peter vajdovich dvm, phd, dipl. of ecvcp associate ... · pdf fileassociate professor...

Assessing & Managing pain in cancer

Peter Vajdovich DVM, PhD, Dipl. of ECVCPassociate professor

Department and Clinic of Internal Medicine,Faculty of Veterinary Science,

Szent István UniversityE-mail: [email protected]

Pain is defined as

„an unpleasant sensory and emotional an unpleasant sensory and emotional experience associated with actual or experience associated with actual or potential tissue damage, or described in potential tissue damage, or described in terms of such damage.terms of such damage.””

Yearly cancer incidence in dogs and cats per 100,000 animals

4.97.9Bone cancer occurrence

48.125.0Lymphoid tumors occurrence

25.4198.8Breast cancer occurrence

11.620.4Mouth and pharynx cancer occurrence

17.035.8Connective tissue cancer occurrence

5.08.5Respiratory cancer occurrence

11.225.2Digestive cancer occurrence

No Data25.0Skin (melanoma) cancer occurrence

34.790.4Skin (nonmelanoma) cancer occurrence

155.8381.2Overall cancer occurrence

CatsDogsCancer site

Source: Withrow Stephen J, and David M. Vail. Small Animal Clinical Oncology. St Louis: Saunders Elsevier, 2007.

PATHOPHYSIOLOGYPain activates the neuroendocrine system, the release of catecholamines, glucagon, insulin, somatostatin.

Gluconeogenesis is favored. This leades to impaired metabolismdespite nutritional intake, resulting in cachexia.

Activation of the renin-angiotensin systemleades to fluid retention, elevated blood pressure, decreased renal perfusion.

Myocardial oxygen consumption is increased, which may be problematic in animalssuffering from heart disease.

Shunt blood from the GI tract, impair motility, and decrease mucosal intergrity.

As a result of bacterial overgrowth, malabsorption, electrolyte abnormalities, and sepsis can occur.

atrophy

Tumor necrosis factor may be released, which alters endothelial permeability, enhances coagulation, and promotes interlekukin 1 secretion, leading to the release of acute reactants.

Pain induces stress response in patients. A prolonged stress response can decrease the rate of healing, can have adverse effects on the cardiovascular and pulmonary systems, fluid homeostasis, and gastrointestinal function.

Surgery is well known to result in the suppression of several immune functions, including natural killer (NK) cell activity, probably as a result of released cytokines, hormones, inflammatory substances.

This suppression of NK cell activity can enhance metastasis.The result of untreated pain can be widespread and sever with an overall negative impact on survival time and response to therapy.

NUMBERS

Pain is common in people with cancer, with the reported incidence varying between 30% and 90%.

An overall average of about 70% of patients with advanced (metastatic) cancer suffer from pain and that 36% of these patients have severe pain that impairs their quality of life.

Pain is experienced by 20% to 50% of human patients when the lesion is diagnosed, by nearly half undergoing active treatment, and by up to 90% of patients have pain with far advanced or terminal cancer.

An estimate is that at least 50% of veterinary cancer patients experience some degree of pain.

Approximately 30% of tumours in dogs and cats are associated with significant pain at the time of diagnosis.

It is estimated that cancer pain can effectively managed in 90% It is estimated that cancer pain can effectively managed in 90% of of humans with currently available drugs and techniques.humans with currently available drugs and techniques.

30%

PainNo pain

TYPES

Tumors most likely associated with pain include those at the following sites: oral cavity, bone, urogenital tract, eyes, nose, nerve roots, gastrointestinal tract, and skin.

Temporal aspectsAcute pain: follows some bodily injury, disappears with healing, and tends to be self-limiting. May be characterized by vocalization, inappetence, abnormal sleeping patterns, lameness, sympathetic hyperactivity (tachycardia, tachypnea). Tumor invasion of tissues associated with malignancy may produce continuous acute pain.

Chronic pain: lasts several weeks to 2-3 months and persits beyond the expected healing time. Specific clinical signs of pain may not be present because of autonomic nervous system adaptation. Chronic tumor pain often increases as a tumor grows and may decrease in intensity as a tumors shrinks.

Breakthrough pain: transient flare-up of pain in the chronic pain setting and can occur even when chronic pain is under control. It can occur even when chronic pain is effectively managed with opioids.

