Managing chronic cancer pain (Proceedings)

It can be estimated that more than half of tumor-bearing pets suffer cancer-related pain. Quality of life and key physiological functions are negatively impacted by pain, and treating it is a priority. Whether cancer pain is confirmed, suspected, or expected to occur, efforts should be spent to treat it effectively. While some patients are relieved adequately and rapidly by treating the underlying malignancy, a vast majority requires symptomatic therapy to achieve improved quality of life, the main objective in veterinary oncology. For cancer pain to be adequately managed, it must be recognized early, properly assessed, and frequently reassessed by both the clinician and the pet owner. Many barriers remain for the appropriate treatment of cancer pain in animals, including its poor recognition with many neoplastic conditions, difficulty to objectively assess the degree of pain in veterinary patients, inappropriate reassessment once therapy is implemented, fear to use or lack of knowledge regarding the analgesic therapeutic arsenal, and suboptimal communication with the caretaker.

TREATING THE UNDERLYING CANCER

The ideal way to alleviate cancer pain, if possible, is to treat the underlying tumor. The option of excising a tumor, or achieving local control with radiation therapy or a remission with chemotherapy, should be weighed. Still, standard analgesics are often needed for proper pain relief while waiting for the anticancer therapy to abrogate the source of pain. Occasionally with resistant, refractory, recurring, or terminal cancers, only supportive and symptomatic therapy can truly benefit the patient (concept of "best supportive care"). Purely palliative therapy does not intend to alter the course of the disease but rather aims to improve the patient's overall quality of life using various analgesic therapies and supportive care, and frequently combining it with traditional anticancer therapeutic modalities.

Surgery

The complete surgical removal of a painful tumor should be performed whenever possible and indicated. With suitable preemptive and multimodal analgesia, most patients with painful tumors will be more comfortable following radical surgeries. Surgery can rapidly remove the source of pain, and various procedures can be performed depending on the tumor type, local extent, and anatomic site. Tumors treated and possibly cured with surgery alone include canine oral squamous cell carcinoma and sarcomas, cutaneous mast cell tumors, mammary tumors, soft-tissue sarcomas, splenic or hepatic tumors with painful capsular distension, nailbed tumors, synovial cell sarcoma, and tumors of the ear canal. Occasionally, patients may benefit from palliative surgeries, where the removal of painful tumors may not impact the survival. A classic example is amputation for appendicular osteosarcoma (OSA) where metastases ultimately determine survival time. In select cases, surgical removal of pulmonary metastases from OSA may provide rapid relief from painful paraneoplastic hypertrophic osteopathy (within 24 hours in a case series). Finally, and though such salvage techniques have yet to be described for the control of cancer pain in pets, peripheral and central neuroablative surgeries are valuable in terminal human cancer patients with poorly responsive pain.

Radiation therapy

Radiation therapy (RT) is invaluable in the treatment of many veterinary cancers. Fractionated protocols (a.k.a. "curative protocols" - multiple small daily doses) are used for radiosensitive tumors where a clinical benefit and survival advantage can be expected. Examples of painful macroscopic tumors that are treated this way include sinonasal tumors, certain oral tumors, solitary osseous plasma cell tumor, certain forms of lymphoma (mediastinal, CNS), and thyroid carcinomas. Certain painful tumors may not respond as well to fractionated protocols, but alleviation of pain is still possible when a small number of large fractions of radiation (typically weekly) are administerd. This is often called palliative RT. Examples of painful tumors treated this way include canine oral malignant melanoma, feline oral squamous cell carcinoma, OSA (appendicular or axial, primary or metastatic), unresectable mast cell tumors (MCT), unresectable SQ or IM hemangiosarcoma, and any bone metastases. Painful early side effects of radiation therapy, especially oral mucositis, acute moist dermatitis, colitis, and conjunctivitis, are more commonly encountered with daily fractionated protocols and need to be addressed. Newer radiation therapy techniques, called stereotactic radiosurgery (gamma knife and CyberKnife®), permit the precise delivery of a very large dose of radiation. These newer techniques permit the delivery of a "curative dose" of irradiation in one or two fractions, while sparing normal tissues, but the availability is currently limited to a handful of sites in the U.S.

