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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
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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
trends.
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.
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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
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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.
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Grief Counseling
Neurolysis, Neuroablation
Radiation Therapy
SCS/PNS
Anticonvulsants, AED
Resiniferatoxin, capsaicin
Acetaminophen, tramadol
NSAIDS, steroids
Antihistamines,TCAs, SSRIs
Topical 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-
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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.
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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
Opioids
Alpha-2 Agonists
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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.
Neurolysis
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
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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.
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