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Oncology Pain in Veterinary Patients

Andrea Looney, DVM, DACVA
Cancer, cancer pain, and the undertreatment of cancer pain are epidemic in both the human and veterinary
medical field. Concerns over recognition, assessment, and treatment of oncologic pain in our veterinary
patients are multiplied when one realizes the interaction of the primary tumor, the pain itself, and even cancer
treatments with fatigue, disability, dyspnea, weakness, impaired gastrointestinal motility, cognition, and
urinary/defecation issues. The patients overall health status, as well as owner psychological and spiritual
distress, plays a large part in quality-of-life decisions. We will discuss classification and assessment of cancer
pain, quality-of-life issues, and therapies for managing cancer pain, including pharmacologic, nonpharmacologic, and interventional techniques. The goal will be establishment of a new oncologic treatment pyramid or
scale for veterinary patients, one that will guide clinicians mechanistically into thinking through the anamnesis,
physical examination, and assessment of the whole patient, and on toward diagnostics and treatments available
for companion animals with cancer.
2010 Published by Elsevier Inc.
Keywords: cancer, pain, supportive care, palliative care, topical agents, infusions, radiation, neurolysis, nonsteroidal antiinflammatory drugs (NSAIDs), opioids, tricyclic antidepressants (TCAs), antihistamines, calcium
channel modulators

urveys performed in the human medical field indicate

pain prevalence of 28% among patients with newly diagnosed cancer, above 50% in patients with existing disease,
and as high as 80% in patients with advanced tumors and
paraneoplastic disease.1 Chances are high that our veterinary
patients experience similar pain, and, as such, relief of this
pain is not only ethically imperative but constitutes one of the
basic tenets of care for the other family physician, that is,
the veterinarian. The undertreatment of cancer pain continues to be very common and has many causes, among which
are lack of recognition of pain and suffering, inadequate or
irregular historical questioning (especially dealing with relatively simple quality-of-life [QOL]issues), diagnostic dilemmas, and lack of both baseline and follow-up assessment.
In the past decade, much research has been turned toward
the biological mechanisms of nociceptive activation, propagation, and accentuation by cancer. Soon, we may have objective tests that reveal the neurochemical nature of tumor
and host, thereby guiding individualized therapy against the
tissues and nerves propagating both disease and pain. Until
that time, however, we are obligated to maintain the health
of the whole patient, answer to the owner, strengthen the
human-animal bond, and, as best we can, isolate and treat

From the Cornell University Hospital for Animals, Cornell University,

Ithaca, New York, USA.
Address reprint requests to: Andrea Looney, DVM, DACVA, Cornell University Hospital for Animals, Cornell University, Ithaca, NY 14853. E-mail:
2010 Published by Elsevier Inc.


the pain. Cancer pain can originate from many sources including direct tumor invasion of tissues, various modalities of
therapy, chronic debilitation that accompanies the neoplasia
(paraneoplastic disease), and even pain that is due to preexisting concurrent disease in the oncology patient.2
The temporal classification of acute, breakthrough, or
chronic time scheme for pain is relevant but frequently provides an inadequate means of classification, especially in the
later chapters of disease.3,4 Acute pain occurs predictably
with cancer during diagnostic and therapeutic interventions
but rarely with the initial cancer (mast cell tumors, thrombosis, or infection of any primary tumor or metastasis), and
includes postoperative pain, pain associated with biopsy or
cytotoxic infusions, radiation, mucositis, and proctitis. Chronic
pain occurs more commonly in cancer patients via neuropathic mechanisms and includes bone pain from metastasis,
referred or distant pain, bone marrow necrosis due to chemotherapeutic agents, arthritides, soft tissue pain from recumbency and disability, neuropathies, and even chronic
pain from poorly treated operative pain.
Pathophysiologic classification often assists in both diagnosis and management of oncology pain. This involves separating pain into nociceptive, neuropathic, and, for human
patients, psychogenic pain. Nociceptive pain results from the
stimulation (direct and inflammatory) of afferent pathways
in either visceral or somatic tissues. The former is diffuse and
difficult to identify, but the latter is often localized. Nociceptive pain usually correlates well with tissue damage and is
treatable initially with a variety of options, including surgery
and analgesic agents like opioids. Neuropathic pain is caused
by innate pathology in anything beyond the nociceptors, either centrally or peripherally, and it can be generated by

Volume 25, Number 1, February 2010

nerve compression, deafferentation, and sympathetic disruption. Neuropathic pain often follows a dermatomal distribution of nerves or nerve roots and is not as responsive to
opioids, especially later in the neoplastic process. Adjunctive
agents such as interventional therapies, antiepileptic drugs
(AEDs), antidepressants, and antiarrhythmics are important
therapeutic options for neuropathic pain.5
Why bother classifying cancer pain? Classification better
guides treatment. Currently, the World Health Organizations (WHO) 3-step ladder of analgesia is the gold standard
for therapy of cancer pain in humans. However, a treatment
approach that determines analgesic therapy based on the individuals entire health (along with a progression of severity)
is truly what is needed. In fact, in veterinary medicine, we
need to refine our therapeutic choices to form a pyramid or
elevator based on didactics and evidence, but shaped by the
family, environment, finances, and role of the animal, which
moves the patient toward global QOL.

Finding and Recognizing Pain in Our Oncology

Patients: History and Physical Examination
One area that has revolutionized palliative care is careful
assessment of complex and troubling complaints, history,
and symptoms in a cancer patient. Scoring systems such as
the Edmonton Symptom Assessment System and the Provocation, Quality, Radiation, Severity, and Temporal Quality
System are used in human palliative care for pain description.4,6 Although not entirely practical for veterinary patients, history-taking cannot be overemphasized in terms of
chronology, characteristics of pain, responses to therapies,
activities of daily living, appetite, bowel and bladder habits,
sleep, mobility issues, and anxiety levels. QOL scoring systems have made identifying chronic and cancer pain possible
in our veterinary patients, and these systems are highly advocated as part of the intake palliative care questionnaire.
The oncology patient is assigned a score of 0 to 10, with 0
equaling a pain-free state and 10 equaling the worst pain
imaginable, based on the owners answers to questions concerning such issues as overall happiness, family interaction,
tail and ear carriage, appetite, gastrointestinal health, bowel
and bladder habits, anxiety and mental state, gait/mobility,
posture, and rising and sleep/fatigue patterns. Examples of
these systems exist within the literature and guide the practitioner toward establishment of his or her own QOL
A complete inventory (including administration and dosage) of drugs (topical, parenteral, and oral), nutraceuticals,
supplements, homeopathic and herbal remedies, as well as
recent and past surgeries, preexisting problems (e.g., cystitis,
dental disease), and current/past chemotherapeutic agents is
necessary. Chemotherapy-related dysfunction and pain are
common in people with cancer (i.e., vincristin and vinblastin
can cause peripheral neuropathies, whereas chlorambucil
and cyclophosphamide can cause cystitis and leukopenias).11
Nutritional analysis is also an integral part of the history that
requires scrutiny in terms of key vitamin, protein, carbohy-

