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Precautions When Using Antiprostaglandins
370
POSTOPERATIVE ANALGESIA
Precautions When Using Antiprostaglandins Peter H. Cribb, BSc, MRCVS From the Department of Veterinary Anesthesiology, Radiology, and Surgery, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
CORTICOSTEROIDS
Although corticosteroids are not administered primarily as analgesics, they do reduce pain as a result of anti-inflammatory effects in conditions such as arthritis and pruritus. Long-term corticosteroid therapy depresses adrenal function, and this should be considered when devising an anesthetic protocol. In humans, there may be depression of adrenal function for as long as 12 months following chronic steroid therapy. In cats and dogs, it would appear that full function returns more swiftly, probqbly in less than 12 weeks. Cats recover more quickly than dogs. 15 Animals that are or have been on long-term steroid therapy may require replacement therapy prophylactically before the stresses of anesthesia and surgeryY The use of combinations of corticosteroids and nonsteroidal anti-inflammatory drugs may act synergistically to produce intestinal ulceration and hemorrhage. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
There are marked species differences in dose requirements as a result of differences in uptake, absorption, distribution, metabolism, and excretion of these drugs. It is important to be aware of these species differences to avoid toxic effects. The nonsteroidal anti-inflammatory drugs (NSAIDs) are analgesic and anti-inflammatory, and most are antipyretic. They are not effective against severe, acute postsurgical pain but may be useful in the alleviation of more chronic pain. The major side effect of NSAIDs is gastrointestinal irritation leading to ulceration and hemorrhage and occasionally vomiting and diarrhea. Other side effects include blood ctyscrasias such as neutropenia, thrombocytopenia and anemia from bone marrow depression, and renal and hepatic toxicity. The cat is more susceptible than the dog owing to the lack of hepatic glucuronyl transferase that is required for conjugation. Similarly animals under 30 days of age do not have full liver function, and NSAIDs should not be used as analgesics in these very young animals. Any animal on longterm NSAID therapy should have bleeding time, urinalysis, hemogram, and clinical chemistry tests performed before anesthesia. Ure& and
POSTOPERATIVE ANALGESIA
371
creatinine may be elevated and hyperphosphatemia, hypercalcemia, hyponatremia, and an increased anion gap may occur as a result of renal damage. The major toxic effects of NSAIDs in humans are on the kidney, where they may cause renal papillary necrosis if given in high doses or when there is insufficient urine. 1A In dogs, hypotension and hypovolemia associated with NSAID administration may contribute to renal damage. 19 Urine output should be carefully monitored during and after anesthesia and fluids administered as required to maintain good renal function. Hypotension should be avoided, and drugs lil
The plasma half-life of aspirin is much longer in the cat (38 hours) than in the dog (8 hours), and toxicity is more likely to occur in this species. Aspirin inhibits platelet aggregation, which is permanent for the life of the treated platelets, and the clinical effects of a single dose of aspirin can last for a week. Handagama 11 recommends that aspirin not be administered for 1 week and Booth2 recommends 2 weeks before major surgical procedures so that blood coagulation is not altered. Bleeding complications are more likely in animals with von Willebrand's disease or with renal or hepatic disease. 11 PARA·AMINOPHENOL DERIVATIVES
