingdom, with remarkably few problems. The benefits of preoperative analgesia are widely recognized, as this prevents the development of CNS hypersensitivity (discussed in the article on analgesics and pain in this issue). 65 Hence, carprofen has significant benefit for perioperative management of pain in small animals. In the United States, carprofen was released much more recently as Rimadyl, and it is only available in tablet form. This makes it much less suitable for perioperative use. There has already been one report of hepatocellular toxicosis in 21 dogs treated with the drug. 32 All of these animals received carprofen for a number of days by oral administration for treatment of musculoskeletal pain. Similar problems have not occurred in Europe; whether this is due to a different dosage regimen or to genetic and environmental differences is unknown. There is absolutely no evidence, however, that single parenteral preoperative dosing at the recommended 4 mg/kg causes any such problem. Ketero/ac, Flunixin, Ketoprofen, and Meloxicam The efficacy of keterolac, ketoprofen, and flunixin in providing postoperative analgesia in dogs has been investigated in a number of studies The NSAIDs were usually given either during anesthesia before surgery started or postoperatively. In most cases, the NSAID performed well against a number of opiate analgesics, particularly against the mixed agonist-antagonist butorphanol. In one study, ketoprofen was a more effective postoperative analgesic than carprofen when each drug was given preoperatively. 22 Ketoprofen prolonged buccal bleeding time, but this did not cause any clinical problems. In general, although the opiates may have produced more profound analgesia initially, the NSAIDs produced adequate analgesia in the majority of cases,

9 NEWER ANALGESICS 727 and their effect was much longer lasting. There were no adverse effects of any significance in these investigations. Nevertheless, ketoprofen, keterolac, and flunixin are potent COX inhibitors, and it is widely accepted that they should either be given postoperatively or, if administered preoperatively, be given with considerable caution and effort to maintain good cardiovascular function. Flunixin has developed a reputation for adverse effects in dogs when it is given pre-operatively. This is based on two reports/4 37 where renal failure developed after a single dose of flunixin was given before major surgery. In both cases, anesthesia was prolonged, blood pressure was not measured, and little support in the way of fluid therapy was given. It is tempting to suggest that any COX inhibitor would be likely to lead to renal failure in such cases, but flunixin may be the most toxic COX inhibitor in dogs. In studies investigating flunixin more closely35 and in the author's unpublished experience, there has been some suggestion that biochemical indicators of renal function were more disrupted by flunixin than by keterolac or carprofen, although all values were close to the normal range and no clinical signs of disease developed. In an earlier investigation in 29 dogs given analgesics at the end of surgery,46 flunixin was reported to be a better analgesic than papavaretum, and no adverse effects were reported. Cats have undergone fewer studies than dogs. In spite of NSAIDs having a reputation for adverse effects in this species, tolerance and excretion of flunixin were reported to be better in cats than in dogs,55 and clinical trials in cats 18 have demonstrated its efficacy as an analgesic with no adverse effects. Ketoprofen was tested in two other studies. One of these reported that ketoprofen analgesia was limited, and the use of an opioid together with the ketoprofen was recommended.3 A more recent report showed that postoperative ketoprofen (2 mg/kg) provided the best analgesia when it was compared with two opioids.51 Meloxicam Meloxicam has been available for postoperative or chronic use in dogs for a few years. This drug is a relatively selective COX-2 inhibitor and might be expected to be safer than the COX-1 inhibitors more commonly used until now. A preliminary study, where hypotensive anesthetized dogs given meloxicam appeared to suffer no adverse renal or hepatic effects,4 suggests that this NSAID may also be suitable for preoperative use. Meloxicam is expected to undergo clinical trials for this indication. Other NSAIDs are likely to be tested for their clinical efficacy in dogs and cats. Tepoxalin, a dual COX/lipoxygenase inhibitor, and eltenac, reputedly a COX-2 inhibitor, are but two coming onto the veterinary market. The relative merits of the dual inhibitors versus COX-only inhibitors and the real value of COX-2 selectivity have yet to be discovered in clinical practice.

