The World Small Animal Veterinary Association (WSAVA) is in a key position to be a champion for compassionate care and pain control on a world wide basis. Veterinarians, regardless of language, culture, race or nationality have an individual obligation: to alleviate the pain and suffering of animals. WSAVA not only has the moral obligation to provide education on pain control and prevention on a global basis, but she is also in a key position to be a catalyst to ensure that veterinarians have access to appropriate drugs and techniques to relieve the pain and suffering of animals. Below is a first step in that process.

INTRODUCTION

Compassionate care is the watchword of veterinary medicine, and pain control is the cornerstone of the caring process. Fortunately, pain control in dogs and cats has recently being investigated and applied seriously. Canine and feline pain management can be difficult; dogs and cats may not exhibit discomfort openly which precludes identifying pain early when it is easiest to treat. The key to compassionate pain control is anticipating the onset of discomfort, therefore allowing timely intervention with analgesics, optimally before pain receptors ever identify discomfort. Many excellent reviews exist for those seeking additional details of pain prevention, control and management.

IDENTIFYING PAIN

The best canine and feline practitioners anticipate and intervene early rather than waiting for clinical signs associated with discomfort. This is especially true in palliative care. In addition, caregivers need to be aware of which procedures are likely to cause discomfort, and preemptive analgesia should be practiced when possible.

Comprehensive management of pain involves careful evaluation and treatment of each dog and cat.^1-6 To maximize quality of life, response to therapy, and survival time for canine and feline patients, adequate pain control must be the highest goal for the veterinary practitioner. Pain control in veterinary medicine come to the forefront of attention, primarily because of the inappropriate attitudes of clinicians, lack of knowledge about analgesic medications, and lack of skill in assessing pain and appropriate therapeutic methods.^2,3 In many cases, analgesics have been withheld because of fear of associated adverse side effects and because research demonstrating the beneficial effects of pain relief in dogs and cats is scanty. Client demand has been an important force in bringing pain control to the forefront of compassionate care. Despite our lack of understanding, we must respond to our patients' needs and our clients' concerns by making pain relief and compassionate care a priority. Every single animal can be helped.

GENERAL CONCEPTS OF PAIN THERAPY

Selection of Medication to Manage Pain^-5

Selection of analgesics can only be done effectively by considering their mechanism of action, potency, duration of efficacy, effect on the central nervous system, anti-inflammatory effects, toxicity, metabolism, drug interactions and price. The best practitioners gain experience with a set number of drugs which allows them to result in maximum pain control based on experience on the afore mentioned parameters. They educate their clients about realistic expectations as well as the benefits and deficits and toxicoses of different pain therapies. The best practitioners begin analgesics prior to the onset of pain and then continually change therapy to meet the pet's needs throughout the course of the disease and the therapy. General categories of drugs, select representative examples and application include:

 Nonsteroidal-Anti-inflammatory Drugs (NSAIDs) such as carprofen, etodolac, deracoxib, ketoprofen, piroxicam, meloxicam, etc., provide mild to moderate anti-inflammatory and analgesic effects. These older, nonspecific analgesics such as aspirin, ibuprofen, ketoprofen and piroxicam may be associated with a greater risk for side effects, but the ease in obtaining these Intrathoracic and intra-abdominal masses along with boney metastases may be effectively treated with this class of drug due to their central analgesic and peripheral anti-inflammatory effects mediated through the inhibition of cyclooxygenase. These NSAIDs are responsible for inhibiting two cyclooxygenase (COX) enzymes, COX-1 and COX-2. The inhibition of COX-1 can result in serious side effects such as gastrointestinal distress and perforation. The newer NSAIDs such as carprofen, etodolac and deracoxib primarily impact the COX-2 enzyme and are often associated with fewer side effects. Selective COX-2 inhibitors such as carprofen, etodolac and deracoxib usually have fewer side effects such as renal and gastrointestinal problems. Regardless, liver and renal function should be evaluated periodically in all animals receiving these drugs. Drugs such as misoprostol are prescribed by some clinicians to reduce the possibility of toxicity to the gastrointestinal tract. Acetaminophen, that is believed to block the newly identified COX-3 enzyme is related to NSAIDs but does not contain any anti-inflammatory effects, but is effective for treating discomfort without side effects such as bleeding due to platelet effects. It is possible that newer drugs will impact only this COX-3 enzyme resulting in fewer adverse effects.