Phenacetin is not particularly effective in the dog. It is not recommended for use in the cat because it is metabolized to acetaminophen. 8 Acetaminophen (Tylenol) is an aniline derivative that is a very popular over-the-counter analgesic for humans. In cats, acetaminophen causes the formation of methemoglobin and anemia. 5 · 10 •17 LC1rge doses may cause hepatic necrosis and failure as a result of toxic metabolites. Acetylcysteine or sodium sulfate and ascorbic acid may be used for treatment. 2·5 •14 When mice are given (lcetaminophen after 1 hour of halothane anesthesia, there is a marked increase in hepatotoxicity with the maximum effect (10 times) occurring if administration is delayed 6 to 12 hours postanesthesia. 22 The use of acetaminophen as a perioperative analgesic in both cats and dogs should be avoided. 2
372
POSTOPERATIVE ANALGESIA
PYRAZOLON DERIVATIVES
Phenylbutazone is most commonly used in horses and has also been used in the dog. By oral administration, phenylbutazone causes less gastric irritation than aspirin. Chronic usage leads to kidney damage and eventually to renal papillary necrosis. The injectable form is highly irritant and must be administered intravenously. Perivascular injection causes tissue necrosis. There have been reports of fatalities, with associated renal damage, in the dog and cat. 3' 20 Blood dyscrasias such as agranulocytosis, anemia, leukopenia, and thrombocytopenia have also been reported, 18, 21 Dipyrone should not be used in conjunction with barbiturates because of interaction with the microsomal enzyme system. 2 Prolonged use may lead to agranulocytosis and leukopenia. Increased bleeding times may result from decreased prothrombin production, NICOTINIC ACID DERIVATIVES/FLUNIXIN MEGLUMINE (BANAMINE)
Flunixin meglumine has been recommended as an analgesic and as prophylaxis and treatment for endotoxic shock. Unlike other NSAIDs, it is a powerful analgesic for visceral pain. Flunixin and corticosteroids should not be used together in the dog because of their combined effect on the gastrointestinal tract. The use of flunixin meglumine before ophthalmic surgery as prophylaxis against postoperative inflammation, pain, and self-trauma should be limited to a maximum of 3 days to avoid toxicity problems. Methoxyflurane is often used in ocular surgery. Flunixin meglumine, however, has been implicated in a specific renal toxicity with methoxyflurane anesthesia, probably related to interference with blood flow through the kidneys. 13 These two drugs must not be used concurrently. Flunixin meglumine has been said to be toxic to cats. 12 OTHER NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
The use of aspirin, phenylbutazone, and oxyphenylbutazone is declining as newer NSAIDs such as meclofenamic acid, ibuprofen, naproxen, and indomethacin come into more general use. Similar precautions should be used with regards to meclofenamic acid as with aspirin. It has also been shown to cause gastrointestinal upset, vomiting, and diarrhea with long-term use in dogs. 16 It should not be given to cats. Naproxen is not licensed for use in either the cat or the dog and is not recommended for use in these species. Gastrointestinal toxicity has been reported in the dog. 6 Ibuprofen has been reported to cause gastric ulceration and renal damage in dogs, 19 Toxicity problems
POSTOPERATIVE ANALGESIA
373
should be expected in the cat. Indomethacin should not be used in small animals. 6 A number of cases of severe gastrointestinal hemorrhage, together with some fatalities, have been reported in dogs. 7 •9 SUMMARY
Antiprostaglandins are effective for relief of pain of low to moderate intensity. The majority of these agents interfere with clotting function, and they should not be used on animals with potential coagulopathies. With high dosage or long-term treatment, gastrointestinal irritation and ulceration are probable. NSAIDs should not be used in conjunction with methoxyflurane because of the potential for renal damage. Care should be taken to avoid hypotension with any anesthetic to obviate renal complications. References 1. Adams SS, Bough RG, Cliffe, eta!: Absorption, distribution, and toxicity of ibuprofen. Toxicol