334 Medical Management of Cruciate Ligament Rupture
for veterinary medicine is defined when sham
medical intervention causes pet care-givers,
such as owners or veterinarians, to believe
that the provided treatment improved the
pet’s condition. A significant care-giver placebo
effect has been documented in dogs with OA
(Conzemius & Evans 2012). The care-giver
placebo effect for owners evaluating their dog’s
lameness occurred 56.9% of occasions. A care-
giver placebo effect for veterinarians occurred
44.8% of the time when they examined dogs
for lameness at a walk or a trot, and 43.1% of
the time when veterinarians evaluated dogs for
signs of pain on palpation of the joint. In all of
these measurements, the owner and veterinar-
ian, who was blinded to the treatment, believed
there were improvements while the dog was on
placebo treatment.
Weight management
The importance of weight management in the
prevention and treatment of OAcannot be over-
estimated. A substantial portion of the patient
population is obese, and it is recognized that
obesity is an important medical disease in
dogs (German 2006; Laflamme 2012; German
2016). Obesity, defined as exceeding ideal body
weight by 15–20%, places excessive forces on
joints and articular cartilage, and is exacerbated
by inactivity, propagating a vicious cycle of
muscle atrophy and decreased overall fitness
(Impellizeriet al. 2000; Kealyet al. 2000). While
there is not a clear cause and effect relation-
ship between obesity and OA, fat is consid-
ered a metabolically active tissue promoting
inflammation (Greenburg & Obin 2006). There
is growing evidence that inflammatory media-
tors released from adipose tissue, including the
cytokines interleukin 6 (IL-6) and tumor necro-
sis factor alpha (TNF-α), and the adipokines lep-
tin, visfatin, adiponectin, adipsin and resistin,
may have roles in the pathogenesis of OA (Frye
et al. 2016). Levels of adipsin and leptin are
associated with knee OA progression in human
beings (Martel-Pelletieret al. 2016). It has also
been proposed that leptin could play a role in
the development of cruciate ligament rupture
in dogs by the alteration of ligament fibrob-
last and collagenase activity. However, further
research is needed to substantiate this claim
(Comerfordet al. 2005; Oteroet al. 2006). Despite
these controversies about the cause and effect
of obesity and OA, weight reduction has been
shown clinically to ameliorate the signs asso-
ciated with OA and to have preventive effects.
Burkholderet al. (2000) demonstrated, in a pop-
ulation of overweight dogs with clinical signs
of hip dysplasia, that appropriate weight loss
markedly improved ground reaction forces and
joint mobility. Additionally, more recently, Mar-
shallet al. (2010) showed decreased lameness
and improved kinetic gait analysis with body
weight reduction in dogs with hip and elbow
OA. A series of studies have assessed the pro-
tective benefits of a calorically restricted diet for
the development of OA(Kealyet al. 2000; Impel-
lizeriet al. 2000; Kealyet al. 2002; Mlacniket al.
2006; Smithet al. 2006).Nonsteroidal anti-inflammatory drugs
NSAIDs are the most commonly prescribed
class of medications to alleviate the clinical
signs of OA and are the mainstay in any medi-
cal management. These drugs are effective, with
relatively low adverse effects. NSAIDs reduce
the formation of inflammatory prostaglandins,
primarily PGE2, and thromboxane production
by inhibiting cyclooxygenase (COX) enzymes in
the arachadonic acid (AA) pathway. With the
inhibition of COX isoenzymes, NSAIDs have a
local effect at the site of injury as well as a cen-
tral effect minimizing spinal nociception and
central sensitization. NSAIDs may also sensitize
mu receptors to the effects of opioids, explain-
ing the synergism between these two medica-
tions. The benefit exerted by NSAIDs in the
treatment of OA is indisputable. Recently, spe-
cific receptor antagonists have been developed
to act on receptors activated by PGE2. Phar-
macologically, these PGE2 receptors are sub-
divided into at least four subtypes (EP1–EP4).
The distribution of these receptors is considered
when explaining the multiple effects of PGE2 in
various tissues (Narumiyaet al. 1999; Kawabata
2011; Kawaharaet al. 2015). There is increasing
evidence that demonstrates the effectiveness of
selective EP4 receptor antagonists as analgesics
in a variety of inflammatory pain models in a
variety of species (Linet al. 2006; Nakaoet al.
2007; Muraseet al. 2008; Colucciet al. 2010), as
well as in clinical trials in dogs (Rausch-Derra
et al. 2015; Rausch-Derraet al. 2016). NSAIDs are