Understanding the mechanisms of action of NSAIDs has been facilitated by
studies linking their pharmacokinetic properties to their pharmacodynamic actions
(PK–PD modelling) for several species (see chapter, “Species Differences in
Pharmacokinetics and Pharmacodynamics” of this text). Moreover, this approach
provides a rational basis for designing dosing schedules that are both safe and
effective. It is likely to be extended to other analgesic drug groups in the near future.
Pharmacokinetic studies of NSAIDs have led to several findings relevant to their
use. Unlike most peripherally administered analgesics of other classes, for which
the plasma concentrations of the drug give a good indication of the clinical effec-
tiveness at a given instant, associated with their ability to cross the blood–brain
barrier rapidly, the actions of NSAIDs on pain associated with peripheral sensitisa-
tion depends primarily on the local peripheral concentration at the site of damage
(Lees and Higgins 1985 ). This effect has been demonstrated in several different
species (McKellar et al 1994 ) and led to the PK–PD modelling described by Lees
et al. (2004b).
Another veterinary aspect of interest is the susceptibility of cats to the risk of
overdosing due to their slow rate of metabolism of some NSAIDs (Yeary and
Swanson 1973 ). However, this does not mean they cannot be used in cats, only
that the dosage interval must sometimes be extended (Glew et al. 1996 ). Moreover,
this slow metabolism and clearance of NSAIDs does not apply to all members of
this class of drug.
Orally administered salicylates are still used in farm animals based on their low
cost; however oral administration of drugs to ruminants and horses can lead to high
variability in bioavailability associated with variable absorption rates, associated
with diet and binding to feed within the digestive tract. Injectable NSAIDs, such as
carprofen, ketoprofen, meloxicam and flunixin are available for farm animal use.
Parenteral dosing provides a more reliable route for administration. However, some
of these drugs are non-selective for COX and others may even inhibit predomi-
nantly COX-1. They are more likely to produce the classic unwanted side-effects on
the gastric mucosa and blood clotting, although reports of unwanted side-effects in
farm animals are very rare (Table 5 ). Carprofen is selective for COX-2 in the dog
and cat but not in the horse, where it is non-selective, whilst in man it is COX-1
selective (Lees et al.2004a).
In recent years there has been a trend away from the use of NSAIDs that are non-
selective COX inhibitors in cats and dogs, and a tendency either to use NSAIDs
with some selectivity for COX-2, such as meloxicam or carprofen (Papich 2000 )or
more recently, the COX-2 selective coxibs such as firocoxib, mavacoxib and
robenacoxib (Table 6 ). There are also now available data on the use of these
drugs in smaller pets (Wright-Williams et al. 2007 ) and non-mammalian species
(Machin 2005 ; Mosley 2005 ) (Table 7 ). The recent increase in the use of NSAIDs
for the control of moderate to severe pain is associated with the greater tolerance to
COX-2 selective drugs, an increased understanding of their role in preventing
sensitisation and an increase in utilising data on their pharmacokinetics as well as
pharmacodynamics (Vane and Botting 1995 ).
Pain and Analgesia in Domestic Animals 179