Appl Pharmacal 15:310-330, 1969 2. Booth NH. Nonnarcotic analgesics.In Booth NH, McDonald LE, eds: Veterinary Pharmacology and Therapeutics VI. Ames, Iowa University Press, 1988, pp 329-362 3. Carlisle CH, Penny RHC, Prescott CW, et a!: Toxic effects of phenylbutazone on the cat. Br Vet J 124:560-568, 1968 4. Clive DM, Stoff JS: Renal syndromes associated with non-steroidal anti-inflammatory drugs. N Eng! J Med 310:563-572, 1984 5. Cullison RF: Acetaminophen toxicosis in sinal! animals: Clinical signs, mode of action and treatment. Compend Cantin Educ Pract Vet 6:315-323, 1984 6. Daehler MH: Transmural pyloric perforation associated with naproxen administration in a dog. JAm Vet Med Assoc 189:694-695, 1986 7. Davis LE: Fever. JAm Vet Med Assoc 175:1210-1211, 1979 8. Davis LE: Species differences in drug disposition as factors in alleviation of pain. In Kitchell RL, Erickson HH, eds: Animal Pain. Bethesda, MD, American Physiological Society, 1983, pp 161-178 9. Ewing GO: Indomethacin-associated gastrointestinal hemorrhage in a dog. JAm Vet Med Assoc 161:1665-1668, 1972 10. Pineo DR, Duncan JR, Schall WD, et a!: Acetaminophen. J Am Vet Med Assoc 166:469-472, 1975 11. Handagama P: Salicylate toxicity. In Kirk RW, ed: Current Veterinary Therapy IX. Philadelphia, WB Saunders, 1986, pp 524-527 12. Krohne SG, Vestre WA. Ophthalmic use of nonsteroidal anti~inflammatory agents. In Kirk RW, ed: Current Veterinary Therapy X. Philadelphia, WB Saunders, 1989, pp 642-644 13. Mathews KA, Doherty T, Dyson DH, et a!: Nephrotoxicity in dogs associated with methoxyflurane anesthesia and flunixin meglumine analgesia. Can Vet J 31:766-771, 1990 14. Oehme FW: Aspirin and acetaminophen. In Kirk RW, ed: Current Veterinary Therapy IX. Philadelphia, WB Saunders, 1986, pp 188-190 15. Papich MG, Davis LE: Glucocorticoid Therapy. In Kirk RW, ed: Current Veterinary Therapy X. Philadelphia, WB Saunders, 1989, pp 54-62 16. Romatowski J: Comparative therapeutics of canine and human rheumatoid arthritis. JAm Vet Med Assoc 185:558-562, 1984 17. Savides MC, Oehme FW, Leipold HW: Effect of various antidotal treatments on acetaminophen toxicosis and biotransformation in cats. Am J Vet Res 46:1485-1489, 1985
374
POSTOPERATIVE ANALGESIA
18. Schalm OW: Phenylbutazone toxicity in two dogs. Can Pract 6:47-50, 1979 19. Spyridakis LK, Bacia JJ, Barsanti JA, Brown SA: Ibuprofen toxicosis in a dog. J Am Vet Med Assoc 188:918-919 20. Tandy J, Thorpe E: A fatal syndrome in a dog following administration of phenylbutazone. Vet Rec 81:398-399, 1967 21. Watson ADJ, Wilson JT, Wilson DM, eta!: Phenylbutazone-induced blood dyscrasias suspected in three dogs. Vet Rec 107:239-241, 1980 22. Wells PG, Ramji P, Ku MSW: Delayed enhancement of acetaminophen hepatotoxicity by general anesthesia using diethyl ether or halothane. Fundam Appl Toxicol 6:299306, 1986
Acupuncture Analgesia Alan M. Klide, VMD From the Section of Small Animal Anesthesia, Department of Clinical StudiesPhiladelphia, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania
Acupuncture has been used to produce surgical analgesia, to produce postoperative analgesia, to treat chronic pain, and to treat disease states. BASIC ACUPUNCTURE Traditional Chinese Medicine
According to traditional Chinese concepts, energy, called Chi, flows through channels in the body called meridians. Along these channels are points at which one is able to influence the flow of energy through the meridians, like dams control the flow of water. Disease is caused by an imbalance in the amount of energy in the diseased organ. The treatment is to reestablish the normal amount of energy. I am not implying that these traditional concepts are the literal mechanism of action for acupuncture. In fact, I think that we can explain all of the things produced with acupuncture in modern neurophysiologic terms. Points
In traditional Chinese medicine, it is thought that when an organ is diseased, a painful point will appear on the surface of the body and
