Last Edited 6-2011
Chronic pain management is one of the most important
aspects of veterinary medicine today, especially in geriatric patients. And
yet, it is one of the most under developed areas of many practices. As a
consequence to injury or as a component of the aging process, chronic pain
can be a major influence in our patient’s quality of life. In larger dogs,
unmanageable pain is often the final determinant in the timing of their
There are many medications that we are all familiar
with that form a basis for pain management. We have been the beneficiaries
of the development of many excellent NSAIDs like RimadylÒ(carprofen),
and PrevicoxÒ (firocoxib).
The chondroprotectants, including Cosequin and Dasequin amongst others, have
been problem free adjuncts that have been well received by our clients even
though clinical studies validating their efficacy are still lacking. The
disease modifying pGAG, Adequan, has more clinical research behind its
ability to support cartilage health while interfering with degradative
matrix metalloproteinases making it a foundational choice for osteoarthritic
A brief review of the anatomic and neurophysiologic
aspects of pain process is necessary to form a basis for more advanced
multimodal pain management. There 3 basic structural components in the pain
pathway: the peripheral pain receptors with cell bodies in the dorsal root
ganglia that synapse with the second order neuron in the dorsal horn of the
spinal cord, the second order projection neuron that synapse with the third
order neuron in the thalamic area of the brain stem, and the third order
neuron that carries the pain impulse to the higher brain structures.
There are both protective and debilitating aspects to
pain. Physiologic pain tells the body when it is at risk for tissue damage
from temperature extremes, chemical agents, and direct tissue injury.
Clearly, physiologic pain is protective. Initially, acute posttraumatic pain
may be protective in that it encourages the patient to guard an injured area
until healing occurs. But the pain and sensory pathways are susceptible to a
variety of influences that alter the sensitivity and the structure of these
neurons. The stronger the painful stimulus and the longer it persists, the
greater the likelihood that chronic pain will continue well beyond the
normal healing period. Chronic pain can be a debilitating affliction, the
presence of which our patients are poorly equipped to effectively
communicate to either owner or veterinarian.
The nociceptors (pain receptors) associated with
physiologic pain have much higher thresholds than the sensory nerves
responsible for general tactile information. There are different nerve types
associated with the sensory (A beta fibers) and nociceptive (A delta and C
fibers) receptors but they all form synapses with neurons in the dorsal horn
of the spinal cord.
The inflammatory mediators that accumulate at the site
of tissue injury cause an amplification of the pain response at the site of
injury. With the nerve threshold lowered even a light touch can evoke a
strong painful sensation. This peripheral sensitization, often referred to
as primary hyperalgesia, can be limited by many drug classes including
NSAIDs, opioids, corticosteroids, local anesthetics, and alpha-2 agonists.
Uncontrolled stimulation of the dorsal horn neurons can
alter the sensitivity and the structure of these neurons. The stimulus
threshold of these neurons decreases not only for the neurons directly
associated with the primary nociceptors of the traumatized tissue but also
for neurons associated with the normal tissues surrounding the injured area.
Secondary hyperalgesia is the term used to describe the exaggerated painful
sensations arising from relatively innocuous stimulation of the pain
receptors in the uninjured tissues surrounding the site of injury.
To add insult to injury, the sensory nerve fibers may
undergo a structural reorganization at the dorsal horn level. This leads to
painful sensations from such innocent contact as the touch of a feather or
the light touch of a cloth all mediated through the sensory fibers. This
component of pain is referred to as allodynia.
Collectively, secondary hyperalgesia and allodynia make
up what is commonly called central sensitization or dorsal horn windup. The
net effect is that innocent sensations are perceived as pain and what should
be mildly painful sensations are perceived to be very painful. NMDA
antagonists, NSAIDs, opioids, local anesthetics, tricyclic antidepressants,
anticonvulsants (gabapentin), and alpha-2 agonists can all help control
The final step in the pain pathway involves the
delivery of the pain impulse from the thalamic region to the cerebral cortex
triggering the conscious perception of pain. Although anesthetic block this
perception of pain, they do NOT prevent the peripheral and central
sensitization process from occurring. Opioids and alpha-2 agonists help
control pain perception. In addition, sedative/tranquilizers can help reduce
the perception of pain and the stress response that can contribute to the
sensitization process. Alone, sedative/tranquilizers are not an appropriate
substitute for proper analgesics but they are valuable adjuncts when
included in a multimodal analgesic program.