drate and fat levels, as well as balance dictated by type of
cancer and body systems affected, and with attention to palatability. Parasite prevention status, vaccination, and titer
information is helpful in determining antigenic load as well
as the need for parasiticides and preventative monthly medications. Ease of in-house chemistry testing likely dictates
that prior bloodwork, heartworm, ehrlichial, and parasite
testing has already been accomplished, leading to baseline
values that can be used for comparison or for general health
Preexisting conditions seed complexity in patients with
cancer pain. Accordingly, the pain practitioner should troubleshoot a problem list in a cancer patient, one that always
includes the actual tumor, surgery, and chemotherapy agents,
but also includes simple issues such as ongoing health
problems (e.g., a carnassial tooth root abscess and history of
pancreatitis). Although an acute flare up of abdominal pain
in a lymphoma patient with such issues in its history is assumed to be recrudescence of lymphoma until proven otherwise, simple assumption without careful history-taking and
pharmacologic inventory could lead to unfortunate premature euthanasia, let alone disastrous management of the case.
Likewise, attention to dosage and frequency of administration of all drugs is essential. For example, steroid treatments
often prescribed for oncology patients may cause severe side
effects, completely debilitating an animals overall demeanor
and health status, allowing underlying infections to prosper,
creating weakness and insomnia, and annoying the family
with polyuria/polydipsia issues. However, these drugs are a
necessary aspect for treatment of some cancers and even
some forms of pain. As such, careful attention to minimal
dosage necessary, as well as frequency of administration, will
allow multimodal forms of therapy with other agents minimizing the above-mentioned side effects yet maintaining the
positive effects of steroids. QOL will be prolonged with cautious initial doses, escalating as needed for pain and combining such steroidal drugs with other agents to attack the pain
focus and change neurons as the cancer progresses.
The physical examination of a painful oncology patient
includes a general physical examination, in-depth scrutiny of
the surgery or tumor site (with caution on deep palpation and
avoidance of aggressive tissue handling), examination of dermatome involvement and possible referred pain, analysis of
gait and movement, complete neurologic and musculoskeletal examination, respiratory pattern assessment, and a generalized behavior assessment. The more acute and severe pain
must be evaluated in adherence to the rules of critical care
(i.e., what is the animals blood volume, hydration, electrolyte status, white and red cell count, glucose, albumin, nutritional status, and so forth). Common diagnostics (complete
blood count, serum chemistries, urinalysis, urine culture/sensitivity, chest radiographs, abdominal ultrasound) often
must be accompanied by advanced imaging (magnetic resonance imaging, computed tomography) and even occasionally somewhat sophisticated diagnostics of thermography,
gait analysis, force plate analysis, scintigraphy, fluoroscopy,
and nerve conduction testing.


Topics in Companion Animal Medicine

Basic Tenets of Palliative Care

Figure 1. Methods of managing cancer pain in veterinary

patients. The red color corresponds to treatments aimed at
underlying primary neoplastic pathology, the green color
corresponds to the basic tenets of palliative care, and the
solid black-colored triangle centers on the therapeutic interventions (pharmacologic, nonpharmacologic, and interventional) used to treat cancer pain.

Regardless of the type of cancer and the animal patient

involved, a broadened wide-scope history, careful subjective
evaluation based on QOL criteria, recognition of general
health status, focus on complete drug/supplement/nutrition
analysis and subsequent polypharmacy issues, and specific
pain testing and imaging all allow pain to be truly diagnosed and determined in the oncology patient. Once diagnosed, the question then becomes how we can treat this to
the best of our abilities with both pharmacologic and nonpharmacologic therapies.

Methods of Managing Cancer Pain

Methods of managing pain can be divided into 3 major
categories (see Fig 1). First, treatment may be aimed at the
underlying pathology via chemotherapy, surgery, and radiation, all methods that attempt to control the disease
process itself. Second, are the approaches used to change
the individuals transduction, transmission, perception,
and sensation of pain. These are what most veterinarians
refer to as the true treatments or therapeutic interventions
for oncologic pain, and they include pharmacologic, nonpharmacologic, and even interventional modalities. Finally, and likely most importantly, the third approach consists of a number of interventions aimed at diminishing the
suffering component of pain and allowing global whole
health care of the patient, the basic tenets of palliative
care. These are all the measures that this author believes
are most important in determining QOL and best treatment schemes for the veterinary oncology patient.