Wind-up: central sensitization attributable to an increase in the excitability of spinal neurons, contributing to the severity of postoperative pain.

Intensity

Patients usually tolerates mild pain without problem and does not exhibit any does not exhibit any behavioral changesbehavioral changes. Patients with mild pain often are not treated.

Patients with moderate pain usually exhibit changes in behavior, appetite, activity changes in behavior, appetite, activity positioning, or posturepositioning, or posture. They respond to palpation of the painful area.

Severe pain is intolerable, and is often manifested as unprovoked crying, often manifested as unprovoked crying, himperinghimpering, howling associated with violent thrashing, howling associated with violent thrashing. Patient may not exhibit these behaviors, because the associated movements enhance the excruciating pain.

Nonspecific physiological responses to pain include elevated heart rate, blood pressure, abnormal cardiac rhytm, panting, salivation, dilated pupils etc.

Cancer pain typically begins as acute mild pain and then potentially progresses to a chronic pain state that may be mild to severe.

Origin

Somatic pain originates from damage to bones, joints, muscle, or skin and islocalized, constant, sharp, aching, and throbbing (ie. osteosarcoma)

Visceral pain arises from stretching, distention or inflammation of the viscera and is described as deep, cramping, aching, or gnawing, without good localization (ie. an enlarging visceral tmor).

Neuropathic pain originates from injury or involvement of the peripheral or central nervous system and is described as burning or shooting, possibly associated with motor, sensory or aoutonomic deficits (many soft tissue tumors have neuropathic component).

These three types of pain may occur alone or in combination in the same patient.

ORIGIN OF CANCER PAIN

Cancer pain can be a direct result of the primary tumour (e.g. invasion, tissue destruction, pressure).

A result of distant metastases (e.g. bone, meninges, pleura).

A result of painful paraneoplastic syndromes (e.g. hypertrophic osteopathy, peripheral neuropathies).

Result of diagnostic (e.g. biopsies) and/or therapeutic procedures (e.g. aggressive surgery /perioperative, postoperative pain, „phantom” limb/, chemotherapy, radiation therapy).

Pain in patients with cancer may also be secondary to unrelated conditions common in older animals (e.g. osteoarthritis).

ASSESSMENT OF PAIN

Four steps in ensuring that pain management is optimized in veterinary patients.

1. Education and training veterinarians about the importance of alleviating pain, assessment of pain, available drugs, potential complications, interventinal techniques.

2. Educating the client about realistic expectations surrounding pain control. Owner involvemement in evaluating the pet and providing feedback on therapy.

3. To assess the pet’s pain thoroughly at the start and throughout the course of therapy, and not just when it gets more severe.

4. Having good support from the veterinary practice or the use of opioids and other controlled substances.

RECOGNIZING PAINCommunication with the owner, technicians and other staff members.

One of the most useful ways of determining if tumour is painful is to palpate the area and evaluate the animal’s response.

Clinically, behavior appears to provide a better estimate. Observing movement, posture, grooming, appetite and thirst, licking of the painful area, drooling ordysphagia, vocalization, and growling or hissing when approached may providesemiobjective information on the degree of pain a given patient is experiencing.

Activity related parameters give important information, too. The owners shouldbe asked about the cancer patient’s interaction with family members, mood, responsiveness, dependence, response to handling, vocalization, ability to sleep, restlessness.

Force plate analysis, used a pressure-sensing floor mat (MatScan System—Tekscan Inc.) to detect gait abnormalities, or used pressure algometers, instruments that measure the pressure required to elicit pain.

Various observer pain scales have been used to estimate pain in animals. The most common types are the visual analog scale (VAS) and the numerical rating scale (NRS). Others include: Dynamic and interactive AVS (DIVA), Compositerating scale (CRS) or Multidimensional rating scale (MRS).

Louis-Philippe de Lorimier, Timothy M. Fan, Understanding and recognizing cancer pain in dogs and cats, Treating cancer pain in dogs and cats VETERINARY MEDICINE. May 1, 2005

TYPES OF CANCER RELATED PAIN

Dull, throbbing pain happens in cancers like osteosarcoma (bone cancer).

Severe pain in the abdomen can occur with bleeding hemangiosarcomas (spleen tumors).