POSTOPERATIVE ANALGESIA
Precautions When Using Antiprostaglandins Peter H. Cribb, BSc, MRCVS From the Department of Veterinary Anesthesiology, Radiology, and Surgery, Western College of Veterinary Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
CORTICOSTEROIDS
Although corticosteroids are not administered primarily as analgesics, they do reduce pain as a result of anti-inflammatory effects in conditions such as arthritis and pruritus. Long-term corticosteroid therapy depresses adrenal function, and this should be considered when devising an anesthetic protocol. In humans, there may be depression of adrenal function for as long as 12 months following chronic steroid therapy. In cats and dogs, it would appear that full function returns more swiftly, probqbly in less than 12 weeks. Cats recover more quickly than dogs. 15 Animals that are or have been on long-term steroid therapy may require replacement therapy prophylactically before the stresses of anesthesia and surgeryY The use of combinations of corticosteroids and nonsteroidal anti-inflammatory drugs may act synergistically to produce intestinal ulceration and hemorrhage. NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
There are marked species differences in dose requirements as a result of differences in uptake, absorption, distribution, metabolism, and excretion of these drugs. It is important to be aware of these species differences to avoid toxic effects. The nonsteroidal anti-inflammatory drugs (NSAIDs) are analgesic and anti-inflammatory, and most are antipyretic. They are not effective against severe, acute postsurgical pain but may be useful in the alleviation of more chronic pain. The major side effect of NSAIDs is gastrointestinal irritation leading to ulceration and hemorrhage and occasionally vomiting and diarrhea. Other side effects include blood ctyscrasias such as neutropenia, thrombocytopenia and anemia from bone marrow depression, and renal and hepatic toxicity. The cat is more susceptible than the dog owing to the lack of hepatic glucuronyl transferase that is required for conjugation. Similarly animals under 30 days of age do not have full liver function, and NSAIDs should not be used as analgesics in these very young animals. Any animal on longterm NSAID therapy should have bleeding time, urinalysis, hemogram, and clinical chemistry tests performed before anesthesia. Ure& and
POSTOPERATIVE ANALGESIA
371
creatinine may be elevated and hyperphosphatemia, hypercalcemia, hyponatremia, and an increased anion gap may occur as a result of renal damage. The major toxic effects of NSAIDs in humans are on the kidney, where they may cause renal papillary necrosis if given in high doses or when there is insufficient urine. 1A In dogs, hypotension and hypovolemia associated with NSAID administration may contribute to renal damage. 19 Urine output should be carefully monitored during and after anesthesia and fluids administered as required to maintain good renal function. Hypotension should be avoided, and drugs lil
The plasma half-life of aspirin is much longer in the cat (38 hours) than in the dog (8 hours), and toxicity is more likely to occur in this species. Aspirin inhibits platelet aggregation, which is permanent for the life of the treated platelets, and the clinical effects of a single dose of aspirin can last for a week. Handagama 11 recommends that aspirin not be administered for 1 week and Booth2 recommends 2 weeks before major surgical procedures so that blood coagulation is not altered. Bleeding complications are more likely in animals with von Willebrand's disease or with renal or hepatic disease. 11 PARA·AMINOPHENOL DERIVATIVES