Evaluation of the environment, elimination of known exposure to carcinogens, alteration of the environment (e.g., using
ramps vs steps, and perhaps carpeting slippery surfaces), acknowledgment of the special status of the animal in the
family, attention to healthy nutrition and different bowel/
bladder habits, as well as establishment of realistic outcomes
with the owner should all be addressed. Most domestic animals do very well with routine and set schedules, so establishment of these may not only assist with feeding, medication, and bathroom breaks, but will likely help the mental
health and well-being of the patient also.
Todays owners are very internet savvy and as such will likely
be researching different diagnostics and therapeutics, as well as
supplements and nutritional remedies, sometimes with a vengeance. Being open-minded, receptive, interested, and attentive
to their questions will make all the difference in their trust with
you, your staff, and their realistic goals for treatment, preservation of well-being, and QOL. Establishing a pain diary to include QOL indicators, as well as regular call back sessions
(initially weekly to terminally daily) will assist in managing your
schedule as well as allowing objectivity in determining true
QOL with distraught owners.
Both constipation and diarrhea, side effects of drug therapies, stress, surgery, and even the cancer itself can be treated
initially with polypharmacy balancing (making sure that no
medications are responsible for the given symptoms), addition of fiber, fecal examination to rule out parasitism, use of
limited fat and protein diets, and relatively simple medications (e.g., sulfa drugs, H2 antagonists, metronidazole, loperamide, and so forth).12,13 Nausea and vomiting, which classically accompany many chronic illnesses in companion
animals, can be treated similarly by first ruling out and eliminating any existing pharmacologic or nutritional agents that
can cause such, and then using various classes of agents from
anticholinergics and antacids, to serotonin receptor antagonists, antihistamines, and H2 blockers, to phenothiazines,
and neurokinin antagonists, to control emesis.14
Appetite may fall short with disease and with therapy, and
as such, nature and palatability of foods and bacterial flora of
the gastrointestinal tract can likewise be modulated. Antihistamines, benzodiazepines, acupuncture, moxabustion, cannabinoids, subcutaneous fluid therapy, and even mild exercise and enrichment can aide in stimulating eating habits.
Likewise, elimination of any drugs that can cause reduction
in appetite is advocated. Attention to dermatologic issues
including mucositis and proctitis, as well as endocrine (thyroid and adrenal) status will greatly assist overall mental
health and reduced stress and anxiety. Urinary incontinence,
urinary tract infections, and straining and retention common
with stress, drug therapies, and a variety of pelvic canal diseases can be treated with many agents including sympathomimetics (e.g., phenylpropanolamine, ephedrine), estrogenic
compounds (diethylstilbestrol), tricyclic antidepressants, antihistamines, benzodiazepines, alpha blockers, and antispasmodics.15,16


Volume 25, Number 1, February 2010

Sleep preservation as well as mental clarity can be modulated with the help of many medications such as selective
serotonin reuptake inhibitors, tricyclic antidepressants, benzodiazepines, neuroleptics, methylphenidate, methylxanthines,
and even basic supplements such as coenzyme Q10 and creatine. Using these agents can promote positive output in
terms of energy, and, in turn, energy levels have much to do
with attitude, daily physical routine, enrichment, and lack of
pain. Mobility devices including orthotics, prosthetics, mobility carts, and even easy-to-wear harnesses (i.e., www.
helpemup.com) and support devices (www.walkaboutharness.
com) aide in allowing patient comfort, activity, and cleanliness,
as well as helping owners with lifting issues and patient support during convalescence.
Because most cancers occur in older animals, being a good
general geriatric practitioner should always be part of the treatment picture. Simple yet common geriatric problems such as
osteoarthritis, cystitis, loss of vision and hearing, overgrown
nails, and obesity, all need to be addressed to support the animal
around the oncologic process and not allow a nidus for infection, inflammation, or paraneoplastic disease. The ability to
recognize signs of disease, perform diagnostics, and treat accordingly is paramount to supportive care.
Finally, mental health and well-being of terminal patients
cannot be underestimated. Although pain control and all
aspects of palliative care prevail, simple attention, love, and
bonding are underrated as a means of analgesia and overall
reduction in concomitant disease. Factors that decrease the
pain threshold in people include insomnia, fatigue, boredom,
anxiety, frustration, isolation, and fear of worsening pain.17
Although a debate exists whether our companion animal
counterparts feel or sense similar emotions, it stands to reason that a steady schedule and environment, sleep/rest, enrichment or diversional activities, companionship, sympathy,
and avoidance of uncomfortable surroundings are all likely
to reverse the discomfort associated with terminal disease.18

Therapeutic Interventions Used in

Oncology Patients
Less than 15 years ago, once given the diagnosis of terminal, patients with cancer would receive steroids such as
prednisone and were sent home to die. We now understand
that the basics of any good pain therapy involve multimodal
foci (vs focus), or, at very minimum, a changing revolution of
pain relievers from different classes, which appropriately
parallels the increasing pain as the cancer itself and underlying concomitant disease progress. Although tolerance may
contribute to the escalation of the dose of analgesics required
to control cancer pain, it is more reasonable to believe that
different pain or stress factors assume a greater importance at different stages in the cancer process.
For example, in osteosarcoma patients, pain behaviors begin before any imaging of significant bone destruction, and
this pain is likely due to prostaglandins and endothelin that
are released by the growing tumor cells and subsequently
activate nociceptors in the marrow. Pain at this stage may be

attenuated by cyclo-oxygenase (COX)-2 inhibitors, endothelin antagonists, and even local topicals. As the tumor continues to grow, sensory neurons innervating marrow are compressed and destroyed, causing a neuropathic pain to develop
that may best respond to treatment with anticonvulsant
drugs and more potent, longer-acting nerve blockade, as well
as opioids. When the tumor begins to induce proliferation
and hypertrophy of osteoclasts, the pain may be best treated
with bisphosphonates or osteoprotegerin.19 Finally, as bone
destruction compromises the mechanical strength of the
bone, antagonists of the transient receptor potential channel,
vanilloid subfamily member-1 (TRPV1; or other mechanically gated channels and ATP receptors in the periosteum),
neuraxial pain relievers, indwelling neurostimulation catheters, radiofrequency neuroablation, as well as support/mobility mechanisms for the rest of the body are required.20
Although this pattern of tumor-induced tissue destruction
and nociceptor activation may be unique to bone cancer, an
evolving set of neuronal events from the peripheral (PNS) to
the central nervous system likely occurs with other cancers.
This complex pattern may in part explain why multimodal or
rotational therapy is necessary for pain relief in cancer patients. In the future, newer molecular techniques using microarrays and proteomics should reveal which specific features of different tumors are important in inducing cancer
pain, which neurons are involved, and potential targets for
future therapies, such as the vanilloid receptor complex. Until then, our major classes of pain-reliever modalities will
include all agents and interventions discussed below and may
best follow an escalating pyramid of treatment (Fig 2) that
exists amid supportive care ideas noted above.