The more severe and complex the pain process, the more
likely you are going to need medications targeting different elements in the
pain pathway. Borrowing from the work done in human pain management, we have
a vast array of effective and reasonably safe methods for managing more
serious pain in dogs and cats. All therapeutic programs should be associated
with careful patient monitoring to include physical examinations and
appropriate laboratory monitoring tests.
Conservative estimates suggest that no less than 20% of
the canine population suffers from OA. It is also suggested that 90% of cats
over 12 years of age have evidence of degenerative joint disease. This is a
large group of patients that not only deserve our assistance but they can
serve as a significant source of income for the practice. We can first look
at osteoarthritis (OA) as an example of chronic pain management, then apply
the same principles to other pain related problems.
Appropriate weight control may be the single most
important aspect of OA management. Proper weight control, in and of itself,
can reduce the frequency of OA development in at-risk dogs from 83% to 50%,
altogether sparing 40% of the patients that would have developed this
debilitating disease. Weight reduction in overweight OA dogs and cats can
dramatically improve their comfort level and often helps to reduce the
amount of medication needed for pain control. Appropriate exercise also is
an important aspect of OA management.
NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
NSAIDs are the most common medication group prescribed
for OA and chronic pain management. No single drug in this class has proven
consistently superior in analgesic efficacy or with respect to the potential
for adverse drug effects.
While COX-2 preferential NSAIDs (carprofen, meloxicam)
and the coxib class NSAIDs (deracoxib, foricoxib) have become popular and
are consistently regarded as “safer” drugs than less selective NSAIDs, COX-2
suppression has its downsides. By selectively sparing COX-1, there has been
a reduction in the frequency of NSAID related GI problems but COX-2
inhibitors can adversely affect important protective renal compensatory
mechanisms and they can delay GI healing. Additionally, there are concerns
about COX-2 inhibitors delaying bone healing in fracture patients. Whether
lipoxygenase inhibition (tepoxalin) will be a real additional benefit is not
ALL NSAIDs have the potential to cause both benefit and
harm. Only by therapeutic trials and careful patient monitoring can you
determine which, if any, NSAID best fits a given patient. Initial treatment
failure may be discouraging, but additional trials with other drugs in the
group will often reveal significantly more patient benefit.
NSAIDs are active at the peripheral and central level.
They are capable of reducing the peripheral inflammatory response and they
help manage central sensitization at the dorsal horn level. They should be
used with caution, if used at all, in patients with preexisting
gastrointestinal, renal, and hepatic disease. Monitoring for adverse effects
is an important aspect of any chronic medication program. Adverse effects
include gastrointestinal, renal, hepatic, and keratoconjunctivitis sicca
Treatment considerations include: whether or not an SID
medication would improve client compliance (etodolac, deracoxib, tepoxalin,
and carprofen), whether or not the availability of inexpensive generics
would relieve the burden of medication expense (etodolac), and whether or
not administration would be easier for the client with a chewable (carprofen,
deracoxib) or a rapidly disintegrating medication (tepoxalin).
NSAIDs should be used with great caution in cats. Whenever possible other analgesics and pain relieving modalities should be
explored before committing to long term NSAID use in cats. Currently,
despite its US black box warnings, meloxicam presents as the most
appropriate choice for long-term NSAID therapy in cats. The most common long
term meloxicam dosing recommendation is 0.1 mg/kg SC, PO on day 1 followed
by 0.05 mg/kg PO SID for up to 4 days followed by 0.025 mg/kg PO every 48 to
72 hours (find the lowest effective dose). For accurate dosing use a TB or
insulin syringe (minus needle).