 Alpha-2-Agonists such as clonidine, romifidine, medetomidine and xylazine provide good to excellent analgesia with moderate to significant sedation and depression. Their short duration of action an tendency to reduce cardiac output and tissue oxygenation may make them an unwise choice for some frail or infirm patients. When combined with an opiate, they can enhance the efficacy of the later.

 Opioids such as sustained release morphine, fentanyl, butorphanol can result in excellent analgesia with low to moderate behavioral changes such as depression. In fact, these drugs are the most predictable, effective analgesics for the use in the cancer patient. These drugs can be administered orally, SQ, IM, IV or transdermally but the efficacy of oral therapy has yet to be clearly documented. As the severity of discomfort increases, the dosage of the opiates can be increased. Toxicity can include bradycardia, diarrhea, vomiting, constipation and sedation although careful dosing can mitigate any problems. Oral morphine is most commonly used long term for cancer pain management. Morphine is a natural opioid agonist. On rare occasions, it may produce depression and sedation, or occasionally an initial excitement manifested by panting, salivation, nausea, vomiting, urination, defecation, and hypo-tension when administered to dogs and cats. These reactions arise from activation of the chemoreceptor trigger zone, vagal stimulation, and histamine release. Oxymorphone is a semisynthetic opioid agonist with analgesic properties that are approximately 10 times more potent than those of morphine; its adverse effects on the respiratory, cardiovascular, and gastrointestinal systems are less pronounced. Oxymorphone is indicated for moderate to severe visceral or somatic pain. Lower doses are used for IV administration. When used alone, however, oxymorphone may result in excitement or hyperalgesia.^2,3,6 Diazepam given concurrently with oxymorphone may help reduce these side effects. Fentanyl is an effective analgesic that can be given IM, SQ, or IV as a pre-anesthetic. It can be administered via an IV bolus, constant rate infusion, or transdermal patch. Fentanyl can cause respiratory depression, bradycardia, and somnolence at higher dosages. It can also prolong return to normal body temperature during recovery from anesthesia. Fentanyl-impregnated transdermal patches reliably release a controlled amount of fentanyl over a 72 hour period. The patches maintain adequate blood levels of fentanyl for 72 hours, but therapeutic levels are not attained for 12 to 24 hours; thus patches may be most effective when used in conjunction with other analgesics or in addition to constant rate fentanyl infusion during surgery or other painful procedures.

 Opioid agonists-antagonists such butorphanol are generally not as effective is opiates. Butorphanol, a synthetic opioid agonist-antagonist that has five times the analgesic potency of morphine and a duration of analgesia of approximately 1 to 4 hours. Adverse effects such as nausea and vomiting are rare, but the drug can induce sedation. Higher dosages are needed for somatic pain, and analgesia lasts only about 2 hours. IV butorphanol may result in transient hypo-tension or bradycardia.^2,3,6 Butorphanol possesses antagonist properties and reverses the effects of narcotics. Therefore, butorphanol must not be given within 12 hours of any pre-or intraoperatively administered narcotics. Buprenorphine HCl, an agonist-antagonist, can reverse opioid-induced respiratory depression while maintaining analgesia.