10 728 TAYLOR Role of Nonsteroidal Anti-Inflammatory Drug Analgesia in Veterinary Anesthesia NSAIDs are now widely used perioperatively, but it is difficult to quantify their precise effect during anesthesia. Carprofen failed to reduce minimum alveolar concentration during anesthesia, 1 and a significant pre-emptive analgesic effect is often hard to demonstrate. Nevertheless, a small study describing preoperative carprofen in dogs has now provided convincing evidence that preemptive analgesia can indeed be provided with an NSAID, 65 leading the way forward to increased use of this technique. Fortunately, adverse drug interactions with anesthetic and ancillary drugs do not appear to be a problem. 33 There is no doubt that the NSAIDs provide excellent pre- and postoperative analgesia under clinical conditions. Clinical perioperative use of these analgesics can undoubtedly be expected to increase, particularly as new and even safer drugs appear and as understanding grows regarding the optimum methods of use. The role of NSAIDs in anesthesia has hardly begun, and the future holds great promise. OPIOIDS Opioids have been used in anesthesia for years. Their role in providing analgesia, suppressing autonomic responses to noxious stimulation, and reducing the required dose of volatile anesthesia agents (minimum alveolar concentration suppression) does not need further description. Cloning of the opiate receptors has opened up enormous potential for better understanding the action of these drugs and how they may be exploited in anesthesia. 26 The accepted mu, delta, and kappa receptors have been substantiated by cloning but should now technically be referred to as OP 3, OPv and OP2 receptors, respectively.u Mu-agonist Opioids Mu- (or OP 3-) receptor agonist opioids provide the most intense analgesia. The longer acting mu opioids morphine, meperidine (pethidine), oxymorphone, and methadone are widely used to provide perioperative analgesia in small animal anesthesia. Their use is well documented. They are commonly used with and without sedative agents for premedication before anesthesia and surgery, and this method of use needs no further description. The increased understanding of spinal cord sensitization and "wind-up" (see article on analgesics and pain in this issue) has led to the belief that analgesics should be given before surgery starts to enhance postoperative analgesia. Pre-operative opiates have been in veterinary use for so long that this method of providing analgesia has been used almost by default. As a consequence, the value of the precise timing, dosing, and drug used preoperatively versus postopera-

11 NEWER ANALGESICS 729 tively has not been widely tested in veterinary practice. Some studies now demonstrate convincing evidence that preemptive analgesia with opioids is possible under clinical conditions Future developments in this field depend less on new drugs than on new dosing schedules or routes of administration. There is no doubt that opiates, both old and new, are going to continue to play a significant role in veterinary analgesia. Fentanyl, Alfentanil, Sufentanil, and Remifentanil In addition to the traditional opioids, shorter acting mu opioids have recently been in veterinary use as supplements to anesthesia by means of incremental boluses and infusion. The fentanyl opioids have been developed for use in human anesthesia both for balanced anesthesia, where they are used to supplement inhalation anesthesia, and for total intravenous anesthesia, where they are used in conjunction with other hypnotic agents. 50 In human medical use, opioids used alone or with nitrous oxide or benzodiazepines only have led to numerous reports of awareness. 5 In the veterinary world, we should learn from this; for anesthesia, the opioids should be used only in conjunction with either volatile anesthetics or hypnotics such as propofol. Fentanyl is not new to veterinary anesthesia. It is regularly used to supplement volatile agent anesthesia, 40 and it is used in numerous intravenous anesthetic protocolsy New methods of delivery such as transdermal skin patch delivery are discussed in the article on analgesics and pain in this issue. Alfentanil is shorter acting than fentanyl and is theoretically better suited to infusion during anesthesia. It has been used in this way in dogs16 as well as for induction of anesthesia for short procedures. 8 It has little veterinary use purely as an analgesic, however. Sufentanil and, more recently, remifentanil have been developed with improved kinetics for intravenous infusion so that the effect is easily switched on and of. 50 Remifentanil undergoes both hepatic and extrahepatic breakdown by nonspecific blood and tissue esterases and is thus ideal for controllable infusion. Both sufentanil and remifentanil have been studied in the dog under experimental conditions, and there is no doubt that both drugs have the potential for clinical use in this species. 9 As of yet, however, there is little clinical experience reported on either drug in small animal practice. Sufentanil/nitrous oxide anesthesia in dogs was satisfactory for recording magnetic motor-evoked potentials, but sufentanil and midazolam suppressed the responses Further evaluation of these new opiates in clinical veterinary practice is awaited. Tramadol Tramadol is a weak mu-agonist opioid agonist similar in some respects to meperidiney It is unique in that it also inhibits the neuronal uptake of norepinephrine and displaces serotonin from the storage vesi-