Chemotherapy

Cytotoxic chemotherapy is used for chemosensitive tumors or cancers, if a clinical remission may result. Lymphoma tends not to cause obvious pain, but certain anatomic sites (CNS, bone) may lead to moderate to severe pain. In addition, patients with marked hepato-splenic involvement can have visceral pain from capsular stretch. Multiple myeloma (MM) is often painful, with multifocal bone lysis that may result in pathologic fractures, and compression of the meninges and spinal cord. Other therapies (RT, bisphosphonates) can be co-administered to MM patients and alleviate their pain, but chemotherapy is crucial for quality of life and survival improvement. Other examples of cancers that may be cause moderate to severe pain and may respond to chemotherapy include unresectable or disseminated MCT, carcinomatosis (intracavitary chemotherapy), and transmissible veneral tumors (TVT) which can cause pain and discomfort of various mucosal surfaces in adventurous sexually-intact dogs. A cure is obtained in a majority of TVT-bearing dogs treated with vincristine monotherapy.

Multimodality therapy

Surgery, RT, and/or chemotherapy are frequently combined to achieve better and longer tumor control, resulting in prolonged and more complete pain alleviation. Examples of cancers best treated with a multimodal approach include feline injection-site sarcomas, canine apocrine gland anal sac adenocarcinoma, high-grade canine MCT and soft-tissue sarcomas, and certain oral tumors.

STANDARD ANALGESIC THERAPY

The World Health Organization (WHO) has proposed a three-step analgesic ladder for cancer pain. With that model, where adjuvant therapy can be added at any level, mild pain is treated with non-opioid drugs, generally NSAIDs. If pain persists or in case of moderate pain, a "weak opioid" such as codeine or tramadol can be added on the second rung. If pain is still not controlled or with severe pain, stronger opioids, preferably full µ agonists, are used for the third step. Some recently recommended that 2 more steps be added for patients with advanced, difficult to control cancer pain, whereby techniques such as intrathecal administration of opioids, neurostimulation, or peripheral neuroablation can be introduced as a fourth step, and central neuroablative procedures added as a fifth step. Others have discussed the use of an "analgesic reverse pyramid" for certain patients where, when chronic pain is present and central sensitization is suspected, a multimodal approach is used first to reverse such changes, before gradually decreasing the dosages or classes of analgesics being administered.

NON-STEROIDAL ANTI-INFLAMMATORY DRUGS (NSAIDS)

By far, NSAIDs (including coxibs) are the class of analgesics most commonly used to treat various types of pain in companion animals, whether acute or chronic. As a class, NSAIDs can be very helpful in the treatment of cancer pain for numerous reasons. Prostaglandins (PGs) play an important role in peripheral sensitization of certain nociceptors, leading to hyperalgesia, an exaggerated response to a mildly noxious stimulus, or allodynia, a painful response following a non-noxious stimulus.The PGs can also changes in the dorsal horn of the spinal cord that result in central sensitization and establishment of a state of chronic pain. Peripheral and central sensitization are common in chronic cancer pain. It seems therefore logical to use NSAIDs, in combination with other drugs, to treat conditions of moderate to severe chronic cancer pain. It is known that NSAIDs are effective to some degree, in human cancer patients, for the treatment of moderate to severe pain from bone metastases, compression of muscles and tendons, and distension of the peritoneum or pleura. Pets with cancer pain also appear to benefit from NSAIDs which are used commonly alone for mild pain, or in combination with opioid drugs and adjuvant analgesics for moderate to severe pain. When used for chronic cancer pain, the various veterinary approved NSAIDs appear to be equianalgesic. The clinical response and toxicity profile may vary between patients receiving a given drug, and this is generally not predictable. If a patient fails to benefit from a given NSAID for pain control, or suffers untoward side-effects, it appears reasonable to consider another NSAID, ideally after a washout period of 5 to 7 days, although the guidelines are poorly established.

Another rationale to use NSAIDs for cancer pain stems from the potential anticancer and chemopreventive effects of these drugs in people and pets. Overexpression of COX-2 is known to occur in numerous human and canine tumors, including many carcinomas (bladder, prostate, mammary gland, intestine, kidney, skin, oral cavity, nasal cavity), as well as malignant melanoma and osteosarcoma. This may lead to a weakened immune response, decreased apoptosis, increased angiogenesis, and increased proliferation. The use of NSAIDs in states of cancer pain may therefore have both analgesic and antitumor effects to benefit the patient. Many canine studies have demonstrated tumor responses with monotherapy with NSAIDs (most commonly piroxicam), and others have shown a possible additive effect when combined with standard chemotherapy agents.