Nutraceutical, Nutritional, and

Supplemental Therapies
Omega fatty acids in the form of fish oils can help decrease
joint inflammation in osteoarthritic animals, but these also
comprise the most important nutraceuticals for cancer patients.
The recommendation for feeding high levels of omega-3 fatty
acids such as eicosapentaenoic acid and docosahexaenoic
acid is based on in vitro cell culture studies, rodent models
and human models of cancer, and clinical trials in dogs with
lymphoma, nasal tumors, hemangiosarcoma, and osteosarcoma.21-23 Matrix metalloproteinases are active enzymes in
animals with neoplasms and may be involved in the pathogenesis of tumor growth and connective tissue invasion. Polysulphated glycosaminoglycans (Adequan; Luitpold Pharmaceuticals, Shirley, NY), tetracycline, doxycycline, and
minocycline will modulate matrix metalloproteinase activity, will assist in reducing connective tissue inflammation,
and may even reduce certain tumor growth.23-25
Key therapeutic dietary points for cancer patients involve
limiting soluble carbohydrate to 25% of the foods dry
matter, using highly digestible dietary protein (up to 40%50%), increasing dietary arginine (which may modulate the
immune system or alter neuroendocrine responses), and increasing dietary fats. Antioxidants such as vitamins C and E,


Topics in Companion Animal Medicine

Grief Counseling

Surgical Analgesic procedures

Neurolysis, Neuroablation

Radiation Therapy


Epidural, spinal and perineural catheterized blockades

Epidural, spinal, and perineural repetitive blockade

Intravenous Infusion therapy

Opioids, Alpha 2 agents

Anticonvulsants, AED

Resiniferatoxin, capsaicin

NMDA antagonists, Na and Ca channel blockers

Acetaminophen, tramadol

NSAIDS, steroids

Antihistamines,TCAs, SSRIs

Physical Rehab modalities (TENS, heat, cold, U/S)/weight management

Complementary therapies (acupuncture, chiropractic, herbal homeopathy)

Topical agents

Neutraceuticals, nutrition and supplemental agents

Figure 2. Escalating pyramid of treatment showing major classes of therapeutic interventions and agents used to treat
oncology pain. (Color version of figure is available online.)
carotenoids, selenium, and glutamine may not only improve
protein metabolism but may also improve systemic immune
response. However, some oncologists believe that these supplements may also protect cancer cells during certain stages
of chemotherapy or radiation therapy.26-28 Garlic and tea
polyphenols (flavones, flavonols, and catechins) have had
demonstrable anticarcinogenic effects in animal studies. Additionally, green tea modulates and increases the efficacy of
cancer chemotherapeutic drugs in some animal models.29,30
The controversy over potential adverse effects of some
nonsteroidal antiinflammatory drugs (NSAIDs) has led many
alternative or complementary medical specialists to seek
more natural cyclooxygenase and lipoxygenase inhibitors.
These supplements often include boswelia, bromelain, grape
seed extract, avocado oils, and rosemary seed extract. At this

point, these natural formulations have neither been studied in standardized trials nor have been approved or controlled by the Food and Drug Administration. Evidence of
NSAID characteristics of a natural-occurring Mediterranean
substance called olecanthal (from fresh extra virgin olive oil)
led researchers to study the cyclooxygenase-inhibiting potential of the substance, which may be the source of many
health-related effects of Eastern European diets and is sought
by many human cancer patients as a natural chemotherapeutic agent.31

Topical Therapies
Although technology has improved over the years, mild to
severe skin reactions still occur in 95% of the patients receiv-


Volume 25, Number 1, February 2010

ing radiation therapy. Likewise, surgical clipping and scrubbing, as well as actual surgical intervention, can also induce
dermatitides. The goals with any topical treatments are to
promote moist healing, prevent infection, and maintain comfort. Much oncologic dermatitis requires aggressive treatment with topical aqueous agents without alcohol, steroids,
antihistamines, anesthetics (e.g., pramoxine, lidocaine), and
even emollients. Silver sulfadiazine, aloe, acemannan, honey,
green tea, colloidal oatmeal, biafine cream as well as compounded, concentrated lidocaine, bupivacaine, bromelain,
phenytoin, misoprostal, and hyperbaric oxygen lotions can
all be used. Specific use is highly dependent on timing of
radiation and stage of healing.32
In people, calendula oil, emu oil, chamomile cream, hyaluronate cream, topical morphine, and almond ointment have
also been used for radiation desquamation. Doxycycline,
tetracycline, niacinamide, and pentoxyfylline are useful adjuncts for mucocutaneous lesions. Compounded combinations of misoprostal, aluminum hydroxide, sucralfate, antihistamines, and viscous lidocaine have assisted much with
healing of oral, mucosal, and mucocutaneous lesions after
surgery, radiation, and chemotherapy.33
Compounding pharmacies have become extremely adept
at combining many agents into adhesive sprays and powders
that will adhere to and assist healing of intact skin. Transdermal liposomal absorptive gels, creams, and sprays containing lidocaine, morphine, methadone, ketamine, clonidine,
gabapentin, ondansetron, and capsaicin may assist with desensitizing nerves leading to painful areas or in allowing absorption of substances normally not orally bioavailable.
These forms of the drugs may even offer means of analgesia
in patients who do not tolerate injectable or oral formulations.34-36 Evidence supporting or denying efficacy of many
transdermal formulations is scant, but anecdotal cases of
relief are encouraging despite supposedly subtherapeutic
blood levels of agents. These may provide yet another avenue
of opportunities for treatment in the face of terminal disease.

Acupuncture and Physical

Rehabilitation Modalities
Acupuncture is an ancient treatment modality used for a
variety of illnesses. Although the empirical principles that
govern acupuncture are based largely on traditional Chinese
medicine (TCM), the latest evidence (basic science and controlled clinical trials in both Eastern and Western medicine
literature) has provided insightful information regarding the
clinical indications for and the neurophysiologic mechanisms
of acupuncture, both of which are beyond the scope of this
review (see the review by Dr. Cantwell in this issue of Topics
of Companion Animal Medicine). However, acupuncture is
used in the oncology realm for both acute and chronic pain
relief, antinausea effects, lymphedema and surgical swelling
reduction, constipation relief, and appetite stimulation.37
Types of treatment range from fine-needle insertion to aquapuncture, electroacupuncture, laser therapy, and moxibus-

tion. TCM practitioners often combine acupuncture with the

use of herbal or food therapies.
When performing acupuncture on cancer patients, certain
precautions should be observed. Care should be taken to
avoid placing needles in the vicinity of the tumor and to avoid
placing more semipermanent needles or beads in neutropenic
or coagulopathic patients. In human medicine, as a group,
cancer patients are frequent users of acupuncture and TCM,
and it is likewise expected that owners will seek similar
means of treatment for their pets, as rates of side effects for
this therapy are quite minimal.38 Integrating alternative therapies that have been demonstrated to be empirically effective
into a health care system that relies solely on scientific methods is difficult, but the benefit to the palliative and analgesic
care of the patient can be quite dramatic.
Physical rehabilitative modalities that are applicable to the
oncology patient are few in veterinary patients but include
electrostimulation therapy, massage therapy, and manual
lymphatic drainage, as well as heat and cold therapy (most
useful for analgesia after surgical procedures). Transcutaneous electrical nervestimulation therapy relies on cutaneous
electrodes to deliver low-voltage stimulation to decrease central pain transmission. High-volt electrostimulation therapy
is useful for edema reduction and increased blood flow but
should not be performed near the primary tumor or surgical
site. Massage increases venous and lymphatic circulation,
decreases muscle spasm, and aids relaxation. Manual lymphatic drainage is a gentle massage technique used to mobilize lymph fluid from a congested area to areas of the body
where it can drain normally. Both can be extremely helpful in
the treatment of postsurgical and chronic oncology pain and