12 730 TAYLOR des in the nerve endings, thus enhancing its analgesic effect. Tramadol is a racemic mixture; the ( +) enantiomer has the opioid and serotonergic action, and the (-) enantiomer has the noradrenergic (uptake-inhibitory) action. The synergism of all three mechanisms accounts for the good analgesic effect seen in humans, where it has been used clinically for a number of years.13 The analgesic effect in animals appears to be predominantly due to an opioid mode of action. In nonprimates, tramadol is rapidly degraded to a metabolite that is primarily a mu agonist, and the other actions are lost. It is thus unlikely that tramadol has advantages over traditional mu-opioid agonists in veterinary practice. One study in dogs comparing tramadol with intercostal nerve block after thoracotomy reported that tramadol was considerably less effective. 25 Partial and Mixed Agonist/Antagonist Opioids A number of "mixed antagonist-agonist" or "partial-agonist" opioids were developed in the search for analgesics that did not cause respiratory depression and dependence. Some of these, for example, butorphanol, a mixed agonist-antagonist, have been widely used in veterinary anesthesia for a number of years. Such mixed agonist-antagonist opioids are agonist at the kappa receptor, providing analgesia, but antagonist at the mu receptor, thus antagonizing the pure mu agonists such as morphine. They tend to cause less respiratory depression than mu agonists, but the analgesia has a "ceiling" and may be insufficient in intense pain. Mixed agonist-antagonist opioids have been employed to reverse the effects of mu agonists such as fentanyl infused during anesthesia in order to reverse respiratory depression or to hasten the return to consciousnessy Because they have an agonist kappa effect, analgesia is still present. Buprenorphine has also been widely used in veterinary clinical practice and is one of the most popular analgesics used in general practice in the United Kingdom. 5 Buprenorphine is a partial mu agonist. It produces analgesia through stimulation of the mu receptor but is less effective than a "full" agonist such as morphine. It is also able to displace the full agonist from the receptor and can be used to reverse, for example, fentanyl anesthesia and respiratory depression. The maximum analgesic effect of a partial agonist such as buprenorphine is less than that of the full mu agonist, leading again to a ceiling effect. Buprenorphine is also famous for its "bell-shaped" dose response curve, where increasing doses lead to a decrease in analgesic effects. 10 It is commonly recommended that buprenorphine should not be used when it is anticipated that a pure mu agonist may be required subsequently, for instance, a fentanyl infusion. The argument is that the buprenorphine may antagonize the mu agonist and reduce the analgesic effect. It is also recommended that a pure mu agonist and not buprenorphine be given when it is anticipated that maximum effective analgesia is necessary. In spite of the theory, there is no doubt that although buprenorphine has a bell-

13 NEWER ANALGESICS 731 shaped dose response curve and is able to antagonize pure mu opioids, the dose at which either of these effects occurs may be different from the doses used on a regular basis in a clinical setting. Because the original pharmacology was defined in rats, application to dogs and cats may indeed be different; some clinical data support this view. In the author's experience, fentanyl infusion during anesthesia after buprenorphine premedication is effective. In addition, two studies in cats have demonstrated that buprenorphine provides better postoperative analgesia in cats than a pure mu agonist (morphine or meperidine). 51, 53 The value of buprenorphine in clinical practice needs further evaluation so that the best dosage schedules can be established. OTHER ANALGESICS Although the NSAIDs and opioids are the two major groups of analgesics used in veterinary medicine, a few others, both old and new, should also be considered in this context. Ketamine Ketamine is widely used in veterinary clinical practice to provide anesthesia and restraint. It is, however, a potent analgesic in its own right. Low doses ( mg/kg) have been used in man to provide both preemptive analgesia 48 and postoperative analgesia, 12 and this approach is worthy of consideration in animals. Alpha 2 Adrenoceptor Agonists It is well recognized that the alpha 2-adrenoceptor agonists are analgesics, but, although they are widely used in veterinary clinical practice, this is primarily for sedation and restraint. Use of these agents specifically to provide analgesia is worthy of further consideration. One study in cats demonstrated that extremely low doses of medetomidine provided some postoperative analgesia. 