Canine NSAID dosing:
CARPROFEN 4 mg/kg initial dose PO, SC followed
by 2 mg/kg PO, SC every 12 hours (or, less ideally, 4 mg/kg every 24 hours)
DERACOXIB 3 to 4 mg/kg PO every 24 hours for up
to 7 days, then 1 to 2 mg/kg PO every 24 hours
ETODOLAC 10 to 15 mg/kg PO every 24 hours
FIROCOXIB 5mg/kg PO every 24 hours
MELOXICAM 0.1 to 0.2 mg/kg SC, PO initial dose
followed by 0.05 to 0.10 mg/kg SC, PO every 24 hours (when used long term
titrate to minimal effective dose)
Tramadol is an excellent choice for canine patients
inadequately controlled on NSAIDs alone and for those intolerant of NSAIDs.
Tramadol and its M1 metabolite, O-desmethyltramadol, exert a multimodal
effect involving opioid, adrenergic, and monoamine receptors. As such,
tramadol has both peripheral and centrally mediated analgesic benefit.
Available in generic form, tramadol is a relatively inexpensive medication
free of significant side effects. While tramadol can be a useful analgesic
for cats its bitter taste and tendency to cause dysphoria limits its use in
Initial dosing usually starts at 3 to 5 mg/kg TID to
QID for dogs. The dose can be increased up to 5 to 10 mg/kg QID for more
difficult to manage canine cases. At these higher doses some sedation may be
evident and constipation may occur with long-term use. While tramadol can be
used at 1 to 2 mg/kg BID for cats, cats are not particularly tolerant of
Tramadol is available in 50 mg tablets. It is
compatible with most medications with the exception of the
monoamine oxidase inhibitors (in particular, MAO-AIs), selective serotonin
reuptake inhibitors, and some tricyclic antidepressants. Tramadol has been
used extensively in combination with the TCA amitriptyline. Under proper
supervision and with careful consideration to the dosing of each drug the
author has not seem any adverse events over several year in our clinical
Tramadol may decrease seizure threshold. It should be
used with caution in patients with a history of seizure activity. Tramadol
may potentiate the sedative influence of other medications. Excretion is by
both the hepatic and renal routes; a dose reduction would be appropriate in
patients with impaired renal or hepatic function.
Amantadine is an NMDA (N-methyl-D-aspartate) antagonist
capable of playing a critical role in acute and chronic pain management.
NMDA receptors play a key role in the dorsal horn windup phenomena so
crucial to central sensitization. Ketamine is an important in-hospital NMDA
antagonist, analgesic adjunct, but ketamine is clearly not suited to home
use. Dextromethorphan is also an effective NMDA antagonist, but its poor
bioavailability when administered orally, its short half-life, and its rapid
clearance make it less well suited to home analgesic use. Amantadine is the
best-suited oral NMDA antagonist available for dog and cat pain management
Amantadine was originally developed as an anti-viral
medication and has been also used to treat Parkinson’s disease. It is an
attractive “third man in” for patients inadequately managed on NSAIDs and
tramadol or it can be teamed with an opioid alone (tramadol or oral
morphine) in NSAID intolerant patients.
Amantadine is dosed at 3 to 5 mg/kg every 24 hours PO
for both cats and dogs. It is available in 100 mg capsules and in a 10 mg/ml
liquid form. While amantadine is considered safe when used for long-term
daily therapy, it is often effective as a pulsed therapy, giving it 2 weeks
on followed by 1 to 2 weeks off drug. This can reduce drug expense and
relieve some of the client’s medication burden.
Although this drug has some monoamine reuptake
inhibitory effects, those effects are dopamine specific and of no real
concern related to serotonin syndrome when combined with tramadol, MAOIs,
SSRIs, and TCAs.
This drug is primarily excreted, unchanged, in the
urine. The dose should be reduced, and patient monitored closely, if used in
patients with renal impairment. As a once-daily medication available in
generic form, amantadine is not a very expensive addition to the pain
Gabapentin was originally developed as an
anticonvulsant drug but it too can be an effective component of chronic pain
management. It has been shown to be particularly effective in neuropathic
pain management (pain from direct nerve injury) and cancer related pain due
to its ability to block the alpha-2, delta-1 subunit of the dorsal horn
calcium ion channels.