Antihistamines, Tricyclic Antidepressants, and

Selective Serotonin Reuptake Inhibitors
Histamine activates pain transduction and transmission fibers through various receptor subtypes. Certain antihistamines, particularly chlorpheneramine, loratidine, clemastine,
hydroxyzine, amitriptyline, and doxepin work particularly
well for treatment of inflammatory tumor pain, surgical pain,
and radiation- and chemotherapy-induced dermatitis. In addition, these drugs provide appetite stimulation and nausea
and vomiting suppression. Antihistamines are particularly
helpful in inflammatory cancers (e.g., pancreatic, mammary,
mast cell), are often coupled with opioids, and are great antiemetics and appetite stimulants for oncologic patients.41
Given their safety profiles and various over-the-counter formulations, their use should be considered first-line viable
options (with opioids) for veterinary cancer patients.
Tricyclic antidepressants (TCAs) can provide pain relief
well before any antidepressant effect of these agents are evident, and likewise are excellent adjunct agents to opioids.
These drugs have many actions as serotonin uptake inhibitors, norepinephrine (NE) uptake inhibitors, anticholinergicantimuscarinic drugs, alpha-1 adrenergic antagonists, and
antihistamines. Most TCAs cause analgesia through modulated

NE and serotonin neurotransmission, H1-antihistaminic blockade, increased endogenous opioid levels, N-methyl-D-aspartate (NMDA) blockade, reduced intracellular calcium levels,
and even ion channel (K, Na) blockade. In people, TCAs
with balanced serotonin and NE reuptake inhibitors (e.g.,
amitriptyline, clomipramine) are considered more effective
pain relievers than selective serotonin reuptake inhibitors
(fluoxetine, paroxetine) or even more selective NE reuptake
inhibition (e.g., bupropion).42,43 Some of the newer antidepressants such as the serotonin modulators (trazadone) or the
combined NE-serotonin modulators (mirtazapine) have tremendous potential in the veterinary pain management arena
because of their current use in behavioral veterinary medicine.

Steroids and Nonsteroidal Antiinflammatory Drugs

Both steroids and NSAIDs are used in oncology as chemotherapeutic agents and also to treat fever, malaise, inflammation, and pain. It is long known that glucocorticoids express
their analgesic and antiinflammatory action by interdicting
the phospholipase pathway by means of activating lipocortins, a group of enzymes that inhibit phospholipase. Nuclear
steroid receptors are ligand-activated transcription factors
that play a key role in a variety of vital physiological phenomena including developmental or endocrine signaling, reproduction, homeostasis, and apoptosis.44 Whether steroids
play a pivotal role in modulating the neuroplasticity of the
central nervous system via these receptors still remains to be
known. The main effect of NSAIDs is doubtlessly accomplished
via the reduction of prostaglandin synthesis by inhibiting cyclooxygenase, lipoxygenase, or epoxygenase. Prednisone,
prednisolone, dexamethasone, and methylprednisone are
among the most common steroids used in veterinary oncology.
There are many classes of NSAIDs but, as a group, prostanoid reduction, inhibition of neutrophil activation via peptides and leukotrienes, interference with G-proteinmediated
signal transduction, and calcium-mediated intracellular
events all play a role in mechanism of action. Further mechanisms of oncologic pain reduction include opioid-like mechanisms, activation of descending serotonin pathways, inhibition of the transcription mediated by the nuclear factor of
activated T-cells, antioxidant activity, uncoupling of intracellular oxidative phosphorylation, and activation of nuclear
factor-kappa-B proteins. COX-2 is now associated with at
least one type of cancer in each of the bodys major tissues
and may be involved in the resistance of tumors to chemotherapeutic drugs.45,46 As such, many NSAIDs, in particular
the coxibs, have been implicated as true chemotherapeutic
In the last 15 years, there has been an unbelievable upsurge
in the number of veterinary NSAIDs, much to the benefit of
our small animal patients, particularly dogs. The most common initial choices for NSAID therapy have been aspirin,
ketoprofen, carprofen, meloxicam, etodolac, naproxen, piroxicam, tolfenamic and meclofenamic acid, firocoxib, dera-

Topics in Companion Animal Medicine

coxib, and tepoxalin. Phenylbutazone and flunixin meglumine, as well as carprofen have been used in horses and
hoofstock. Ibuprofen and indomethacin probably should not
be prescribed to small animals because of the high risk of
gastrointestinal (GI) side effects.
Side effects of all NSAIDs include GI toxicity, reduction in
renal blood flow, inhibition of normal coagulation cascades,
and hepatotoxicity. Therapies for prevention of GI side effects include histamine-2 blockers, proton pump inhibitors,
and prostaglandin analogs.47 Regardless of the side effects,
NSAIDs are one of the first lines of therapy in malignant pain.
They constitute a mainstay of oncology pain treatment and
should be used unless contraindication exists. This author
recommends use of the lowest possible effective dose, reduced washout periods, rotation of NSAIDs, and alternation
with other nonopioid analgesics such as tramadol and acetaminophen. Cardiovascular side effects reported in people,
such as hypertension, thrombotic events, and myocardial
ischemia from the coxibs, have not been identified in companion animal species as of yet.