Phenacetin is not particularly effective in the dog. It is not recommended for use in the cat because it is metabolized to acetaminophen. 8 Acetaminophen (Tylenol) is an aniline derivative that is a very popular over-the-counter analgesic for humans. In cats, acetaminophen causes the formation of methemoglobin and anemia. 5 · 10 •17 LC1rge doses may cause hepatic necrosis and failure as a result of toxic metabolites. Acetylcysteine or sodium sulfate and ascorbic acid may be used for treatment. 2·5 •14 When mice are given (lcetaminophen after 1 hour of halothane anesthesia, there is a marked increase in hepatotoxicity with the maximum effect (10 times) occurring if administration is delayed 6 to 12 hours postanesthesia. 22 The use of acetaminophen as a perioperative analgesic in both cats and dogs should be avoided. 2
372
POSTOPERATIVE ANALGESIA
PYRAZOLON DERIVATIVES
Phenylbutazone is most commonly used in horses and has also been used in the dog. By oral administration, phenylbutazone causes less gastric irritation than aspirin. Chronic usage leads to kidney damage and eventually to renal papillary necrosis. The injectable form is highly irritant and must be administered intravenously. Perivascular injection causes tissue necrosis. There have been reports of fatalities, with associated renal damage, in the dog and cat. 3' 20 Blood dyscrasias such as agranulocytosis, anemia, leukopenia, and thrombocytopenia have also been reported, 18, 21 Dipyrone should not be used in conjunction with barbiturates because of interaction with the microsomal enzyme system. 2 Prolonged use may lead to agranulocytosis and leukopenia. Increased bleeding times may result from decreased prothrombin production, NICOTINIC ACID DERIVATIVES/FLUNIXIN MEGLUMINE (BANAMINE)
Flunixin meglumine has been recommended as an analgesic and as prophylaxis and treatment for endotoxic shock. Unlike other NSAIDs, it is a powerful analgesic for visceral pain. Flunixin and corticosteroids should not be used together in the dog because of their combined effect on the gastrointestinal tract. The use of flunixin meglumine before ophthalmic surgery as prophylaxis against postoperative inflammation, pain, and self-trauma should be limited to a maximum of 3 days to avoid toxicity problems. Methoxyflurane is often used in ocular surgery. Flunixin meglumine, however, has been implicated in a specific renal toxicity with methoxyflurane anesthesia, probably related to interference with blood flow through the kidneys. 13 These two drugs must not be used concurrently. Flunixin meglumine has been said to be toxic to cats. 12 OTHER NONSTEROIDAL ANTI-INFLAMMATORY DRUGS
The use of aspirin, phenylbutazone, and oxyphenylbutazone is declining as newer NSAIDs such as meclofenamic acid, ibuprofen, naproxen, and indomethacin come into more general use. Similar precautions should be used with regards to meclofenamic acid as with aspirin. It has also been shown to cause gastrointestinal upset, vomiting, and diarrhea with long-term use in dogs. 16 It should not be given to cats. Naproxen is not licensed for use in either the cat or the dog and is not recommended for use in these species. Gastrointestinal toxicity has been reported in the dog. 6 Ibuprofen has been reported to cause gastric ulceration and renal damage in dogs, 19 Toxicity problems
POSTOPERATIVE ANALGESIA
373
should be expected in the cat. Indomethacin should not be used in small animals. 6 A number of cases of severe gastrointestinal hemorrhage, together with some fatalities, have been reported in dogs. 7 •9 SUMMARY
Antiprostaglandins are effective for relief of pain of low to moderate intensity. The majority of these agents interfere with clotting function, and they should not be used on animals with potential coagulopathies. With high dosage or long-term treatment, gastrointestinal irritation and ulceration are probable. NSAIDs should not be used in conjunction with methoxyflurane because of the potential for renal damage. Care should be taken to avoid hypotension with any anesthetic to obviate renal complications. References 1. Adams SS, Bough RG, Cliffe, eta!: Absorption, distribution, and toxicity of ibuprofen. Toxicol Appl Pharmacal 15:310-330, 1969 2. Booth