Mast cell tumors likely produce burning pain in the skin or in other locations.

Pressure-associated pain can happen with nasal tumors like fibrosarcomas.

Bladder tumors like transitional cell carcinomas cause burning and irritation leading to urgency to urinate.

Tumors may cause pain by stretching the capsule of certain visceral organs or by causing flow obstruction (in the biliary, urinary, or gastrointestinal tract).

A tumor can become painful because of inflammation or secondary infection.

PAIN CAUSING THERAPEUTIC PROCEDURES

Some routinely performed staging procedures, such as soft tissue biopsies (Tru-Cut, punch, wedge), bone marrow aspiration or biopsy, and bone biopsies, predictably result in mild to moderate pain.

Aggressive surgical approaches such as amputation, hemipelvectomy, thoracotomy, radical mastectomy, large en bloc tumor resection with dorsal spinous processes, mandibulectomy, and maxillectomy might cause aggressive pain.

Chemotherapy

Colitis from doxorubicin

Constipation from vincristine in cats

Sterile hemorrhagic cystitis from cyclophosphamide

Pancreatitis from various agents burning sensation at the catheter site during dacarbazine infusion (low pH)

Occasioanlly painful peripheral neuropathies are known to occur with drugs such as vincristine, cisplatin

Vinca rosea

Multiple venipunctures and catheter placement causes also sterss and pain

Perivenous extravasation of certain chemotherapy agents, including vincristine, doxorubicin, vinblastine, mechlorethamine, and dactinomycin, causes painful tissue destruction, sometimes severe enough to necessitate surgical débridement

Implanted vascular access ports in the jugular veins of patients requiring repeated intravenous therapy over weeks to months are an option to avoid pain

Radiation therapy

Normal tissue toxicity may result in moderate to significant pain.

Mucositis is an early radiation side effect that commonly occurs with curative-intent protocols, it can be fairly painful.

The most common sites of painful radiation-induced mucositis are the mouth (stomatitis, glossitis) when oral or sinonasal tumors are irradiated and the large intestine (colitis, proctitis) when pelvic irradiation is performed.

Occasionally, pain may result from late side effects of radiation therapy, including osteoradionecrosis causing pathologic fracture and peripheral neuropathies.

Kim L. Cronin, DVM, Dipl. ACVIM. Oral tumors: Know the extent of disease prior to surgery. DVM NEWSMAGAZINE. Oct 1, 2006

ANALGESIA PRINCIPLES

Preemptive analgesia is the administration of analgesic therapy before a patient is exposed to noxious stimuli.

Multimodal analgesia takes into account the complexity of pain transmission and uses various methods or classes of drugs with different mechanisms of action to control pain.

Mechanism based analgesia means that specific molcular mechanisms involvedin pain sensation, and the development of pain sensitization (central and peripheral) can be affected to treat perioperative pain.

The World Health Organization (WHO) has proposed a three-step analgesic ladder for controlling mild, moderate, and severe pain in people. Within the same category of drugs, there can be different side effects for individuals. If possible it may be best to substitute drugs within category before switching therapies.

Mild pain is treated initially with nonopioid drugs, generally NSAIDs.

If pain persists after treatment with a nonopioid or if the pain is moderate, a weak opioid (codeine or tramadol) can be added on the second step.

If pain is not controlled with that combination or if the pain is severe, increase the dose of the opioid, or stronger opioids, preferably full mu agonists, are used for the third step of the ladder.

For patients with advanced, difficult-to-control cancer pain. Techniques such as intrathecal administration of opioids, neurostimulation, and peripheral neuroablation can be introduced as a fourth step.

Central neuroablative procedures can be added as a fifth step.

Copyright VGMTP 2008

METHODS OF PAIN RELIEF FOR CANCER PATIENTS

Surgery.

Benefit of palliative surgeries to remove painful tumors, although the surgery itself may not positively affect the overall prognosis for survival.

A classic example is a painful appendicularosteosarcoma, amputating the limb provides immediate relief to the patient, and adjuvant chemotherapy is administered to prolong survival and delay the growth of micrometastatic disease.

Surgically removing pulmonary metastatic lesions to provide relief from painful paraneoplastichypertrophic osteopathy has been described.

The most rational way to alleviate cancer pain, whenever possible, is to treat theunderlying tumor.