 Ketamine is an N-methyl-D-aspartate (NMDA) receptor antagonist that is important in the "wind-up" phenomenon. When the drug is administered at microdosages during and up to 24 hours after a painful procedure, the need for additional analgesics are reduced and pain control maximized with little if any behavioral or cardiovascular effects. Typically a bolus of 0.5 mg/kg IV is administered IV followed by a constant rate infusion of 2 ug/kg/min for the first 24 hours after surgery. For simplicity, if an infusion pump is not available, the ketamine can be mixed in a liter bag of crystalloids. To administer ketamine at the drip rate of 10 ml/kg/hr, 60 mg of ketamine (0.6 ml) can be added per liter of fluids to deliver the ketamine at 10 mcg/kg/min. Obviously, if one wants to decrease the dosage to 1 mcg/kg/min, the fluid rate is reduced to 1 ml/kg/hr.

 Tranquilizers do not generally provide analgesia but their use in management of the cancer patient can be quite profound in CRI = constant rate infusion that fear, apprehension and anxiety may magnify the response to pain. Examples include acepromazine, diazepam and midazolam. The later two should only be administered with an opioid in the alert patient as excitation may occur otherwise.

 Tricyclic Antidepressants have antihistamine effects. They block the reuptake of serotonin and norepinephrine to the central nervous system. The drugs such as amitriptyline and imipramine are used at very low dosages to induce analgesic effects and enhance the analgesic effects of opiates.

 Palliative radiation is commonly used to reduce discomfort associated with some tumors, especially those involving the skeletal system. When combined with low dosage chemotherapy the enhanced effect may be prolonged. Generally a third of the treated patients have good to excellent results, one third transient adequate responses and a third of the cases have no noticeable improvement in pain control.

 Bisphosphonates are being used more and more commonly in veterinary medicine to treat primary or metastatic disease to bones. Pamidronate, given every 3-6 weeks has been associated with enhanced comfort and re-ossification of lytic sites to bone associated with osteosarcoma, mammary, prostate and other malignant processes.

 Strontium-89, when administered intravenously is taken up in places of active bone turn over. This update of the radio-pharmaceutical results in release in high quantities of radiation locally with enhanced comfort in approximately 50% of the cases treated.

 Acupuncture is used to treat a wide variety of pain due to cancer or cancer therapy such as surgery or radiation therapy. It is often used in concert with pharmacologic agents to reduce the dosage and enhance overall wellness. Acupuncture can also be helpful for reducing nausea associated with chemotherapy, anesthesia and the administration of certain antibiotics.

 Local anesthetic agents such as lidocaine and bupivacaine can be injected to block sensory or motor nerve fibers. Local anesthetics, such as 2% lidocaine HCl, are administered to effect near an incision and provide regional analgesia for about 1 hour. Bupivacaine HCl (0.75%) can be given to effect to provide 6 to 10 hours of regional analgesia for peri-incisional pain. Lidocaine can be administered at or near intercostal nerves proximal to a thoracotomy incision to reduce postsurgical pain. This agent is also frequently administered into the pleural cavity prior to bupivacaine administration to decrease discomfort associated with thoracotomy. Lidocaine or bupivacaine can be used as a maxillary or mandibular nerve block for oral surgery. Lidocaine can also be administered as a constant rate infusion to enhance analgesic effect of other drugs while causing depression and anesthesia. The following are a few examples of specific nerve blocks that are commonly used to treat the patient:

 Intercostal Nerve Block

 Infraorbital Block

 Mandibular Nerve Block

General Approach to Pain Management

^aIn each case treat the underlying disease
^bNSAIDs and acetaminophen. Use with caution in patients with renal disease.

General Examples of Procedures and Associated Discomfort (and Associated Pain Management)

Selected Analgesics for dogs⁵

Selected Analgesics in Cats^2-5

CRI = Constant Rate Infusion.

Rotes of Administration^1-5

The efficacy of a drug or drug combination can be enhanced by considering the optimal route of administration. As a general rule, oral analgesics can be quite effective for mild to moderate discomfort. However, when the degree of discomfort increases, the efficacy of these same or related drugs can be increased by administering the same drugs intramuscularly, subcutaneously or intravenously. The efficacy can be improved even further by giving the same drug epidurally. A brief discussion of the routes of administration are as follows:

 Oral administration is the easiest and cheapest, but probably associated with the lowest level of compliance. NSAIDs are most often administered via this route however oral morphine or sustained release morphine are also quite effective by this route for mild to moderate pain.

