Abstract

Recognizing Pain in Veterinary Patients

Pain Localization

The localization of pain to a particular area of the body is the responsibility of the central nervous system (CNS). Pain may be poorly localized due to a low density of sensory nerve fibers in the peripheral tissue or because of pain pathways that frequently branch and converge, making it difficult for the brain to localize the sensation. Pain inflicted to tissues with a high density of pain receptors such as the skin is generally much more precisely localized than the pain associated with internal organs.

In many cases, an animal initially reacts to pain by attempting to escape from the source. If this fails to bring relief, aggression or vocalization often follows. Animals experiencing acute postoperative or traumatic pain may also respond by biting, licking, rubbing, or scratching at the source of discomfort. Chronic, low-grade pain often associated with prolonged hospitalization, radiation, and chemotherapy or with severe osteoarthritis may manifest itself by an animal’s failure to groom, lack of interest in surroundings, reluctance to move, anorexia, weight loss, constipation, or dysuria. Elderly animals experiencing chronic pain often appear withdrawn and quiet. It is important to realize that not all signs of pain may be present at one time and that no single sign is a reliable indicator of the level of pain experienced.

Geriatric Considerations

Pharmacokinetic and pharmacodynamic changes independent of disease can be seen in geriatric patients. Generally, drug absorption remains unchanged with aging, despite increased gastric pH, mucosal atrophy, and decreased gastrointestinal motility. Age-related changes in drug distribution secondary to body composition are common. Some of the most important changes are an increase in body fat, decrease in lean body mass, and decrease in total body water. Older patients also frequently have decreased hepatic albumin production.

The ability of the aging liver to metabolize drugs does not decline equally for all agents. Glomerular filtration rate (GFR) gradually declines with age. Along with a decreased GFR, there is a decrease of almost 50% in renal plasma flow, resulting in a significant rise in filtration fraction with age. Loss of renal tubular and resorptive function also occurs with aging. The use of non-steroid anti-inflammatory drugs (NSAIDs) in elderly patients is common, and it is in this group that adverse side effects occur most frequently. Inhibition of prostaglandin-mediated renal vasodilation by NSAIDs along with the renal changes already outlined can lead to severe nephrotoxicity in elderly patients. The concurrent use of diuretics, presence of congestive heart failure, use of general anesthesia for surgical procedures (e.g., dentistry), or existence of other conditions leading to poor perfusion all can contribute to renal toxicity during NSAID use.

Analgesic Drugs - Narcotics

Morphine

Morphine is considered to be the prototypic narcotic analgesic. Two advantages of morphine are analgesia and sedation. The effects of morphine can be reversed by antagonists such as naloxone. Adverse effects of morphine administration include respiratory and CNS depression. Care should be taken when administering morphine to geriatric patients with compromised renal or hepatic function, because drug elimination may be significantly prolonged. At higher doses, morphine can be excitatory for cats. Morphine given in lower doses or combined with a tranquilizer appears to reduce the untoward effects in cats.

Fentanyl Citrate

Fentanyl (Sublimaze®) is a highly potent, synthetic phenylpiperidine derivative with action similar to that of morphine but with 100 times the potency.

Fentanyl has a short duration of action with peak effects lasting only 30–45 min. Like morphine and meperidine, the effects of fentanyl can be reversed with narcotic antagonists such as naloxone. Although fentanyl is an excellent analgesic, its use in veterinary medicine has largely been precluded (with the exception of continuous i.v. infusion or transcutaneous patches) because of its short half-life.

Transdermal application of fentanyl has recently become popular in veterinary medicine for the treatment of perioperative pain. Permeability of the stratum corneum varies widely; it is affected by body site, skin temperature skin blood flow, skin color, and the presence of skin damage or disease. Application of fentanyl citrate patches (Duragesic®) designed to deliver 50 µg/hr to dogs resulted in an average of 1.6 ng/ml at a steady-state concentration. In humans plasma levels of between 1 and 2 ng/ml are considered to be analgesic. Transdermal fentanyl patches work particularly well in geriatric patients because they do not cause sedation or significant respiratory depression. Patches should be placed at least 24 hr prior to surgery to allow for adequate plasma levels to develop. Fentanyl is absorbed from the patch continuously for 72 hr.

