New Drugs for Pain Management
World Small Animal Veterinary Association World Congress Proceedings, 2004
Paul Flecknell, MA, VetMB, PhD, DLAS, DECVA, DECLAM, MRCVS
Comparative Biology Centre, Medical School, Framlington Place
Newcastle upon Tyne

Recognition of the need to prevent and treat pain in animals has developed relatively slowly over the last few decades. Numerous factors have hampered the introduction of effective pain management protocols, including a lack of awareness of the pathophysiological consequences of pain, misconceptions concerning the nature and biological purpose of pain and a failure to recognise the presence of pain in our patients. We still have no fully validated, practically applicable pain scoring systems, but a number of reasonably useful systems are being introduced into clinical practice. However one major impediment to implementing pain management regimens that persisted until recently was the apparent lack of analgesic agents for use in animals. Clearly, since all of the analgesics available for use in man were developed and tested for safety and efficacy in animals, appropriate agents have been available for many years. However, many veterinarians have been reluctant to use these analgesics as the vast majority had no license for use in companion or farm animals and clinical trial data in these target species was often unavailable. These problems have been exacerbated by the over-emphasis in many older veterinary texts of the clinical significance and likely incidence of adverse side effects of analgesics. The last decade or so has seen the gradual introduction of a range of analgesics for veterinary use. The growing market for analgesics in veterinary practice is now driving a program of drug development and licencing that is already resulting in the rapid availability of novel analgesics.

Opioids

Two main developments in pain management are of particular significance:

 The widespread clinical use of transdermal drug delivery, primarily fentanyl patches (notably in North America)

 The marketing of buprenorphine as a veterinary product (in the UK)

Fentanyl patches have been developed for use in man, as a means of providing analgesia for prolonged periods. Although formulated to provide appropriate fentanyl release rates for absorption through human skin, it has been shown that effective plasma levels can also be attained in dogs and cats. It is important to note that in animals, the variation in plasma concentrations of fentanyl varies considerably between individuals, and in some animals it is unlikely that significant analgesia will be produced (refs). It is therefore particularly important to carry out regular assessments of the adequacy of pain relief in animals treated with patches, and to be prepared to provide additional analgesia when required.

Buprenorphine's analgesic properties in animals were first described in 1977 (Cowan et al), and it has been used extensively in laboratory species as a means of managing acute post-operative pain. It also was used extensively for pain management in clinical practice, although the lack of veterinary product licensing restricted this. This analgesic is now licensed in the UK for use in dogs. Although it is widely used, misconceptions arising from misinterpretation of early animal studies have hampered its use in clinical pain management. Buprenorphine has been classified as a partial mu agonist and early studies indicated that it exhibited a "bell-shaped" dose response curve, with high dose rates producing a paradoxical reduction in analgesic efficacy. These initial results in laboratory animals were uncritically translated into clinical opinion, that additional doses of buprenorphine would reduce the agents analgesic effects. Although repeated dosing with buprenorphine may eventually reach a plateau in terms of analgesic efficacy, inspection of the available animal data shows that dose rates far in excess of those used clinically are required for "self-reversal" (Roughan and Flecknell, 2002).

NSAIDs

The treatment options available to clinicians using this group of drugs has developed greatly over the last few years, especially with the introduction of COX-2 selective analgesics, notably the coxibs. There have also been developments in the formulations available.

Cyclooxygenase (COX) inhibitors

Cyclooxygenase is an enzyme that catalyses the first step in the synthesis of prostanoids--the conversion of arachidonic acid to prostaglandin H2. The prostanoids are important mediators of inflammation, and both directly and indirectly influence the degree of pain associated with tissue injury and other inflammatory processes. NSAIDs exert their main effects by inhibiting the action of COX (Vane, 1971). In the early 1990s, it was discovered that COX existed in two isoforms, COX-1 and COX-2. A third isoform, COX-3 has now been described (Chandrasekharan et al, 2002). COX-1 mediates essential physiological responses in a wide range of body tissues, in contrast, COX-2 is expressed by cells that are involved in inflammation (e.g., macrophages) and it has emerged as the isoform primarily responsible for the synthesis of prostanoids involved in acute and chronic inflammatory states.