 Intravenous, intramuscular and sub-cutaneous administration of drugs is associated with the most predictable efficacy with the intravenous constant rate infusion technique being most optimal.

 Epidural or subarachnoid drug therapy can result in good to excellent long term analgesia. Sterile, preservative free drugs that have been used in this route include opiates, NSAIDs, ketamine, alpha-2 agonists and of course local anesthetic agents.

 Transdermal administration of fentanyl and clonidine, or topical treatment of drugs such as lidocaine and eutectic mixture of local anesthetics [EMLA] cream can result in good long term pain management, but is subject to many variables such as rate of absorption and body condition.

 Transmucosal therapy with drugs such as codeine, morphine, buprenorphine, may be very helpful in controlling mild discomfort.

 Local nerve blocks provide the precise delivery of local anesthetics directly to the anatomic site of choice with reduced toxicity.

Preventing and Treating Pain and Discomfort¹

The best way of managing pain is to prevent it. This is especially true with palliative care. When that is not possible, then the discomfort and pain must be treated appropriately and the treatment adjusted continuously as the disease or treatment progresses. Adequate pain therapy can only be achieved by ensuring the entire team is highly knowledgeable about pain and all approaches that can be employed to manage discomfort. This includes the client who is most intimately aware of the patient's quality of life and behavior patterns. The client's perception of the animal's quality of life should be trusted and believed above all.

Pain may be best prevented and treated by dividing it into the categories of acute and chronic pain. In most species the severity of pain is far more important than the duration of pain with regard to the "memory" of pain. In other words, the severity of discomfort at any point in time will result in a repetition of that same degree of discomfort when the same stimulus is applied subsequently. To make the point that preventative analgesia is important, it is important to realize that pain begets pain through the windup phenomenon whereupon pain makes certain nerve receptors even more "sensitive" to subsequent impulses that will be perceived as a greater degree of discomfort than before.

Acute pain can be due to the disease, trauma or surgery itself, the treatment or a diagnostic procedure. If discomfort is likely to be inflicted, then a preemptive, immediate post stimulus and post-stimulus plan must be designed and implemented. To ensure that this is done effectively, then one must determine if the pain to be inflicted is likely to be mild, moderate or severe. The later information is needed to appropriately select the drugs or procedures that are likely to be effective to meet the possible needs of the patient.

Chronic pain can also be caused by a number of diseases including cancer and even possibly by a diagnostic or therapeutic procedure. The former is illustrated by a metastatic bone lesion from a dog with mammary adenocarcinoma where as the later is illustrated by chronic infection and implant/plate/screw loosening from a limb sparing surgery. Both result in unrelenting pain that can last for weeks or months.

Mild Pain^1,3,6

The treatment of mild pain must begin first by eliminating the underlying cause along with general compassionate care that includes a comfortable environment, appropriate bedding, and effective bandaging if indicated. Dogs and cats will respond well to comforting, petting and talking. This is often followed with oral NSAIDs and if indicated, local nerve blocks and/or acupuncture.

 Nonsteroidal antiinflammatory drugs (NSAIDs) such as carprofen, deracoxib, etodolac, aspirin, piroxicam, meloxicam or ketoprofen, provided renal function is normal and there is no evidence of gastric inflammation. If NSAIDs are ineffective, an agent from one of the other categories is selected based on what works best in that patient