Oxymorphone Hydrochloride

Oxymorphone (P/M Oxymorphone HCl) is a semisynthetic narcotic analgesic that is approximately 10 times as potent an analgesic as morphine. It has duration of action ranging from 4–6 hr. Adverse effects are similar to those of morphine; however, it appears to cause less respiratory depression and gastrointestinal stimulation.

Epidural Opioids

For postoperative epidural analgesia in veterinary patients, morphine is used most commonly. Subarachnoid or epidural administration of preservative-free morphine (Duramorph PF® or Astramorph/PF®) has been quite efficacious. Epidural morphine is an excellent technique for providing postoperative analgesia after pelvic limb surgery. Administered at the lumbosacral space, it has been used after thoracic surgery but depends upon cephalad migration of the drug within the cerebrospinal fluid. The dose of epidural morphine should be administered 30–60 min prior to recovery from anesthesia. The duration of analgesia is from 6–24 hr.

Butorphanol

Butorphanol (Torbugesic®) belongs to a group of synthetic analgesics with combined agonist and antagonist properties. Butorphanol is considered to be a weak antagonist at the µ-receptor but a strong agonist at the k-receptor. Butorphanol is three to five times more potent an analgesic than morphine. The antagonist activity of butorphanol is nearly 50 times less than that of naloxone. The respiratory depression produced by butorphanol is similar to that of morphine; however, it has a “ceiling effect” beyond which higher doses fail to increase the depression further. Butorphanol is also a well-established antitussive and has been used as an anti-emetic in cancer patients. Similar to other narcotics, butorphanol is metabolized by the liver and has a plasma half-life to 3–4 hr in dogs. Butorphanol has a relatively short half-life and is a better analgesic for visceral than somatic pain. Clinically, butorphanol is a safe drug and appears to act as a good analgesic for mild to moderate pain.

Buprenorphine

Buprenorphine (Buprenex®) is a mixed agonist/antagonist, which is very popular in Europe as an analgesic and sedative drug. This drug differs from butorphanol in that its association and dissociation with the opioid receptor occur slowly. Because of its slow receptor association, it may take up to 30 min after i.v. injection for buprenorphine to take effect. Buprenorphine has a longer duration of action than butorphanol because of its tight binding to and slow dissociation from, opioid receptors. Because it binds tightly to its receptor, buprenorphine’s effects can be difficult to reverse with naloxone.

Naloxone

Naloxone is primarily used to reverse respiratory depression and given at 0.4 to 0.8 mg either intramuscularly or intravenously. There is rapid reversal of opioid compounds. Antagonist activity will last from 1–4 hr depending on the initial dose given. When naloxone is used to reverse a pure agonist, readministration to prevent “renarcotization” may be necessary, because many opioids have a longer half-life than naloxone.

NSAIDs

NSAIDs include a wide variety of different agents or different chemical classes. Most of the drugs have three major types of effect: anti-inflammatory, analgesic, and antipyretic. In general, all of these effects are related to the primary action of the drugs: inhibition of arachidonate cyclooxygenase (COX) and thus inhibition of the production of prostaglandins and thromboxanes. There are two types of COX: COX-1 and COX-2. COX-1 is a constitutive enzyme produced in most tissues, including platelets, and is involved in cell-to-cell signaling. COX-2 is induced in inflammatory cells when they are activated and is believed to be responsible for producing most of the prostanoid mediators of inflammation. Most of the NSAIDs inhibit both COX-1 and COX-2 to varying degrees. The untoward effects of most NSAIDs are secondary to their inhibition of COX-1. Selective COX-2 inhibitors are currently being developed.