Radiation therapy

For painful tumors that may not respond as well to fractionated protocols, a protocolthat uses coarse fractions of radiation, often called palliative radiation therapy, canhelp alleviate pain in many patients.

Radiation induced mucositis can be treated with oral rinse solutions (weak green tea solution, chlorhexidine rinse, or mixture of viscous lidocaine, liquid diphenhydramine, and magnesium hydroxide) and systemic nonsteroidal anti-inflammatory drugs(NSAIDs) with a weak opioid as needed. In humans acetylcisteine is used, too.

Signs of colitis or proctitis can be effectively relieved with a corticosteroid enema.

Patients with acute moist dermatitis may benefit from topical application of colloidaloatmeal, wheat extracts, or aloe gel extract.

Note: benefit of antioxidants.

Chemotherapy.

Systemic cytotoxic chemotherapy is used to treat chemosensitive tumors or cancers in patients.

Lymphoma with bone, central nervous and/or hepatosplenic involvement may occasionally have visceral pain from capsular distention.

Multiple myeloma is often painful, with osteolysis occurring in multiple osseous sites, and can also result in pathologic fractures or compression of the meningesand spinal cord. Multiple myeloma can be treated by other therapies to alleviate pain rapidly, including radiation therapy and anti-osteoclastic drugs such as bisphosphonates.

Hemorrhagic cystitis caused by cyclophosphamide can be treated by mesna(sulphydril component) and oxybutinin.

http://missinglink.ucsf.edu/lm/IDS_101_histo_resource/images/osteoclasts.jpg

Many patients with painful mast cell tumors may benefit from systemic chemotherapy when their disease is unresectable or disseminated.

Painful carcinomatosis is occasionally treated with intracavitary chemotherapy.

Finally, transmissible venereal tumors are found most typically on mucosal surfaces of the external genitalia and can cause pain. Chemotherapy helps.

Mesothelioma in DogsLaurena A. Kavula, DVM; Kenneth S. Latimer, DVM, PhD; Perry J. Bain, DVM, PhDClass of 2003 (Kavula), Department of Pathology (Latimer, Bain), College of Veterinary Medicine, The University of Georgia, Athens, GA 30602-7388Veterinary Clinical Pathology Clerkship Program

Multimodality therapy

Surgery, radiation therapy, or chemotherapy are frequently combined to achieve better and longer tumor control, translating into prolonged and more complete pain alleviation. Examples of cancer best treated with multimodality therapy include feline vaccine-associated soft tissue sarcomas, canine apocrine gland anal sac adenocarcinoma, high-grade canine mast cell tumors and soft tissue sarcomas, and certain oral tumors.


ANALGESIC DRUGS AND PROCEDURES

NSAIDs.

Veterinary patients with cancer pain also appear to benefit from the use of NSAIDs, and they are often used alone for mild pain or in combination with opioid drugs and adjuvant analgesics for moderate and severe pain.

Another rationale to use NSAIDs for cancer pain stems regarding the potential anticancer and chemopreventive effects of these drugs in human and veterinary patients (ie. meloxicam, firocoxib). Note: transitional cell carcinoma, oral and nasalcarcinomas, inflammatory mammary carcinoma. Good for everything?

Few NSAIDs are approved for cats, and their use has been rendered difficult because of marked differences in metabolism when compared with dogs. Most NSAIDs have been formally investigated in dogs, although good information does exist for meloxicam in cats.Personal opinion: firocoxib is beneficial in oral squamous cell carcinoma, too.

Acetaminophen possesses beneficial effects of analgesia (despite the low anti-inflammatory activity); minimal risk for bleeding in thrombocytopenic patients (in case of myelosuppressive chemotherapy); synergism with opioid analgesics, such as codeine (Dogs: 10-15 mg/kg po q 12 h for 5 days + codeine 10-15 mg/kg, for cats not recommended). Acetaminophen may be helpful for breakthrough pain control in dogs already receiving NSAIDs.

Mild to moderate pain that arising from intrathoracic, intraabdominal masses, and bone tumors and metastases, can be releived with NSAIDs.

NSAIDs have opioid sparing effect!!!!

Side effects can commonly occur while using NSAID’s.

Specific signs such as melena, vomiting, lethargy, decreased appetite, depression, yellow discoloration of mucous membranes and sclera, and altered water intake and urine output.