Acetaminophen and Tramadol

Acetaminophen (known in Europe and Central American as
paracetamol) remains one of the analgesics of choice for general chronic pain. Although the mechanism of action is not
fully elucidated, scientific data point more toward activation
of serotonergic pathways, inhibition of nitric oxide synthases, inhibition of L-arginine nitric oxide, and inhibition of
prostaglandin synthesis, likely via COX subtype inhibition.48,49 It is effective for both acute and chronic pain and is
well tolerated anecdotally in most species except the cat (deficient glucuronidation systems can result in toxicity with
even a single dose). Side effects are rare. Platelet inhibition,
gastric irritation, coagulopathy, and decreased renal function
do not occur in humans at therapeutic doses.50 Sadly, though,
antiinflammatory effects are also less effective than other
nonsteroidals. This is truly an underused analgesic for canine
patients and appears synergistic with opioids, other NSAIDs,
and even prednisone, in this authors experience. It should be
used with caution in chronic liver disease patients because of
toxicity potential.
Tramadol is a synthetic analog of codeine with a lower
affinity to mu-opioid receptors. Its main analgesic effect is
produced by inhibition of NE and serotonin reuptake. It is
considered mildly more potent than acetaminophen and
NSAIDs with few GI effects. More than 20 metabolites have
been identified, but only one has been shown to play a significant role in tramadols analgesic properties. Tramadol
has a role in oncology pain, along with selective serotonin
reuptake inhibitors, gabapentin, lidocaine, and opioids.51 GI
distress, reduced seizure threshold, and serotonin syndrome
are common side effects.52 Cats and horses have a very narrow therapeutic window, whereas dogs can tolerate a wider
dose range and appear to have less narcosis from the drug.
Tapentadol is a newly approved drug similar to tramadol. It
is also a mu-opioid agonist but also inhibits reuptake of NE


Volume 25, Number 1, February 2010

with little effect on serotonin.53 Both tramadol and acetaminophen should be used as adjunct agents with opioids or alpha-2 agonistic drugs because of their potential to cause side
effects when given solo at higher doses.

therapeutic window was seen in humans with intrathecal

administration. Severity of the side effects ranged from dizziness, confusion, and nystagmus, to urinary retention, stupor, and coma.61,62

N-methyl-D-aspartate Antagonists, Sodium and

Calcium Channel Modulators

Resiniferatoxin and Capsaicin

The NMDA ionophore is located on postsynaptic neurons in

the dorsal horn. Release of glutamate from the presynaptic
terminal activates the channel, causing an influx of calcium,
which eventually cascades into other neurotransmitter release and central hypersensitization. Magnesium ion binding
within the channel inhibits calcium conduction, and the
channel can be blocked competitively by antagonists such as
ketamine, dextromethorphan, memantine, and amantadine.54 Although amantadine has been shown to potentiate
osteoarthritic pain relief,55 use of this agent does not seem to
greatly help most oncology patients. However, dextromethorphan and guaifenesin cough elixirs seem to assist in some
forms of neuropathic pain, muscle relaxation, and cough
reduction of metastatic lung disease. Ketamine is best used in
intermittent mini-dose subcutaneous form or continuousrate infusions, both of which seem to reduce body surface
and somatic pain. Methadone is a unique mu-opioid agonist
with NMDA antagonist properties and lacking GI and hallucinatory effects of other opioids while retaining impressive
pain-relieving qualities.56,57
The development of spontaneous and evoked pain after
nerve injury is mediated in part by an increase in the density
and distribution of sodium and calcium channels. At least 7
different sodium channels have been isolated, and, accordingly, blockade of these will result in diminished pain, oftentimes with effects occurring at plasma concentrations that
will not produce motor or sympathetic blockade.58 Lidocaine
is likely the most well known of these agents and has also
been shown to inhibit the expression of nitric oxide and
subsequent release of proinflammatory cytokines, thus providing substantial antiinflammatory activity as well.59 Lidocaine can be administered in intravenous infusion, topically
in gels and creams, in neuraxial blockade, and is also available in patch form. Mexilitene is an oral sodium channel
antagonist that is reported to be efficacious for various neuropathies, despite the lack of correlation between serum levels and pain relief. Tocainide and flecainide are 2 antiarrhythmics that have shown pain-relieving effects in people with
malignant neuralgia, but the drugs are not without significant
side effects.60
Although at least 6 types of calcium channels are expressed
throughout the nervous system, the N-type calcium channels
have the most effect on acute thermal and mechanical thresholds. Ziconotide, a synthetic version of a naturally occurring
peptide found in the venom of the conus marine snail, specifically binds to these channels, resulting in reduced or alleviated allodynia commonly seen in postinjury neural states.
Because it is administered directly into the central nervous
system, side effects are predominantly neurologic. A small

Capsaicin is a naturally occurring component of the red chili

pepper. For many centuries, chili peppers were compounded
into a variety of topical mixtures or advocated even orally for
the treatment of pain. Resiniferatoxin is an ultrapotent capsaicin analog that binds to the transient receptor potential
channel, vanilloid subfamily member 1 (TRPV1). There is a
large body of evidence supporting a role for these ion channels (which transmit calcium, magnesium, sodium) in noxious-mediated and inflammatory hyperalgesic responses.
When both capsaicin and resiniferatoxin bind to these receptors chronically, neuronal cells (predominantly C fibers) are
overwhelmed with an influx of calcium, resulting in the inability to function. Eventually, because of calcium overload,
the neurons degenerate, undergo apoptosis, or minimally are
unable to transmit pain signals.
Capsaicin is used as over-the-counter topical creams or
lotions in strengths ranging from 0.025% to 0.075% for
treatment of osteoarthritis pain in veterinary and human patients.63 Resiniferatoxin has been studied in vivo and in vitro
for osteosarcoma and pancreatic cancer pain and has also
been administered intrathecally and intraarticularly for osteoarthritic pain.64,65 Prolonged antinociceptive effects were
seen in dogs despite profound hemodynamic effects. The potential of drugs acting through TRPV1 for the management
of some types of cancer pain appears to be significant according to recent literature.