In the last 15 years, a large number of veterinary NSAIDs became available, much to the benefit of our canine patients. Additionally, a few non-veterinary products may be used, piroxicam having a certain support from the literature. Even if no veterinary-approved NSAID is approved for cancer pain, they are commonly used for that purpose, at the chronic dosage, alone or combined to other analgesics. It is recommended to perform bloodwork and urinalysis to evaluate renal and liver functions prior to chronic administration of NSAIDs in veterinary patients, especially when of geriatric age. The minimum database should include serum urea nitrogen and creatinine, urine specific gravity, liver enzymes (ALP and ALT) and occasionally bile acids, when liver enzymes are elevated. A baseline value is indicated, followed by a recheck 2-4 weeks later, and periodic reassessment every 2-4 months with chronic therapy. Owners should be instructed to look for specific signs such as melena, vomiting, lethargy, depression, altered water intake and urine output. The common side effects of all non-steroidal drugs are gastrointestinal irritation (NSAIDs), nephrotoxicity (NSAIDs), hepatotoxicity (acetaminophen, idiosyncrasies with NSAIDs), and anti-thrombotic effects (especially aspirin).

Fewer NSAIDs are approved for use in cats owing in part to marked differences in metabolism when compared to dogs. Species differences in the glucuronoconjugation pathways play an important role in the metabolism of many such drugs, and account for the prolonged half-life of NSAIDs in cats. The most common NSAIDs used with relative safety in cats include meloxicam, tolfenamic acid, ketoprofen, carprofen, piroxicam, tepoxalin, and soon robenacoxib. Kidneys are the target ogan of toxicity from NSAIDs in cats, though liver and gastrointestinal toxicity can also be seen. Using the lowest effective dosage and frequency and avoiding their use in cats with altered renal function is the basics of safe NSAID administration in that species. Acetaminophen should never be used in cats.

Opioids

Opioids are the mainstay of cancer pain therapy in humans and are likely underused in veterinary oncology. They provide good analgesia and have no ceiling effect. Side effects are more important at higher dosages and with chronic use, but are relatively predictable and tolerable, except for dysphoria in cats and certain canine breeds. Other side effects include sedation, constipation, bradycardia, respiratory depression, panting, mydriasis (cats), cough suppression, altered laryngeal reflexes, vomiting, and histamine release (worse with morphine). Some of these side effects can be treated symptomatically (constipation, vomiting). Opioids are used for moderate to severe pain and provide better analgesia when used concurrently with other classes of analgesics.

The standard opioid remains morphine, a pure mu receptor agonist. Morphine is inexpensive, has predictable side effects, and can be administered via various routes. Other mu agonists are also very useful in the treatment of cancer pain, and include fentanyl (transdermal, IV infusion), hydromorphone (injectable), oxymorphone (PO) and oxycodone (PO). The partial agonist buprenorphine has a long duration of action, and can be especially useful via the transmucosal route in cats for the treatment of breakthrough pain. Butorphanol, a mixed mu antagonist and kappa agonist, is generally inadequate for the treatment of cancer pain, especially when moderate to severe owing to the lesser analgesic potency and short duration of analgesia when compared to the duration of sedation, often leading to a false interpretation of comfort in sedated but uncomfortable patients. Methadone is increasingly used for cancer pain in people and, in addition to its mu receptor agonistic activity, also provides non-competitive antagonism of the N-methyl-D-aspartate (NMDA) receptors. The use of methadone for chronic pain in companion animals may increase in years to come.

Weaker opioids include codeine and tramadol and are useful for moderate pain. Tramadol is a good analgesic for moderate cancer pain in humans, and tends to cause less inconvenient side effects than equipotent true opioids. The wide clinical use of tramadol for chronic pain in pets (mainly dogs) is chiefly based on anecdotal experience, along with pharmacokinetic and pharmacodynamic studies, because solid clinical studies are lacking and difficult to perform. Anecdotally, tramadol appears safe and effective for various chronic pain conditions of dogs. Tramadol acts as a µ receptor agonist, and also has serotonin and noerpinephrine reuptake inhibition effects. To avoid the potential risk of a "serotonin syndrome" developing, tramadol should not be used concurrently with selective serotonin reuptake inhibitors, tricyclic antidepressants, and monoamine oxidase inhibitors.