Almost immediately, the search was underway for NSAIDs that had a selective action on COX-2, but with minimal or no effect on COX-1. The hope was that such drugs would have reduced toxicity in comparison to nonselective NSAIDs. The original, relatively simple view of the functions of COX, and the effects of COX-1 and COX-2 inhibition have become steadily more complex. The clinical relevance of some of these effects still remains uncertain, but a careful consideration of the new compounds becoming available enables us to critically review the use of NSAIDs in veterinary clinical practice.

One of the problems that arises when trying to interpret information about new and older NSAIDs is the wide variation of assays used to determine COX-1 and COX-2 inhibitory effects. This is further compounded by the use of both EC50 and EC80 for comparison, and the failure in some studies to link these data to the tissue concentrations that are likely to be produced when the drug is used clinically. Two other problems arise--inevitably, once a drug is licenced for use in one species, it is likely to be used in other species. The drug concentration produced, the relative COX-1:COX-2 inhibition, and the duration of action of the drug is likely to vary between species. It is therefore important to balance an enthusiasm to provide the most effective pain management with the need for caution when using drugs in different species. It is clear, however, that the new generation of highly selective COX-2 NSAIDs, in particular the coxibs such as celecoxib, deracoxib, firocoxib, are likely to provide effective pain relief with a reduced risk of side-effects.

Current clinical use of NSAIDs

At present, NSAIDs are widely used for the management of both acute and chronic pain, but as discussed earlier, undesirable side-effects are a recognised clinical problem, particularly when these analgesics are used for prolonged periods.

Post-operative pain

NSAIDs may be used both alone and in conjunction with opioids to provide effective post-surgical pain relief. More effective analgesia is often provided if the NSAID is administered pre-operatively, however early case reports of serious side-effects in the dog when flunixin was administered in this way discouraged this approach (ref). The introduction of carprofen, a relatively weak cyclo-oxygenase inhibitor and meloxicam, an NSAID with greater COX-2 selectivity than older agents, has now lead to more widespread adoption of pre-operative use of these analgesics. The availability of NSAIDs with even more specific COX-2 inhibitory effects, such as deracoxib and firocoxib, should further encourage this.

Although the coxibs have clear advantages, such as a lack of effect on platelet function, so that inhibition of clotting intra-operatively is no longer a concern, other potential side-effects have been recognised. Use of NSAIDs to control pain after fracture repair has been a concern for some time, as prostaglandin production is involved in this process. COX-2 may potentially affect both osteoblast and osteoclast function and may also inhibit angiogenesis, which could affect delivery of osteoblasts and osteoclasts to the cartilage matrix interface for continued endochondral ossification (Gajraj, 2003). Although effects on bone healing have been demonstrated, effects of potential clinical significance have only resulted when prolonged (7 days or greater) treatment has been employed. Any potential adverse effects must also be balanced against the advantages of improved analgesia and consequent earlier mobility and weight bearing. At present there are no clinical trials in animals or man demonstrating a negative effect of COX-2 inhibitors on fracture healing, and it seems reasonable to conclude that they can be used safely for at least several days perioperatively.

Chronic pain

One of the most common chronic painful condition encountered in small animal practice is lameness in dogs due to osteoarthritis. The associated pain and loss of mobility can have a significant impact on the affected animals' quality of life. The causes of osteoarthritis are complex and include genetic and husbandry influences, as well as other factors. The end result of the condition is impaired mobility caused both by physical changes in the affected joints and pain occurring both during movement and also at rest. At present, therapy to reverse the chronic changes associated with osteoarthritis is not available (McLaughlin, 2000), so treatment is aimed at:

 Alleviating the animal's pain and discomfort

 Preventing the occurrence of further degenerative changes

 Restoring the affected joint or joints to as near normal and pain-free function as possible

NSAIDs have been widely used to treat the pain and inflammation associated with arthritis for many years, despite the undesirable side effects of many of these agents. The most significant of these are gastro-intestinal irritation and ulceration and renal toxicity (Mathews, 2000). Several approaches have been pursued to reduce the clinical importance of these side-effects, including the concurrent administration of gastro-protectants and the development of NSAIDs with a higher therapeutic index. Currently, the approach that appears to offer the greatest immediate clinical benefit is the use of NSAIDs with greater selectivity for COX-2. In man, where osteoarthritis is also a significant clinical problem, use of coxibs has become widespread, so much so that the continued use of non-selective NSAIDs has been questioned (Crofford, 2002). The greatly reduced side-effect profile of these agents is likely to lead to similar widespread use in animals, and a number of agents are already licenced, or in the process of being licenced, for this purpose (e.g., deracoxib, firocoxib).