Anticonvulsant Therapies and Antiepileptic Drugs

The main actions of antiepileptic drugs (AEDs) can be summarized as modulation of voltage-gated sodium and calcium
channels or enhancement of the gamma-aminobutyric acid
(GABA) inhibitory system. Many of these agents still carry a
heavy burden of side effects. They are enzyme-inducing drugs
that may hasten the metabolism of steroids or reduce the
effects of certain chemotherapy agents (e.g., vinca alkaloids,
methotrexate) when used for treatment in the cancer patient.
Carbamazepine has been used to treat generalized and partial
seizures in both human and veterinary patients and is Food
and Drug Administration approved for trigeminal neuralgia
in people. It suppresses spontaneous A delta and C fiber
activity implicated in the genesis of pain. Oxycarbazepine,
like carbamazepine, blocks sodium channels but modulates
calcium channels as well.66
Modulation of voltage-gated calcium channels, as mentioned above, poses a very effective mechanism of action of
some AEDs. The intracellular-free calcium concentration is
only 1 of 10,000 that of extracellular environments, and
reduction of influx of this ion has a huge impact on a neuron.
Pregabalin and gabapentin both bind to the alpha-2 delta


Topics in Companion Animal Medicine

subunit of voltage-gated calcium channels, resulting in inhibition of calcium influx and reduction in pain transmission.
Side effects are somnolence, dizziness, fatigue, and weight
gain. Pregabalin has less side effects and more predictable
pharmacokinetics than gabapentin.67 The benzodiazepines
have been frequently used as adjunct agents in the treatment
of both acute and chronic pain, despite the fact that only
clonazepam has shown efficacy in the treatment of neuropathic pain. Their muscle relaxant and anxiolytic effects are
due to GABA-A activity. Although not true analgesics, they
do appear to alter the unpleasantness of the pain experience
in people.68

Likely one of the most efficacious means of providing pain

relief with opioids in veterinary patients with advanced cancers is neuraxial blockade using opioids and local anesthetics.
Although repetitive and chronic neuraxial administration of
opioids often results in immunosuppression, constipation,
urinary retention, pruritus, and nausea in human patients,
these agents prolong and strengthen the analgesia provided
by local anesthetics in surgical patients and provide a means
of dealing with moderate to severe terminal pain via catheterization as well.73


Medetomidine and dexmedetomidine have potent analgesic

activity in veterinary patients but often cause moderate to
severe decreases in cardiac output, even with microdose usage. Despite this effect, alpha-2 agonists can be used in transdermal forms, neuraxially to complement local anesthetics
and opioids, in intermittent injections and even transmucosally. Although they are not first-line agents in veterinary
oncology because of their requirement for parenteral administration and their cardiovascular side effects, certain alpha-2
agonists such as clonidine, dexmedetomidine, and tizanidine
are agents that have been used in neuraxial (epidural and
spinal) injections and infusions for human cancer pain
patients with refractory pain.74 This author has used transmucosal dexmedetomidine in cats, microdose epidural and
paraplexus or perineural dexmedetomidine, as well as transdermal clonidine for oral opioidintolerant patients with severe pain. The case response has been excellent, and other
drug-sparing effects and synergism have been noted.

Considered the mainstay of cancer pain therapy in human

oncology, veterinary patients in both acute and chronic pain
also enjoy analgesia and comfort thanks to these agents. Reasons for use are safety with dose titration, reliable and predictable analgesia, few and tolerable side effects, compatibility with other drugs (allowing regulated polypharmacy or
multimodal agent use), and reversibility if needed. The clinically used and best opioids for oncology patients surgical,
breakthrough, and recurrent pain are mu-receptor agonists;
however, opioid receptor mixed agonists and antagonists at
the mu, kappa, and delta receptors have all been used.
The mainstay of chronic opioid cancer therapy remains
morphine in human patients. In veterinary patients, chronic
oral opioid therapies include hydrocodone, oxycodone, morphine immediate and sustained release, and methadone. Buprenorphine undergoes significant mucosal absorption in
cats.69 Overall, even though codeine exists in oral form, its
analgesic activity is weak at best, and gastrointestinal side
effects in dogs are moderate. Injectable opioids for use in
chronic oncologic pain include buprenorphine, oxymorphone, hydromorphone, morphine, methadone, fentanyl,
and remifentanil. Anecdotally, encapsulation of some of
these drugs may provide more repository forms for sustained
and prolonged release in veterinary patients.
Fentanyl patches are rectangular transparent units that allow fentanyl to be released from the system proportional to
the surface area. Designed for use in human patients, they
tend to be rather unreliable in veterinary patients because of
epidermal thickness, difficulty with adhesion, and skin temperature differences, which make absorption erratic in some
species.70 However, they do provide a means (however unreliable) to administer a potent opioid without intravenous
infusion. When patients with chronic severe pain cannot tolerate oral opioids, intermittent subcutaneous administration,
transdermal delivery, and neuraxial injections should be considered.
Transdermal liposomal forms of many opioids have been
created by compounding pharmacies for veterinary patients
in whom oral administration is not possible. Nebulized forms
of morphine have also been used to treat dyspnea in human
patients.71 Intranasal and rectal suppository forms of opioids
are advocated for breakthrough pain in human patients.72

Alpha-2 Agonists

Intravenous Infusion Therapy

In the past decade, intravenous infusion therapies have been
used to treat a variety of chronic pain conditions. Pharmacologic agents and mechanisms used for this purpose range
from bisphosphonates reduction of osteoclast and inflammatory mediator activity in bone cancer patients, through
lidocaines sodium channel blockade, ketamines NMDA antagonism and calcium channel blockade, to phentolamines
antiadrenergic effects. Also administered intravenously,
magnesium is a bivalent cation that antagonizes and blocks
the NMDA receptors calcium channels, and adenosine is an
endogenous nucleoside used to treat supraventricular arrhythmias.75-77
Although infusion therapies have not been studied systematically in randomized controlled trials in human medicine,
all of these agents have been used as infusions to treat a
variety of chronic pain conditions ranging from cancer pain,
to sympathetically mediated pain, to neuropathic pain.78 Human pain clinics offer outpatient infusions administered over
1- to 4-hour periods. These therapies attempt to evaluate a
patients response to certain classes of similar oral medications, as well as offer longer-term (hours to weeks) benefit
from single infusions. This author uses monthly infusions of
rotating agents (particularly bisphosphonates, ketamine, and


Volume 25, Number 1, February 2010

lidocaine) for patients with osteosarcoma, fibrosarcoma, and
squamous cell carcinoma, as well as pancreatic cancers.