24 AlphaTadrenoceptor agonists have also been given by spinal and epidural routes for a number of years; this technique is described in the article on analgesics and pain in this issue. New Analgesics The quest for analgesics for human use that do not cause dependence and respiratory depression continues unabated. A number of novel nonopioid compounds have analgesic activity and are under investigation for their potential clinical value. Some of these, for instance, the tricyclical antidepressants, are used in man for severe chronic pain

14 732 TAYLOR and have not found a place in veterinary medicine. Others do have potential for veterinary use. Adenosine Kinase Antagonism It has been recognized for some time that adenosine has analgesic properties, but its use is associated with a number of undesirable side effects. A new approach has been to block the adenosine kinase that destroys the adenosine, thereby increasing its effect without exogenous dosing Investigations into this approach are at an early stage, and no clinical experience in dogs or cats has been reported yet. Epibatidine Epibatidine was isolated from the skin of an Ecuadorian frog and found to be intensely analgesic. 58 The original compound, however, was extremely toxic, and it is only recently that analogues such as ABT-594 have shown any promise as potential less toxic analgesics. Investigations in rodents are promising, but no clinical studies in dogs, cats, or humans have yet been carried out. CONCLUSIONS The choice of analgesics and of ways in which to use them is considerable, and many approaches can be recommended. There is no doubt that balanced analgesia is the best way forward; a combination of different agents acting by synergistic mechanisms provides the best overall analgesia for the patient. A combination of opioid and COXsparing NSAIDs given as premedication followed by infusion or incremental doses of a noncumulative opioid during anesthesia is, both theoretically and in practice, a good approach to the use of analgesics in association with anesthesia. Analgesia produced by the two drug groups is synergistic, and there is little added risk of cumulation or toxicity. Additional cover can be given with local blocks as well as with spinal or epidural medication. There is convincing empirical and experimental evidence that combined use of these different analgesic drugs and routes of administration is safe. There is also much evidence that analgesia is enhanced; hence, combination balanced analgesia has to be the way forward in providing excellent perioperative analgesia for our small animal patients. References 1. Alibhai HI, Clarke KW: Influence of carprofen on minimum alveolar concentration of halothane in dogs. J Vet Pharmacal Ther 19:320, 1996

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16 734 TAYLOR 25. Jitasombuti P, Kalpravidh M, Brahmasa A: Comparison of analgesic effects of tramadol HC! and buvivacaine HC! in dogs after intercostal thoracotomy. In Proceedings of the Sixth International Congress of Veterinary Anaesthesia, Thessaloniki, Greece, 1998, p Lambert DG: Recent advances in opioid pharmacology. Br J Anaesth 81:3, Lascelles BD, Butterworth SJ, Waterman AE: Postoperative analgesic and sedative effects of carprofen and pethidine in dogs. Vet Rec 134:187, Lascelles BD, Cripps P, Mirchandani S, et a!: Carprofen as an analgesic for postoperative pain in cats: Dose titration and assessment of efficacy in comparison to pethidine hydrochloride. J Small Anim Pract 36:535, Lascelles BD, Cripps PJ, Jones A, et a!: Post-operative central hypersensitivity and pain: The pre-emptive value of pethidine for ovariohysterectomy. Pain 73:461, Loll PJ, Garavito RM: The isoforms of cyclooxygenase: Structure and function. Expert Opinion on Investigational Drugs 3:1171, Loll PJ, Picot D, Garavito RM: The structural basis of aspirin activity inferred from the crystal structure of inactivated prostaglandin H 2 synthase. Nature Structural Biology 2:637, MacPhail CM, Lappin MR, Meyer DJ, et al: Hepatocellular toxicosis associated with administration of carprofen in 21 dogs. JAVMA 212:1895, Martinez EA, Wooldridge AA, Hartsfield SM: Effect of ketorolac tromethamine on atracurium-induced neuromuscular blockade in anesthetized dogs. Vet Surg 26:510, Masferrer JL, Zweifel BS, Seibert K, eta!: Selective regulation of cellular cyclooxygenase by dexamethasone and endotoxin in mice. J Clin Invest 86:1375, Mathews KA, Paley DM, Foster RA, et al: A comparison of ketorolac with flunixin, butorphanol, and oxymorphone in controlling postoperative pain in dogs. Can Vet J 37:557, McKellar QA, Delatour P, Lees P: Stereospecific pharmacodynamics and