Adjuvant analgesics

Sodium channel blockers

Local anesthetics are invaluable in many situations and, being often utilized for local or regional blocks, their intravenous, oral, or transdermal application (lidocaine alone or with prilocaine) can also be helpful in certain conditions. A local or regional block may help provide adequate pain control and permit much lower doses of systemic drugs. The systemic administration of certain sodium channel blockers, such as intravenous lidocaine and oral mexiletine, to potentiate analgesia from other drugs, is becoming more common in the treatment of cancer pain in humans and pets.

NMDA antagonists

This class of drugs includes ketamine, amantadine, dextrometorphan, and memantine. Ketamine is a dissociative agent that acts as a N-methyl-D-aspartate (NMDA) receptor antagonist. It is especially useful for chronic or neuropathic pain, often combined with other agents permitting adequate analgesia with lower dosages of opioids (sparing effect), and less side effects. Its use at a microdose in a CRI for perioperative analgesia, often combined with lidocaine and fentanyl or morphine, is common practice. Amantadine was initially developed as an antiviral (influenza), is available for oral administration (capsule or liquid), and also used in Parkinson's disease. It has NMDA receptor antagonistic activity and has been reported for chronic cancer pain in people. A single study describes its benefit in dogs with osteoarthitic pain, when combined to an NSAID, and anectodal clinical experience supports similar safety and subjective efficacy for chronic cancer pain in pets.

Anticonvulsants

Multiple studies support the use of certain anticonvulsants in the management of neuropathic pain in people. The best described drug is gabapentin, a structural analogue of gamma-aminobutyric acid (GABA) that provides analgesia through modulation of voltage-gated calcium channels. While the use of gabapentin remains poorly described in the veterinary literature, it is known to be well tolerated, highly bioavailable and rapidly metabolized in dogs, and anecdotally appears to work best when used in combination with other analgesic agents, such as NSAIDs. There is accumulating anecdotal evidence of its utility for various pain syndromes in dogs and cats. Newer anticonvulsants have yet to show a marked pharmacoeconomic advantage over gabapentin for neuropathic pain conditions.

Tricyclic antidepressants

Evidence supports the use of tricyclic antidepressants TCA), both for non-malignant neuropathic pain conditions and for chronic cancer pain. The main TCA described for such pain conditions is amitriptyline. While its use as an adjuvant analgesic agent is still poorly described in veterinary medicine, it appears to be best suited for combination therapy with other classes of analgesic. Though the analgesic effects of amitriptyline are attributed to actions on endogenous monoaminergic pain modulating systems using noerpinephrine and serotonin, other effects could be directed at the microglia, sodium channels, and the NMDA receptor according to recent studies.

Aminobisphosphonates

Synthetic analogues of inorganic pyrophosphate, bisphosphonates help in the management of malignant bone pain via specific binding to sites of active bone turnover and osteoclastic inhibition. The more potent intravenous aminobisphosphonates, including pamidronate and zoledronate, are preferred for osteolytic bone pain from metastatic carcinoma and multiple myeloma in people, and studies have shown safety and some efficacy in dogs and cats with primary and metastatic bone cancer such as appendicular osteosarcoma (dog) and oral squamous cell carcinoma (cat).

Corticosteroids

Corticosteroids have a mild analgesic effect, and can be occasionally considered for cancer pain. They are especially useful with intracranial tumors, spinal cord compression, and pain from lymphoid malignancy or MCT. They should never be used concurrently with NSAIDs.

Combination therapy and drug interactions

A multimodal approach (2 or more analgesics) is ideal for alleviation of moderate to severe or refractory cancer pain. Caution is required when treating geriatric patients with many drugs, and it is prudent to introduce one at a time, in a sequential manner. If side effects are encountered or a drug is used at its maximum safe dosage without benefit to the patient, it should be stopped. The possibility of drug interactions should be carefully evaluated whenever multiple drugs are used concurrently.

Complimentary therapies and rehabilitation medicine

Complimentary therapies are included in the therapeutic regimen for cancer pain in humans. Such therapies include acupuncture, massage, stretch and manipulation, hydrotherapy, play therapy, superficial heat and cold, percutaneous electrical stimulation, transcutaneous electrical nerve stimulation, laser therapy, ultrasound, and pulsed magnetic field therapy. Still not described in the veterinary literature for cancer pain, their increasing availability, anecdotal reported efficacy, and excellent tolerability profile make them an attractive addition to the therapeutic options in that setting.