490 Canine Sports Medicine and Rehabilitation
Selective serotonin reuptake inhibitors
and selective serotonin norepinephrine
reuptake inhibitors
Serotonin and norepinephrine reuptake inhibi-
tors (SSRIs and SSNRIs, respectively) come in
various degrees of selectivity for these inhibitory
neurotransmitters. Most are labeled as antide-
pressants, revealing the shared pathways and
well‐established comorbidity of depression and
chronic pain. Newer SSRIs and SSNRIs such
as milnacipran (Savella®) and duloxetine
(Cymbalta®) have been developed for chronic
neuropathic pain states in humans. Duloxetine’s
label has expanded from treatment of diabetic
neuropathy, postherpetic neuralgia, and fibro-
myalgia to include OA and low back pain.
Pharmacokinetic studies of duloxetine in dogs
are conflicting. The European Medicines Agency
(2005) found very low bioavailability (Patel et al.,
2011; KuKanich, 2013), yet a more recent study
suggested a dose‐dependent increase of plasma
levels equivalent to those found in humans (Baek
et al., 2013). Another SNRI, venlafaxine, has dem-
onstrated efficacy in human OA (Sullivan et al.,
2009), and in dogs appears to have approxi-
mately 50% oral bioavailability (Howell et al.,
1994). While no clinical studies exist regarding
use of any SNRIs in canine OA, both duloxetine
and venlafaxine come as non‐controlled generics
and may hold possible promise in that area.
Fluoxetine (Prozac®), an SSRI, reveals a less
robust impact on chronic pain in humans, sug-
gesting that it is the noradrenergic more than
the serotoninergic effect that elicits the most
significant pain‐modifying effect. Some studies
suggest the possible efficacy of fluoxetine for
OA in humans (Chappell et al., 2011), and its
relative safety margin and low expense may
make fluoxetine a consideration in some dogs
with OA or other chronic pain states. As veteri-
narians can neither classify nor diagnose clini-
cal depression in dogs, we cannot know to what
degree any clinical response to these drugs
might be attributed to improved comfort ver-
sus improved state of mind or both.
Other drugs in class
● Trazadone (with many trade names) is an
antidepressant serotonin antagonist and
reuptake inhibitor (SARI) gaining some util-
ity as an adjunct to SSRIs, opioids, and anti-
convulsants for an anxiolytic, tranquilizing,
and relaxant effect (Calandre et al., 2011). Its
properties as an analgesic are less certain
but in humans its off‐label use for some neu-
ropathic pain conditions has been reported.See Figure 19.3 for cautions regarding possible
serotoninergic drug interactions.AnxiolyticsAnxiety contributes directly to the hyperalgesic
state through cholecystikinin‐mediated nocebo
effect (Benedetti et al., 2006). Many studies sup-
port the clinical relevance of this in humans, and
in animals as well where restraint, social defeat,
and rotation (all common veterinary patient
experiences) contribute to hyperalgesia
(Martenson et al., 2009). The first leg of a strong
transoperative pain management protocol
involves the use of anxiolytics (i.e., tranquiliz-
ers/sedatives). Clinicians may choose between
phenothiazines (e.g., acepromazine), benzodiaz-
epines (midazolam or diazepam), or alpha‐2
agonists (dex/medetomidine). Additional but
significant mindfulness should be granted
towards non‐pharmacological patient‐calming
strategies: well‐established low‐stress and fear‐
free handling techniques, a patient setting
including the use of facial pheromones, the influ-
ence of smell and noise, and the benefit of human
voice and touch.Disease‐modifying osteoarthritic agentsDisease‐modifying osteoarthritic agents
(DMOAAs) may not have a primary analgesic
mechanism of action, but still have a positive
influence on OA in terms of reducing pain and
slowing progression of the disease. The only
veterinary FDA‐approved drug in this category
is Adequan®, a polysulfated glycosaminogly-
can (PSGAG). PSGAGs inhibit degradative
enzymes such as collagenase and metallopro-
teinases, and reportedly promote the formation
of fibrocartilage (Altman et al., 1989; Fujiki et al.,
2007), with additional studies that support effi-
cacy. CartrophenVet® is a PSGAG available
outside the United States.