Gabapentin is useful for both dogs and cats. It is
generally free of adverse effects or adverse drug interactions although some
patients will show a transient drowsiness usually limited to a few days
duration. Dogs are typically dosed at 5 to 10 mg/kg BID to QID PO although
doses as low as 2 mg/kg BID have been reported to be effective in some cases
while doses as high as 120 mg/kg/day have been required in other cases. Cats
are typically dosed at 2 to 10 mg/kg BID PO.
Gabapentin is available in 100 mg, 300 mg, 400 mg, 600
mg and 800 mg sizes. Use of the 50 mg/ml liquid product is not recommended
due to its xylitol content. The widespread availability of generic
gabapentin has made this an affordable analgesic even for larger patients.
This drug is primarily excreted, unchanged, in the
urine. The dose should be reduced, and patient monitored closely, when used
for patients with renal impairment. Gabapentin may potentiate the sedative
influence of other medications. Withdrawal of this drug should be done
gradually to avoid rebound pain.
Amitriptyline, the tricyclic antidepressant, is another
drug with centrally mediated analgesic potential. This drug inhibits
monoamine reuptake (norepinephrine and serotonin), may have some opioid
receptor activity (or opioid receptor enhancement activity), as well as
blocking sodium channels, microglial activity, and NMDA receptors.
Dogs are dosed at 0.25 to 2 mg/kg PO SID to BID. Cats
are also dosed at 0.25 to 2 mg/kg PO SID to BID. It is available in 10, 25,
50, 75, 100, and 150 mg tablets. In man, doses below the behavioral oriented
range are often effective at controlling pain.
Amitriptyline should be used with great caution, if at
all, when mixed with other TCAs, SSRIs, or MAOIs due to the risk of
serotonin syndrome. Concomitant use with tramadol is not an uncommon pairing
but should be done with caution. The author has used this combination for
many years without any adverse outcomes but dosing of both tramadol and
amitriptyline needs to be carefully factored into the decision making
process. Amitriptyline’s use with amantadine is not considered to be a
problem for the reason noted above. Amitriptyline does have anticholinergic
properties that should be taken into account particularly when planning
anesthetic events. Amitriptyline may potentiate the sedative influence of
other medications. Amitriptyline may decrease seizure threshold. It should
be used with caution in patients with a history of seizure activity. This
drug is metabolized by the liver. Dose reductions would be appropriate in
patients with hepatic impairment. In addition, the patient’s cardiac status
should be monitored.
Opioids delivered by the transdermal, transmucosal, and
oral route are often considered in the later phases of difficult pain
management cases. Mu agonists like morphine and fentanyl are associated with
more adverse effects than the medications discussed above. These scheduled
drugs also require significantly more record keeping. Sedation and
constipation are the most common of these unwanted effects. Drug tolerance
can also complicate long-term opioid therapy. NMDA antagonists like
amantadine can help reduce opioid tolerance.
The first-pass effect typically removes 85 to 95% of
opioids absorbed from the gastrointestinal tract. This explains why
buprenorphine and butorphanol are such ineffective analgesics when
swallowed. Opioids are not without their ability to provide some analgesia
when administered orally however. Morphine is the most commonly used opioid
analgesics felt to be of benefit when given by the oral route.
Codeine is not a recommended analgesic for dogs or
cats. It is generally only available in combination with acetaminophen which
makes it completely unsuited to feline use. Its use in dogs is discouraged
as most dogs lack the CYP2D6 enzyme primarily responsible for the conversion
of codeine to morphine, its most active metabolite. That being said, there
may be some analgesic value to codeine in dogs via the C6G metabolite.
Morphine is a more attractive long-term oral opioid
with oral bioavailability of about 15%. Dogs are dosed at 0.5 to 2.0 mg/kg
QID PO. Cats are cautiously dosed at 0.2 to 0.5 mg/kg TID to QID PO.
Morphine is available in capsule, tablet, and liquid forms. The sustained
release morphine products offer no real advantage over the non-sustained
release form when given to dogs and cats.