Gastrointestinal irritation and nephrotoxicosis. Administering misoprostol can help to provide GI protection.

Hepatotoxicosis can also occur with acetaminophen or because of idiosyncratic reactions to NSAIDs.

Antithrombotic effects can also occur with aspirin and ketoprofen (firocoxib no).

NSAIDs that are more selective for inhibition of COX-2 seem to have fewer GI effects and potentially fewer renal effects. These include carprofen, meloxicam, deracoxib, firocoxib, tepoxalin.

If clinical effectiveness is not achieved with one NSAID, it should be discontinued and another started 7 days later.

Opioids.

One reason opioids are so helpful is that their dosage can be gradually and safelyincreased as needed to provide the desired level of analgesia.They are reversible with naloxone or nalmefene if unacceptabe side effects occur.

They are used mostly for moderate to severe pain, and their effects are potentiated when used concurrently with other analgesics, including NSAIDs.

Parenteral opioids should be used in the perioperative period and should be discontinued when a patient can be switched to oral medication (ie. morphine, oxycodone, buprenophine, and codeine).

The dosing of opioids is individual.

The standard opioid remains morphine, a pure mu-receptor agonist (such as oxymorphone, fentanyl, codeine, meperidine). Full mu antaginists induce best analgesia and are not limited by a ceiling effect.

Morphine and hydromorphone should be the most commonly used injectable opioidfor the acute treatment of cancer-related pain.

Oxymorphone is only available as an injectable analgesic.

Meperidine is short acting, limiting its use in patients that have cancer.

Codeine alone or with acetaminophen can be given orally.

Fentanyl is an injectable drug and is appripriate or continuous infusionbecause it is short acting. It is recommended rather than the intermittent iv., im. sq. administration as patients can be painful before and their dose and extremely sedated after dosing. The use of transdermal fentanyl patch in companion animals has been recently reviewed. Fentanyl patches require 12-24 hours to take effect and last 2-4 days in dogs. Additional analgesia must be provided during the 1st 0.5 to 1 day after patch placement. These patches is related to unreliable plasma levels in dogs, and may not provide enough analgesia for severe pain.

Oxycodone, an excellent oral analgesic in dogs, may be used for primary pain control or for breakthrough pain. It induces less sedation and dysphoria than oral morphine, and better in pain control than codeine.


The partial mu agonist buprenorphine does not produce the same degree of analgesia as morphine and has a ceiling effect. It has a long duration of action (6-12 hours) and can be useful, especially with the effective transmucosal (mouth) route in cats, for treating breakthrough pain. I fan animal does not have adequate analgesia after receiving buprenorphine, dosing with morphine-like drug may not produce any results because of buprenurphine’s strong affinity for mu-receptors.

Butorphanol, a mixed mu antagonist and kappa agonist, is not considered adequate for treating cancer pain.

An opioid that is increasingly used for cancer pain in people is methadone. This is notonly is a mu-receptor agonist but also produces additional analgesic effects throughnoncompetitive antagonism of the N-methyl-D-aspartate (NMDA) receptors..

Weaker opioids, such as codeine and tramadol, can be useful for moderate cancer pain. Tramadol (a serotonin reuptake inhibitor) it is useful for chronic pain. Can bridge the gap between an NSAID alone and the addition of an oral opioid (dose for dogs and cats: 2-3 mg/kg po bid, tid.)

Side effects can be more important at higher dosages but are relatively predictable and tolerable, except for dysphoria (a state of dissatisfaction, anxiety, restlessness, or fidgeting) in cats and Nordic canine breeds.

Other main side effects include sedation, constipation, bradycardia (administered parenterally – if it occurs anticholinergic atropine, glycopyrrolate should be given instead of discontinuing the opioid), respiratory depression, panting, mydriasis(cats), cough suppression, altered laryngeal reflexes, vomiting, and histamine release (mostly morphine, especially with rapid intravenous dose) and dysphoria.

The initial GI effects occur most frequently with the first injection in the perioperativeperiod and usually do not occur with subsequent dosing. These effects usually do not occur with oral dosing.