Side Effects of NSAIDs

Adverse drug reactions are common with the use of NSAIDs, especially when they are used chronically and at high doses for musculoskeletal pain. Adverse gastrointestinal events are the most common untoward effects of NSAIDs in animal and human patients. Gastric ulceration, nausea, emesis, and diarrhea commonly occur in dogs given NSAIDs. A direct irritant effect on gastric mucosa may contribute to damage, as it is known that tablets are more likely to cause problems than capsules, suspensions, or solutions. “Slow-release” and “enteric-coated” preparations also cause fewer problems. NSAID-induced gastric ulceration, however, is predominantly due to the drug inhibition of prostaglandin synthesis. Prostaglandins normally are responsible for inhibiting gastric acid secretion as well as stimulating mucus production and mucosal blood flow. Concurrent administration of the prostaglandin analogue, misoprostol (Cytotec®) has been shown to diminish gastric ulceration in dogs when associated with NSAID use.

Salicylates

Salicylates commonly used in clinical veterinary practice include aspirin and bismuth subsalicylate (Pepto-Bismol®). Salicylates are effective in relieving pain associated with peripheral inflammation such as muscle and joint disease but have virtually no effect on deep or visceral pain. Salicylates have antipyretic effects because of their ability to reduce prostaglandin-induced fever.

Clinical use of aspirin has centered on the management of inflammatory and degenerative joint diseases. Aspirin may be used in the cats as long as it is administered no more than every 36–48 hr.

Carprofen

Carprofen (Rimadyl®) is a new NSAID approved for use in the dog. It has been shown to be anti-inflammatory, antipyretic, and analgesic. Carprofen is a reversible inhibitor of COX-1 and COX-2 and a moderately potent inhibitor of phospholipase A₂. The mean half-life of elimination is approximately 8 hr after a single oral dose. Carprofen is the first propionic acid NSAID approved in the United States for use in dogs as a first-line therapy for degenerative joint disease.

Naproxen

There are a considerable number of propionic derivatives on the market. Naproxen (Naprosyn®) has effective anti-inflammatory, analgesic, and antipyretic qualities and is an effective COX inhibitor. Naproxen has approximately 20 times the potency of the related drug ibuprofen. In humans, naproxen has been used successfully to treat musculoskeletal diseases. The toxicity of naproxen is similar to that of other NSAIDs. Because naproxen has a long duration of action in the dog, it can be administered once daily.

Meclofenamic acid

Meclofenamic acid (Arquel®) inhibits COX and may also block cell surface receptors for prostaglandins. The drug has gained popularity for treating musculoskeletal pain in the dog that is refractory to aspirin. Toxic side effects are similar to those of other NSAIDs have been observed in the dog.

Flunixin Meglumine

Flunixin meglumine (Banamine®) is an NSAID with both analgesic and antipyretic effects. Flunixin is considered to be one of the most potent COX inhibitors available. The analgesic potency of the drug is greater than that of phenylbutazone, meperidine, or codeine.

Flunixin is recommended for relief of persistent, severe inflammation and pain associated with degenerative joint disease that is nonresponsive to milder analgesics. Because flunixin is such a potent COX inhibitor, it also frequently causes severe gastric irritation. Its use in the dog should not exceed 1 mg/kg once daily for 3 days.

Phenylbutazone

Phenylbutazone (Butazolidin®) has analgesic, anti-inflammatory, and anti-pyretic effects similar to those found in the salicylate family. As a member of the pyrazolone family, it has been associated with significant toxic side effects in humans and, less commonly, in animals.

Clinically, phenylbutazone has been used in the dog for treatment of musculoskeletal diseases and is considered to inhibit COX more effectively than aspirin but less effectively than meclofenamic acid or naproxen. Phenylbutazone is known to cause gastrointestinal irritation, renal disease, hepatic disease, and rarely, bone marrow suppression with prolonged use in the dog.