Fentanyl patches are not a particularly attractive
long-term opioid analgesic. Their efficacy is quite variable with some
studies suggesting that 1/3 of cats fail to absorb therapeutic fentanyl
levels. The patch would need to be changed every 3 to 5 days. Some patients
develop pronounced dermatitis at the patch site.
Transmucosal buprenorphine, unlike oral buprenorphine,
is an extremely effective, albeit somewhat expensive long term opioid
analgesic for cats. Sheila Robertson’s work has clearly shown that
transmucosal absorption is an efficient method of buprenorphine delivery
with the same bioavailability as IM administration. The clients are
instructed to “tuck the syringe inside the cheek pouch”. A less challenging
routine than attempting to have the cat swallow a liquid medication over a
sustained period of time.
There have been persisting suggestions that
buprenorphine can an effective analgesic when mixed with V.A.L. syrup,
clavamox, or amoxicillin for postoperative use in cats. Although this might
seem attractive on the surface, it is not an appropriate use of this opioid
due to the first-pass effect.
A sustained release (SR) formulation of buprenorphine
has been available for a few years. It is currently building validation via
research at Colorado State University. Currently, dosing is recommended at
0.12 mg/kg SQ with expected duration of about 72 hours. The author precedes
the SR product with a loading dose of standard buprenorphine at 0.020 mg/kg
IM or IV to insure adequate CNS biophase transfer.
Constipation from long-term opioid administration,
should it occur, can usually be managed through diet modification and by
acupuncture at the GV1 acupuncture point.
Lidocaine patches (LidodermÒ)
are less well known option for pain management. Although there is no
systemic uptake, lidocaine patches applied over areas of pain have been
shown to be beneficial for human and, it appears, veterinary pain
management. Unlike fentanyl patches, LidodermÒ patches can, and should, be cut to proper size and shape. They may be placed
adjacent to, but not directly over, incisions, over areas of spinal pain,
painful joints, bone tumors in peripheral limbs, and fractured bones.
Ongoing work at the University level suggests benefit even in large dogs
with pelvic fractures.
While the lidocaine patch will transfer drug into the
tissue under the patch for only 12 to 24 hours, the beneficial pain relief
may last far longer. The patch should be applied to a clipped area of
healthy skin. Wipe the area gently with a slightly dampened sponge to remove
the loose hair and scale. Let the area dry then apply the patch. Cover the
area with a bandage to help maintain skin adhesion but also to make sure the
patient does not ingest the patch.
Patch ingestion can lead to lidocaine toxicity (CNS
stimulation and CV depression). If you cannot adequately limit the patient’s
access to the area, do NOT use a lidocaine patch. While there is no expected
drug transfer past the first 12 to 24 hours, the patch can usually be left
in place for many days without causing any skin irritation. Each patch costs
about $6.00. They should be available with a prescription from your local
pharmacy or many of the full service medical suppliers.
CONSTANT RATE IV INFUSIONS & Epidural Injections
Constant rate infusions (also called manually
controlled infusions; MCIs) and epidural analgesic injections can be
extremely beneficial initial measures in a chronic pain management strategy.
Severe pain can respond well to intravenous infusions that combine ketamine,
lidocaine, and a mu agonist opioid (most commonly morphine or fentanyl).
Epidural injections of mu agonist opioids, local anesthetics, ketamine,
alpha-2 agonists, and midazolam can be included to further enhance initial
chronic pain control. These combination works mainly at the dorsal horn
level to quiet the sensitization process described above.
For more information on MLK CRIs see: http://www.vasg.org/constant_rate_infusions.htm.
For more information on epidural injections see: http://www.vasg.org/epidural_injections.htm.
long-term analgesic therapy should be done gradually whenever
possible. Gradual drug withdrawal would be most important when using the
opioids and gabapentin. This is not necessary with respect to the NSAIDs and
by coordinating compatible medications and treatment modalities, the various
aspects of the pain pathway can be targeted for a total benefit unachievable
by any one medication alone. Balanced analgesia allows for lowered doses of
any one drug, potentially allowing a patient to remain on a medication it
would otherwise have been intolerant of. Therapeutic trials are normally
required to help fine-tune the medication combinations for the most
cost-effective and efficacious long-term management strategy with minimal
adverse drug effects.