Medical Therapy for Stifle Osteoarthritis 335not without adverse effects and must be used
judiciously, especially in dogs with pre-existing
conditions.
The primary selection of an NSAID is based
on individual analgesic and adverse responses.
Despite similar efficacies between different
NSAIDs, there can be a dramatic difference in
individual response. It may be necessary to try
different NSAIDs until an acceptable level of
analgesia is obtained or the patient experiences
an adverse response. Given that a patient may
need to be medicated with different NSAIDs,
there is extensive debate concerning the neces-
sity or length of washout between the admin-
istration of sequential NSAIDs with little data
to support any particular dosing protocols (Las-
celleset al. 2005; Ryanet al. 2007). However,
there is one situation in which a washout period
can strongly be considered, which is following
the use of aspirin. Aspirin use induces aspirin-
triggered lipoxins (ATL), which have protective
effects on the stomach lining. ATLs diminish
gastric mucosal injury from nitric oxide pro-
duced by traumatized vascular endothelium
(Souzaet al. 2003). The concurrent or immediate
administration of other NSAIDs, particularly
COX-2 selective or COX-1 sparing drugs, will
completely block these lipoxins and their pro-
tective effects, thus increasing the risk of gastric
ulceration.
Additional analgesics
Although NSAIDs are traditionally the first
line of pharmaceuticals used to treat OA, they
incompletely suppress the inflammatory pro-
cess through a limited mechanism of action
and, therefore, are not completely effective at
obviating the clinical signs of OA. A multi-
modal approach incorporating additional anal-
gesics with differing mechanisms and sites of
action is often indicated for improved pain con-
trol while lowering the therapeutically effective
dose, thereby minimizing the adverse effects of
NSAIDs (Lascelleset al. 2008).
Amantadine
Amantadine, first recognized as an anti-viral
agent, has gained popularity for the treatment
of chronic pain disorders via the inhibition of
N-methyl-D-aspartate (NMDA) receptors.
NMDA receptor activation, secondary to
chronic stimulation of A delta and C fibers, is
believed to be the primary component lead-
ing to ‘spinal windup.’ A study by Lascelles
et al. (2008) compared the effects of adjunctive
amantadine with meloxicam in a population
of dogs with chronic OA refractory to NSAID
therapy alone. Dogs treated with meloxicam
in conjunction with amantadine had improved
client-specific outcome measure scores and
overall activity, compared with the administra-
tion of meloxicam alone.Tramadol
Tramadol is an opioid analgesic acting at the mu
receptor while inhibiting serotonin uptake and
norepinephrine re-uptake (Raffaet al. 1992). Tra-
madol also inhibits central pro-inflammatory
cytokines and acts as an agonist of the transient
receptor potential vanilloid 1 (TRPV1) recep-
tor, influencing various neuronal cation chan-
nels while locally decreasing IL-6 and substance
P (Marincsaket al. 2008). Only one investigation
has been conducted in dogs with OA to eval-
uate the effects of oral tramadol in a blinded
study using positive and negative controls. A
significant improvement was noted in the pos-
itive control group (carprofen, 2.2 mg kg–1
twice daily) and the tramadol (4 mg kg–1three
times daily) group compared with the placebo
group (administered three times daily) using
the canine brief pain inventory questionnaire
(Malek et al. 2012). However, several other
outcome measures in this study showed no
improvement over placebo or baseline during
the administration of tramadol. Thus, the lim-
ited data from this study is difficult to assess in
terms of recommending tramadol use in dogs
with OA.Gabapentin
Gabapentin is structurally similar to the
central inhibitory neurotransmitter gamma-
aminobutyric acid (GABA). The latter is
synthesized from glutamate, an excitatory
neurotransmitter. During periods of chronic
pain, there is an upregulation of glutamate and
subsequent NMDA receptor activation with a