Epidural, Spinal, and Perineural Blockade

Advocated greatly for treatment of surgical and acute pain,
nerve blockade performed blindly or guided through ultrasound or electrostimulation can also assist with treatment of
chronic pain. Because these procedures require significant
imaging, sedation, and adherence to strict aseptic preparation and discrete technique, the decision to proceed with
interventional pain control must be undertaken with utmost
care. Appropriate patient selection, life expectancy, intolerance to other analgesic means, choice of drugs, mode of
administration, and potential complications must all be considered. With the delivery of different agents capable of modulating dorsal horn neurophysiology or via catheterization,
blockade can be attained and even maintained long term,
especially via the use of different agents in the injectate or
ambulatory pumps and devices.79
Among the many drugs chosen for neuraxial and perineural blockade are opioids, alpha-2 agents, ketamine, adenosine, amitriptyline, ziconotide, local anesthetics, sarapin
(pitcher plant extract), and microdose steroids.80,81 The
blockade, whether single shot or involving implantable and
external devices (such as catheters and pumps), is conducted
under strict aseptic technique with appropriate antibiotic administration as required. Complication rates are surprisingly
low in veterinary patients but do include wound infections,
meningitis, neuritis, and catheter-related difficulties.81,82
Need for diagnostic imaging in placement and maintenance
of indwelling and sometimes even single-shot doses might
cause these techniques to be placed later in line as realistic
analgesic options. Sympathetic nerve blockade may even be
useful for pancreatic pain or carcinomatosis in veterinary
patients, having been used for complex regional pain syndromes, sympathetically mediated pain, visceral pain syndromes, and neuralgias in people.81

Spinal Cord and Peripheral Nerve Stimulation

Neurostimulation began shortly after Wall and Melzack proposed the gate control theory of analgesia in 1965. The goal
of spinal cord stimulation or peripheral nerve stimulation
(PNS) therapy is to place an electrode close to a nerve or in
the epidural space to provide electrical stimulation via an
implanted pulse generator. Via this electrode, paraesthesias
are created, which modulate pain via altering the local neurochemistry in that zone, thereby suppressing the hyperexcitability of the wide, dynamic range interneurons. There is also
evidence of increased levels of GABA, serotonin, and suppressed levels of excitatory amino acids with both spinal cord
stimulation and PNS.83,84
Although used for failed back syndromes, ischemic pain,
post chemotherapeuticinduced neuropathies and phantom
limb pain in people, significant costs of the units, the need for
imaging, surgical approaches to placement of some elec-

trodes, as well as upkeep difficulties have limited this treatment modality so far in veterinary patients. However, given
the relative ease of pacemaker placement in animals with
cardiac arrhythmias, focus on particular patients with similar
respect to pain and availability of imaging techniques would
allow appropriate case selection. Knowing the vast increase
in imaging modalities currently experienced in the veterinary
market, with careful attention to technical issues, this analgesic means could allow some positive results in patients that
fail to respond to other more conservative therapies.

Radiation Therapy for Analgesia

Understanding the radiobiology of fractionated radiation
therapy allows a better perspective to understand external
beam radiation therapy for palliation of pain and radiation
therapy for bone metastases in particular. Suffice it to say
that explanation of such therapy is well beyond the means of
this article, but net pain relief (duration of pain relief compared with duration of survival) from this therapy should be
considered carefully in veterinary patients. An area of ongoing controversy is in the study of the optimal dose and fractionation regimen, and selecting the optimal regimen is not
always straightforward.85 Veterinary patients commonly undergo palliative radiation for primary osteosarcoma, chondrosarcoma, and metastatic bone tumors. Historically, radiations role in provision of pain relief was thought to be from
cell kill and tumor shrinkage, similar factors used in the curative setting. However, several observations do not support
this. Instead, mechanisms such as inhibition of cells that secrete prostaglandins, activation and induction of transforming growth factor-beta isoforms, and even mild bone healing
may all play a role in radiations analgesic mechanisms.86

Chemical neurolytic agents have been used since the beginning of the 20th century to cause destruction of nerve roots or
major nerve trunks for analgesic purposes. Pitcher plant extract, phenol, ethanol, glycerol, hypertonic saline solution,
and ammonium compounds have all been delivered intrathecally, perineurally, and epidurally.87 Although chemical neurolytic agents are used in many countries where more expensive means of analgesia are not available, neurolysis in the
United States usually occurs via cryoneurolysis or radiofrequency (RF) blockade.88 RF lesioning involves the insertion
of a small, insulated electrode with an uninsulated tip near a
nerve, leading to a painful or chronically inflamed area. Heat
is generated at the tip of the electrode, causing neurolysis and
subsequent analgesia for a well-defined but fairly limited anatomic location.
Cryoneurolysis involves destroying a nerve through the
application of extreme cold. Both RF and cryoneurolysis
should be preempted with a test block and can provide
months of analgesia, but are not without complications
including regrowth of nerves, neuroma formation, and induction of neuritis in adjacent nerves.89 Also, both require

expensive equipment and imaging modalities (usually fluoroscopy). Chemical neurolysis is easier and less expensive.
Because of the invasive nature of the therapies and high incidence of the pain returning, neurolytic techniques are usually
reserved for human patients with less than 1 year life expectancy. Veterinary patients have the succinct disadvantage of
not being able to verbalize exact location of pain. Thus, with
neurolysis techniques of any type, we have the subsequent
disadvantage of not being able to separate motor and sympathetic from sensory function, leading to difficulty in identifying and blocking exact and appropriate locations.

Topics in Companion Animal Medicine




Surgical Analgesic Techniques

It is well documented that malignant disease frequently metastasizes to bones. Between 30% and 70% of malignant
disease in people involves vertebrae.89 The result is chronic
back pain, pathologic fracture, and motor impairment, the
latter of which is likely to result in euthanasia of our patients.
Therapeutic and palliative radiation is an alternative to surgery for malignant bone pain. However, it may not be affordable or available to some patients. Percutaneous vertebroplasty, first described in 1987 as a treatment for vertebral
body hemangioma, involves fixation of compression fractures via injection of polymethylmethacrylate into the vertebral body. Kyphoplasty is a similar technique that involves
injection of poly (methyl methacrylate), or PMMA, into a
balloon inserted into the compressed bone and inflated to
better stabilize the fracture before injection.90 Although not
used in veterinary patients, these techniques may represent
future therapies for bone cancers and metastatic spinal disease given imagings recent surge within our profession.
Surgical neuroablative techniques are often considered the
top and final rung (i.e., last resort) on the pain treatment
ladder. They range from peripheral techniques of sympathectomy, neurectomy, and dorsal rhizotomy to more central
techniques of cordotomy, myelotomy, even thalamotomy,
and hypophysectomy.91 The effectiveness of modern pharmacologic methods of pain control has greatly reduced dependence on these techniques in the recent past in human
medicine, although stereotactic RF surgery and radiosurgery
(gamma knife) techniques might allow resurgence of these
techniques for both human and veterinary patients within the
next decade.











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