Page 317 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 16 Supportive Care for the Cancer Patient 295

treatment of cats with chronic painful diseases. Interestingly, the able to overcome this problem. When buprenorphine is admin-
EP receptor has been implicated in cancer metastasis in murine istered concurrently with other drugs, less frequent dosing of
4
buprenorphine often is required.
models. EP activity on tumor and host cells promotes breast can-
114

VetBooks.ir cer progression via tumor cell migration, invasion, angiogenesis,
4
Therefore EP pharmacologic block-
94–98
and lymphangiogenesis.
4
ade may not only mitigate pain, but also attenuate multiple protu- Tramadol
morigenic properties. This potential benefit has yet to be studied Tramadol, a synthetic derivative of codeine, is classified as an
in the setting of clinical veterinary oncology. opioidergic/monoaminergic drug. 115,116 The pharmacodynamic
effects of tramadol result from complex interactions between opi-
Acetaminophen ate, adrenergic, and serotonin receptor systems. However, trama-
dol undergoes extensive metabolism. Thus the analgesic efficacy of
Acetaminophen is a nonacidic NSAID. Many authorities do not tramadol may vary between species because of differences in the
consider it an NSAID because it probably acts by somewhat dif- metabolic profiles of this drug. Tramadol is considered efficacious
ferent mechanisms. Some evidence indicates an antiinflamma- in a variety of human conditions, including cancer pain. 117 The
99
tory effect in dogs. 100 The exact mechanism of action remains benefits arise in part from opioid receptor–mediated activity of the
controversial, 101 and the antiinflammatory features of this drug active metabolite, O-desmethyltramadol (M1), which arises from
are associated mainly with the inhibition of central prostaglandin hepatic demethylation of tramadol. Several studies have reported
synthesis. 102 Other potential antinociceptive mechanisms include lower circulating concentrations of tramadol M1 metabolite in
the serotonergic descending inhibitory pathway, 103 the endo- dogs compared with humans and cats, 108,118–123 and clinical ben-
cannabinoid system, 104 and possibly brain TRPV-1 and TRPA1 efits have not been observed after oral administration in dogs with
88
receptors. 105,106 Although highly toxic in the cat, it can be effec- chronic pain associated with OA. It is important to highlight
tively used in dogs for pain control in the acute setting. 100,107 that little is known about the side effects of tramadol in dogs, and
No studies of toxicity in dogs have been done, but if toxicity is almost nothing is known about the side effects when tramadol is
encountered, it probably will affect the liver. In common with all combined with other drugs in human or canine medicine.
NSAIDs and opioids, acetaminophen should be used cautiously In contrast to dogs, oral administration of tramadol induces
in dogs with liver dysfunction. The author (BDXL) often uses antinociceptive behaviors in cats in a dose-dependent manner. The
acetaminophen as the first line of analgesic therapy in dogs with analgesic effects of tramadol in cats are supported by pharmaco-
renal compromise, in which NSAIDs should be avoided, and in kinetic data that cats do produce the active metabolite M1. 124,125
dogs that appear to be otherwise intolerant to NSAIDs (e.g., vom- Recently, prospective studies in a research colony of cats with
iting or gastrointestinal ulceration). naturally occurring OA demonstrated that oral tramadol at 3 mg/
kg every 12 hours for 19 days resulted in measurable pain relief
Opioids without clinically important adverse effects. The most common
adverse events were mydriasis, sedation, and euphoria. 126 Trama-
Opioids are considered an effective part of the management of dol is difficult to administer to cats because of its highly aversive
cancer pain in humans, particularly when they are used as part of a taste. Even custom flavoring of compounded liquid formulations
multimodal approach (i.e., including NSAIDs or adjunctive anal- has been largely ineffective at improving palatability. Nonetheless,
gesics). The use of opioids in cancer patients is recommended in the drug can be of significant value in cats that will tolerate oral
moderate to severe cases of pain. Moreover, a recommended mea- administration and in cats with feeding tubes (e.g., esophagos-
sure is to combine the use of opioid and nonopioid drugs both tomy and gastrostomy).
to relieve pain and to reduce the opioid dosage and consequent Serotonin syndrome, which is manifested as altered mental
adverse events. status and neuromuscular and autonomic dysfunction, can fol-
Oral morphine, transdermal fentanyl, oral butorphanol, sub- low co-administration of two or more drugs that affect serotonin
lingual buprenorphine (cats only), and oral codeine have been signaling. Thus caution is advised when prescribing tramadol in
tested for the alleviation of chronic cancer pain. However, none patients also receiving drugs such as trazodone or mirtazapine,
of these drugs has been fully evaluated for clinical toxicity when which are commonly used in veterinary cancer patients.
administered long term or for efficacy against chronic cancer pain. The dosages given in Tables 16.4 and 16.5 are for the regular
Furthermore, recent evidence has indicated that oral opioids may form of tramadol, but not for the prolonged release form, which
not reach effective plasma concentrations in dogs when dosed at has not yet been thoroughly evaluated for toxicity in the dog or
the currently recommended levels due to a high first-pass effect in cat.
dogs. 108–111 Given this fact, and the ongoing opioid crisis in the
human population, we do not recommend using or dispensing N-Methyl d-Aspartate Antagonists
oral opioids in companion animals. Also of concern is the dis-
pensing of fentanyl patches, although data does support efficacy The NMDA receptor appears to be central to the induction and
in dogs and cats. 112,113 maintenance of central sensitization, 127,128 and the use of NMDA
Currently no information is available on the long-term use of receptor antagonists is beneficial when central sensitization has
oral opioids for chronic pain in the cat. Buprenorphine, a partial become established (i.e., especially chronic pain). Ketamine, tilet-
μ-agonist, appears to produce predictable analgesia when given amine, dextromethorphan, and amantadine have NMDA antago-
sublingually 114 and is well accepted by most cats. The small vol- nist properties, among other actions.
ume required (maximum 0.066 mL/kg [20 μg/kg]) makes admin- Ketamine is not obviously useful for the management of
istration simple. Based on clinical feedback from owners, this is an chronic pain because of the formulation available and the ten-
acceptable technique for home use. Inappetence can occur after dency for dysphoric side effects even at low doses. Furthermore,
several days of treatment, but lower doses (5–10 μg/kg) may be oral ketamine has not been evaluated in dogs or cats for long-term