In order to be of practical value in the treatment of canine osteoarthritis, it is important that the NSAID selected has a number of other characteristics, in addition to a low incidence of side-effects. It is clearly important that the agent should have good bioavailability when administered orally, can be formulated in a palatable base, and should have a long half-life so that administration can be once daily. These factors are particularly important in ensuring owner-compliance with any treatment regimen. A number of products have been marketed that meet some of these aims. For example, carprofen, etodolac, meloxicam and vedaprofen are all marketed for veterinary use, for the management of pain associated with osteoarthritis in dogs. In man, an even wider range of agents is available, including both COX-2 selective and nonselective NSAIDs. One factor influencing the range of agents available for use in man is the considerable variability in individual patient responses to both the beneficial effects of different agents, and the susceptibility to side-effects. Anecdotal evidence indicates that similar individual differences occur in animals. It is therefore probable that clinicians will need to select NSAIDs on a case-by-case basis, however it is likely that the initial drug of choice for many animals will be a coxib, rather than one of the older, less selective agents.

Other opportunities for pain management

The introduction of highly selective COX-2 inhibitors should encourage their use in a wide range of clinical situations in which pain is a significant problem. A wide range of common clinical conditions have a major inflammatory component, for example otitis externa, abscess formation and ocular conditions. Pain is clearly apparent when animals with these conditions are examined. Pain is also associated with some types of neoplasia. Although pain will be reduced or eliminated when these conditions are treated, immediate pain relief can often be achieved by use of NSAIDs. Palatable formulations for oral use can then be prescribed to provide continued analgesia while the underlying cause of the pain is addressed.

Pain in man has been termed "the fourth vital sign" and the need to recognise and control pain has been emphasised repeatedly. Pain management in animals has lagged behind, but with the introduction of new analgesic agents, many of the obstacles to the provision of effective pain relief have been removed. We do, however, need to review and update our attitudes to animal pain, so that we recognise it as an undesirable clinical sign that should be alleviated whenever possible.

References

1.  Chandrasekharan, N.V., Dai, H, Roos, K.L.T., Evanson, K.N., Tomsik, J., Elton, S.T. and Simmons, D.L. (2002) COX-3, a cyclooxygenase-1 variant inhibited by acetaminophen and other analgesic/ antipyretic drugs: Cloning, structure, and expression.

2.  Cowan, A, Doxey, J. C. and Harry, E. J. R. (1977b) The animal pharmacology of buprenorphine, an oripavine analgesic agent. British Journal of Pharmacology 60, 547-554

3.  Crofford, L.J. (2002) Is there a place for non-selective NSAIDs in the treatment of arthritis? Joint, Bone, Spine, 69, 4-7

4.  Gajraj, N.M. (2003) The Effect of Cyclooxygenase-2 Inhibitors on Bone Healing, Regional Anesthesia and Pain Medicine, 28, 5, 456-465

5.  Mathews, K.A. (2000) Nonsteroidal anti-inflammatory analgesics. Indications and contraindications for pain management in dogs and cats.

6.  McLuaghlin, R. (2000) Management of chronic osteoarthritic pain. Veterinary Clinics of North America, Small Animal Practice, 30, 933-49

7.  Nolan, A. (2000) Pharmacology of analgesic drugs. In Pain Management in Animals, Flecknell PA, Waterman-Pearson A. (eds). Harcourt Publishers, London, 2000 pp 21-52

8.  Roughan, J.V and Flecknell, P.A. (2002) Buprenorphine: A reappraisal of its antinociceptive effects and therapeutic use in alleviating post-operative pain in animals. Laboratory Animals,

9.  Vane J. (1971) Inhibition of prostaglandin synthesis as a mechanism of action for the aspirin-like drugs. Nature 231:232-235.

Speaker Information
(click the speaker's name to view other papers and abstracts submitted by this speaker)

Paul Flecknell, MA, VetMB, PhD, DLAS, DECVA, DECLAM, MRCVS
Comparative Biology Centre, Medical School, Framlington Place
Newcastle upon tyne, UK


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