Alpha2 agonists

The main alpha2 agonists are medetomidine, dexmedetomidine and xylazine, which are useful in the context of multimodal and preemptive analgesia. Their analgesic effects are especially pronounced when combined with other agents such as opioids and ketamine. They provide excellent visceral analgesia but only for 20 minutes to 2 hours. Their effects can be reversed with yohimbine or atipamezole. They reduce cardiac function and oxygenation. Alpha2-agonists have synergistic effects with opioids. When used in microdoses (0.5-1 µg/kg iv, 1-3 µg/kg/h), this effect can be useful after surgery for inducing additional analgesia and alleviating dysphoria.

N-methyl-D-aspartate (NMDA) receptor antagonists

They include ketamine, tiletamine, amantadine, and dextromethorphan, provides somatic but poor visceral analgesia; it reduces postoperative analgesia.

NMDA antagonist doses inducing an indirect analgesic effect, essentially allowing other analgesics to work.

Microdose ketamine decrease the incidence of opioid-induced dysphoriaafter surgery.

Amantadine is used as an antiviral agent, an oral anti-influenza A medication also has NMDA antagonist effects, can be administered at 3 mg/kg po, sid, to prevent wind-up.

Adjuvant drugs

These include tranquilizers (acepromazine, benzodiazepines /diazepam, midazolam, alprazolam) local anesthetics, anticonvulsants (gabapentin – have a role in decreasing incisional pain, arthritis, and neuropathic cancer pain; dose 2.5-10 mg/kg, and can be escalated up to 50 mg/kg bid, tid), tricyclic antidepressants (amitrpityline, clomipramine, imipramine – serotonin reuptake blockers and have antihistaminic effects), aminobisphosphonates (for osteosarcoma and bony metastases inhibit osteoclast-induced resorption – pamidronate 1-2 mg/kg in saline iv over a 2-4 hour period at 3-5 weeks, or alendronate po.), corticosteroids.

http://missinglink.ucsf.edu/lm/IDS_101_histo_resource/images/osteoclasts.jpg

Local anesthetics

Most commonly used local anesthetics include lidocaine and bupivacaine. Lidocaine has a short onset (<1 minute) and lasts approx. 60-90 minutes. Doses. 1.5-2.0 mg/kg. Bupivacaine takes approx. 20 min. to take effect but may last for 5-8 hours. The 5% lidocaine patch produces local tissue concentrations far lower than thosecapable of producing toxicity but high enough to produce clinically effective local analgesia for periods of up to 24 hours without complete sensory block.

Epidural drug administartion

Epidural morphine is commonly administered in the perioperative period to provide analgesia, but not anesthesia, in the abdomen or more caudally. It maybe effective for throax and forelimb. This may last up to 24 hours. Local anesthetics may also be administered epidurally as a low dose. A catheter can also be placed in the epidural space for severe pain.

A good 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 treating cancer pain in people. The systemic administration of local anesthetics for analgesia in dogs and cats is relatively recent and may increase in the near future.

Other Pain-Relieving Modalities.

Local whole body radiation can enhance drug effectiveness.

Intravenuos administration of strontium-89 has also been shown to provide analgesia related to bony metastases.

Acupuncture can be used as a pain-relieving modality with conventional therapy. It may allow lower doses o drugs.

Copyright 2007 TOPLINE [email protected]

Acupuncture ChartCanine chart highlighting some

primary acupuncture points

Mucositis can be treated by analgesics, green tea rinses, sucralfate, 2% viscous lidocaine, and a 1.1 combination of 2% lidocaine viscous to aluminium hydroxide, 64 mg/ml – „Pink lady”).

Complementary therapies include acupuncture, massage, stretch and manipulation, hydrotherapy, play therapy, superficial heat and cold application, percutaneouselectrical stimulation, transcutaneous electrical nerve stimulation, laser therapy, ultrasound, and pulsed magnetic field therapy.


Pain control should be achievable by following ABCs

A. Asses the pain. Ask the owner’s perceptions!B. Believe the owner. The owner seest the pet each day in its own environment. C. Choose appropriate therapy following the WHO ladder and other specific paradigms.D. Deliver therapy in a logical coordinated manner.E. Empower the clients to participate actively in their pet’s well-being.

ThankThank youyou forfor youryour attentionattention

peter vajdovich dvm, phd, dipl. of ecvcp associate ... · pdf fileassociate professor...

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