pharmacokinetics of carprofen in the dog. J Vet Pharmacal Ther 17:447, McNeil PE: Acute tubulo-interstitial nephritis in a dog after halothane anaesthesia and administration of flunixin meglumine and trimethoprim-sulphadiazine [comments]. Vet Rec 131:148, Mitchell JA, Akarasereenont P, Thiemermann C, et a!: Selectivity of nonsteroidal antiinflammatory drugs as inhibitors of constitutive and inducible cyclooxygenase. Proc Nat! Acad Sci U S A 90:11693, Nolan A, Reid J: Comparison of the postoperative analgesic and sedative effects of carprofen and papaveretum in the dog. Vet Rec 133:240, Nolan AM, Reid J: The use of intraoperative fentanyl in spontaneously breathing dogs undergoing orthopaedic surgery. J Vet Anaesth 18:30, Pascoe PJ: The case for maintenance of general anesthesia with an injectable agent. Vet Clin North Am Small Anim Pract 22:275, Pibarot P, Dupuis J, Grisneaux E, et al: Comparison of ketoprofen, oxymorphone hydrochloride, and butorphanol in the treatment of postoperative pain in dogs. JAVMA 211:438, Picot D, Loll PJ, Garavito RM: The X-ray crystal structure of the membrane protein prostaglandin H 2 synthase-1. Nature 367:243, Poon A, Sawynok J: Antinociception by adenosine analogs and inhibitors of adenosine metabolism in an inflammatory thermal hyperalgesia model in the rat. Pain 74:235, Popiliskis S, Jordan D, Laurent L, et a!: Comparison of keterolac and oxymorphone on postoperative pain relief and neuroendocrine response in dogs. In Proceedings of the Sixth International Congress of Veterinary Anaesthesia, Thessaloniki, Greece, 1998, p Reid J, Nolan AM: A comparison of the postoperative analgesic and sedative effects of flunixin and papaveretum in the dog. J Small Anim Pract 32:603, Robert B, Robert JM, Khettab EN, et a!: Effect of a NSAID which does not inhibit cyclooxygenase on cerebral level of PGE 2 in rat experimental brain oedema. Pharmacal Toxicol 70:67, 1992

17 NEWER ANALGESICS Roytblat L, Korotkoruchko A, Katz J, et al: Postoperative pain: The effect of low-dose ketarnine in addition to general anesthesia. Anesth Analg 77:1161, Saxena PN, Beg MM, Singhal KC, et al: Prostaglandin-like activity in the cerebrospinal fluid of febrile patients. lndian J Med Res 70:495, Sear JW: Recent advances and developments in the clinical use of LV. opioids during the perioperative period. Br J Anaesth 81:38, Slingsby LS, Waterman-Pearson AE: Comparison of pethidine, buprenorphine and ketoprofen for postoperative analgesia after ovariohysterectomy in the cat. Vet Rec 143:185, Solomon LM, Juhlin L, Kirschenbaum MB: Prostaglandin on cutaneous vasculature. J Invest Dermatol 51:280, Stanway GW, Brodbelt DC, Taylor PM: A comparison of preoperative morphine and buprenorphine in cats. J Vet Anaesth 23:78, Strub KM, Aeppli L, Muller RKM: Pharmacological properties of carprofen. Eur J Rheumatollnflamm 5:478, Taylor PM, Winnard JG, Jefferies R, et al: Flunixin in the cat: A pharmacodynamic, pharmacokinetic and toxicological study. Br Vet J 150:253, Taylor PM, Delatour P, Landoni FM, et al: Pharmacodynamics and enantioselective pharmacokinetics of carprofen in the cat. Res Vet Sci 60:144, Toto RD: The role of prostaglandins in NSAID induced renal dysfunction. J Rheumatol Suppl 28:22, Traynor JR: Epibatidine and pain. Br J Anaesth 81:69, Van Ham LM, Nijs J, Vanderstraeten GG, et al: Comparison of two techniques of narcotic-induced anesthesia for use during recording of magnetic motor evoked potentials in dogs. Am J Vet Res 57:142, Van Ham LM, Nijs J, Mattheeuws DR et al: Sufentanil and nitrous oxide anaesthesia for the recording of transcranial magnetic motor evoked potentials in dogs. Vet Rec 138:642, Vane JR: Inhibition of prostaglandin synthesis as a mechanism of action for aspirinlike drugs. Nature New Biology 231:232, Venturini CM, Isakson P, Needleman P: Non-steroidal anti-inflammatory drug-induced renal failure: A brief review of the role of cyclo-oxygenase isoforms. Current Opinions in Nephrology and Hypertension 7:79, Wallace JL, Reuter BK, Cirino G: Nitric oxide-releasing non-steroidal anti-inflammatory drugs: A novel approach for reducing gastrointestinal toxicity. J Gastroenterol Hepatol (Suppl 1):540, Wang B, Tang J, White PF, et al: The effect of GP683, an adenosine kinase inhibitor, on the desflurane anesthetic requirement in dogs. Anesth Analg 85:675, Welsh EM, Nolan AM, Reid J: Beneficial effects of administering carprofen before surgery in dogs. Vet Rec 141:251, Williams TJ, Peck MJ: Role of prostaglandin-mediated vasodilatation in inflammation. Nature 270:530, Wilson DE: Role of prostaglandins in gastroduodenal mucosal protection. J Clin Gastroenterol 13(Suppl 1):S65, Xie W, Chipman JG, Robertson DL, et al: Expression of a mitogen-responsive gene encoding prostaglandin synthase is regulated by mrna splicing. Proc Natl Acad Sci U S A 88:2692, 1991 Address reprint requests to P. M. Taylor, MA, VetMB, PhD, DVA, MRCVS Department of Clinical Veterinary Medicine University of Cambridge Madingley Road Cambridge CB3 OES UK