Corticosteroids

When given therapeutically, corticosteroids have powerful anti-inflammatory and immunosuppressive effects. They inhibit both the early and late manifestations of inflammation (i.e., not only the initial heat, pain, and swelling but also the later stages of wound repair). They affect all types of inflammatory reactions whether they are caused by pathogens, toxins, or physical stimuli or are immune mediated.

Despite their significant side effects, corticosteroids are very useful in “dampening the fire” of acute inflammation. Useful corticosteroids for treating inflammation include hydrocortisone, prednisolone, and prednisone. The anti-inflammatory effects of prednisone and prednisolone are five times greater than those of cortisone. Corticosteroids are frequently used as short-term (3–5 days) anti-inflammatory drugs in the treatment of acute exacerbation of chronic musculoskeletal pain.

Selective Nerve Blocks

The use of local anesthetics to selectively block peripheral nerves following surgery allows for the relief of pain without the side effects associated with systemic use. Selective blocking of intercostal nerves prior to chest wall closure after thoracotomy has been shown to provide analgesia equal to that of systemic morphine. The technique involves injecting 0.5% bupivacaine (Marcaine®) at intercostal nerves as they pass behind the rib heads for two to three intercostal spaces in front of and behind the incision site. A maximum total dose of 4–5 mg/kg in dogs and 2–3 mg/kg in cats should be used to avoid systemic toxicity. Complete blocking of the intercostal nerves with bupivacaine should provide analgesia for 4–5 hr without the respiratory depression associated with narcotic use.

Selection of the Appropriate Analgesic

Published literature can provide a useful source of information on appropriate analgesia.^1-6 When selecting an analgesic drug for the treatment of pain, animals should be divided into at least two categories: those with acute pain resulting from surgery or acute trauma and those experiencing chronic, low-grade pain, frequently of musculoskeletal origin. Patients with acute pain generally benefit the most from short-term opioid use. When anxiety, as demonstrated by excessive vocalization, is involved with acute pain, low doses of tranquilizers may be added to the narcotic regimen. Patients with musculoskeletal diseases, including primary and metastatic bone neoplasia, benefit the most from NSAIDs. In general, the most effective therapeutic approach is to start with aspirin and then advance to more potent drugs such as meclofenamic acid, carprofen, or piroxicam. When administering NSAIDs in geriatric patients, the veterinarian should remember to evaluate existing renal function and hydration status to avoid a worsening of their condition.

Principles of analgesic therapy in the cat should follow the same basic parameters as those in the dog. Of the NSAIDs available, only aspirin is recommended for use in the cat. Aspirin given orally every 48 hr is generally effective for musculoskeletal pain. Narcotics are effective in controlling acute pain in the cat. Drug doses are generally somewhat lower than those in the dog to avoid the excitatory effects sometimes observed in the cat.

Literature Cited

1.  Boothe DM. 1995. The analgesic-antipyretic-antiinflammatory drugs. In: Adams HR, ed. Veterinary Pharmacology and Therapeutics. ed. 7. Iowa State University Press, Ames, Iowa. P. 432.

2.  Branson KR, ME Gross, NH Booth. 1995. Opioid agonists and antagonists. In: Adams HR, ed. Veterinary Pharmacology and Therapeutics. ed. 7. Iowa State University Press, Ames, Iowa. P. 274.

3.  Kyles AE, M Papich, EM Hardie 1996. Disposition of transdermally administered fentanyl in dogs. Am. J. Vet. Res. 57:715.

4.  McMurphy RM. 1987. Postoperative epidural analgesia. Vet. Clin. North Am. Small Anim. Pract. 23:703.

5.  Short CE. 1987. Pain, analgesics and related medications. In: Short CE, ed. Principles and Practice of Veterinary Anesthesia. Williams & Wilkins, Baltimore, Maryland. P. 28.

6.  Sackman JE. 1997. Pain and its management. Vet. Clin. North Am. Small Anim. Pract. 27:1487.