 Local nerve blocks or acupuncture

Moderate pain can be treated by eliminating the cause while providing compassionate care, local analgesia, acupuncture when possible and NSAIDs (e.g., carprofen, etodolac, deracoxib, piroxicam, meloxicam ketoprofen) in judicious combination with opiates. As with all analgesics, the parenteral, continuous administration of these drugs usually results in a more optimal effect than oral therapy. Constant rate infusion of fentanyl or microdose ketamine are excellent examples. Transdermal delivery of drugs such as fentanyl can provide a background of analgesia via a continuous release delivery system, however this is rarely adequate alone to prevent perioperative or procedural discomfort. When these therapies are not adequate, then it is prudent to consider drugs from one of the following categories:

 a₂-Adrenergic agonists

 Opioid agonist-antagonists

 Anxiolytics

 Tricyclic Antidepressants

When an acutely painful procedure is considered, then drugs for the patient are often divided into pre, peri and postoperative analgesics.^1,2

 Preoperative analgesics often include an opiate such as morphine with or without acepromazine to calm the patient and to result in anxiolysis. Atropine or glycopyrrolate are often administered to prevent bradycardia associated with the opiate. Nerve blocks are employed whenever possible.

 Perioperative therapy is often done well by adding fentanyl as a continuous intravenous infusion. This can decrease the need for additional analgesia. This may be combined with microdose ketamine to prevent the wind-up phenomenon.

 Immediately postoperatively is often best done well by using local nerve blocks and continuing the fentanyl and microdose ketamine. Later postoperatively, acepromazine can be used to reduce any dysphoria and diazepam and midazolam can also be used to reduce dysphoria.

Severe Pain^1,3,6

Therapy for moderate to severe pain can be difficult emotionally and physically for the entire veterinary health care team and the family. Everyone should be aware of the difficulty of this type of emotional and physical stress and supported to prevent the concept known as compassion fatigue.

Therapy for severe pain is as outlined for moderate pain (above) however the dosages of certain drugs, notably the opiates are continuously adjusted to a balance between maximum efficacy and minimal toxicity. The efficacy of drugs can be maximized by switching to more effective routes of administration such as epidural morphine, constant rate infusion of fentanyl etc. When drugs are combined, additive toxicity must be monitored. Palliative procedures such as the use of radiation therapy at sites of bone pain may be profoundly beneficial as can the intravenous infusion of bisphosphonates. When the degree of discomfort increases, dosages can be escalated in those opiates where there is no ceiling effect (e.g., morphine) or by changing the route of administration for analgesics (e.g., switching from subcutaneous to intravenous administration or to epidural therapy) may be effective. As with moderate discomfort, sustained-release fentanyl patches, which are applied to the skin and slowly release the analgesic over 72 hours, may be helpful.

Summary

Pain therapy is without a doubt one of the most important aspects of therapy, especially palliative therapy. It is important not only for the patient, the client, but the entire veterinary health care team. By meeting and hopefully preventing pain with well thought out therapeutic approaches, everyone can feel they have done the right thing. There are many options for managing discomfort and many more to come. It is the responsibility of the veterinary health care team to stay up to date on these therapies and to gain experience in the optimal management of the veterinary patient. Lastly, the stress of managing the cancer patient can be difficult emotionally. Everyone should be aware of the phenomenon known as compassion fatigue and how to prevent and treat it.

References

1.  Gaynor JS, Muir WS (eds): Handbook of Veterinary Pain Management. St. Louis, Mosby, 2002 pp 13-447.

2.  Tranquilli WK, Grimm KA, Lamont LA (eds): Pain Management for the Small Animal Practitioner, Jackson, Teton NewMedia, 2000, pp 13-69.

3.  Pascoe PJ: Patient aftercare, in Slater D (ed): Textbook of Small Animal Surgery, ed 2. Philadelphia, WB Saunders, 1993, pp 230-240.

4.  Hendrix PK, Hansen B: Acute Pain Management, in Gonagra JD (ed): Current Veterinary Therapy XIII: Small Animal Practice. Philadelphia, WB Saunders, 2000, pp 57-61.

5.  Heller PW, Gaynor JS: Acute postsurgical pain in dogs and cats. Compend Contin Educ Pract Vet 20:140-153, 1998.