NH. Nonnarcotic analgesics.In Booth NH, McDonald LE, eds: Veterinary Pharmacology and Therapeutics VI. Ames, Iowa University Press, 1988, pp 329-362 3. Carlisle CH, Penny RHC, Prescott CW, et a!: Toxic effects of phenylbutazone on the cat. Br Vet J 124:560-568, 1968 4. Clive DM, Stoff JS: Renal syndromes associated with non-steroidal anti-inflammatory drugs. N Eng! J Med 310:563-572, 1984 5. Cullison RF: Acetaminophen toxicosis in sinal! animals: Clinical signs, mode of action and treatment. Compend Cantin Educ Pract Vet 6:315-323, 1984 6. Daehler MH: Transmural pyloric perforation associated with naproxen administration in a dog. JAm Vet Med Assoc 189:694-695, 1986 7. Davis LE: Fever. JAm Vet Med Assoc 175:1210-1211, 1979 8. Davis LE: Species differences in drug disposition as factors in alleviation of pain. In Kitchell RL, Erickson HH, eds: Animal Pain. Bethesda, MD, American Physiological Society, 1983, pp 161-178 9. Ewing GO: Indomethacin-associated gastrointestinal hemorrhage in a dog. JAm Vet Med Assoc 161:1665-1668, 1972 10. Pineo DR, Duncan JR, Schall WD, et a!: Acetaminophen. J Am Vet Med Assoc 166:469-472, 1975 11. Handagama P: Salicylate toxicity. In Kirk RW, ed: Current Veterinary Therapy IX. Philadelphia, WB Saunders, 1986, pp 524-527 12. Krohne SG, Vestre WA. Ophthalmic use of nonsteroidal anti~inflammatory agents. In Kirk RW, ed: Current Veterinary Therapy X. Philadelphia, WB Saunders, 1989, pp 642-644 13. Mathews KA, Doherty T, Dyson DH, et a!: Nephrotoxicity in dogs associated with methoxyflurane anesthesia and flunixin meglumine analgesia. Can Vet J 31:766-771, 1990 14. Oehme FW: Aspirin and acetaminophen. In Kirk RW, ed: Current Veterinary Therapy IX. Philadelphia, WB Saunders, 1986, pp 188-190 15. Papich MG, Davis LE: Glucocorticoid Therapy. In Kirk RW, ed: Current Veterinary Therapy X. Philadelphia, WB Saunders, 1989, pp 54-62 16. Romatowski J: Comparative therapeutics of canine and human rheumatoid arthritis. JAm Vet Med Assoc 185:558-562, 1984 17. Savides MC, Oehme FW, Leipold HW: Effect of various antidotal treatments on acetaminophen toxicosis and biotransformation in cats. Am J Vet Res 46:1485-1489, 1985
374
POSTOPERATIVE ANALGESIA
18. Schalm OW: Phenylbutazone toxicity in two dogs. Can Pract 6:47-50, 1979 19. Spyridakis LK, Bacia JJ, Barsanti JA, Brown SA: Ibuprofen toxicosis in a dog. J Am Vet Med Assoc 188:918-919 20. Tandy J, Thorpe E: A fatal syndrome in a dog following administration of phenylbutazone. Vet Rec 81:398-399, 1967 21. Watson ADJ, Wilson JT, Wilson DM, eta!: Phenylbutazone-induced blood dyscrasias suspected in three dogs. Vet Rec 107:239-241, 1980 22. Wells PG, Ramji P, Ku MSW: Delayed enhancement of acetaminophen hepatotoxicity by general anesthesia using diethyl ether or halothane. Fundam Appl Toxicol 6:299306, 1986
Acupuncture Analgesia Alan M. Klide, VMD From the Section of Small Animal Anesthesia, Department of Clinical StudiesPhiladelphia, University of Pennsylvania School of Veterinary Medicine, Philadelphia, Pennsylvania
Acupuncture has been used to produce surgical analgesia, to produce postoperative analgesia, to treat chronic pain, and to treat disease states. BASIC ACUPUNCTURE Traditional Chinese Medicine
According to traditional Chinese concepts, energy, called Chi, flows through channels in the body called meridians. Along these channels are points at which one is able to influence the flow of energy through the meridians, like dams control the flow of water. Disease is caused by an imbalance in the amount of energy in the diseased organ. The treatment is to reestablish the normal amount of energy. I am not implying that these traditional concepts are the literal mechanism of action for acupuncture. In fact, I think that we can explain all of the things produced with acupuncture in modern neurophysiologic terms. Points
In traditional Chinese medicine, it is thought that when an organ is diseased, a painful point will appear on the surface of the body and