Toxicity of pain medications (Proceedings)

Aspirin

Aspirin (acetylsalicylic acid, ASA) is available as tablets, capsules, powders, effervescent tablets and oral liquid preparations. Aspirin reduces pain and inflammation by reducing prostaglandin and thromboxane synthesis through inhibition of cyclooxygenase. At very high dosages, aspirin and other salicylates uncouple oxidative phosphorylation, leading to decreased ATP production. Salicylates also impair platelet aggregation.

Aspirin is rapidly absorbed from the stomach and proximal small intestines in monogastric animals. Aspirin is metabolized in the liver and excreted through the urine. The elimination half-life increases with the dosage. In dogs, the half-life at the therapeutic dosage is 8.6 hours. Cats are deficient in glucuronyl transferase and have prolonged excretion of aspirin due to decreased metabolism. Feline dosages of 5-12 mg/kg have a half-life of 22 - 27 hours, while dosages of 25 mg/kg have a half-life of approximately 44 hours. Elimination is also slower in neonates and geriatric animals.

In dogs, toxicosis has occurred at dosages of 100 - 300 mg/kg/day PO for 1 - 4 weeks. Dosages of 325 mg twice a day were lethal to cats. Signs may include vomiting (± blood), hyperpnea, respiratory alkalosis, metabolic acidosis, gastric hemorrhage, centrilobular liver necrosis, and bleeding diathesis. Fever and seizures may be seen due to the uncoupling of oxidative phosphorylation. Renal insufficiency is uncommon with salicylate toxicoses but could develop secondary to rhabdomyolysis (from seizuring) or hypotension.

The primary goal of treatment is to prevent or treat gastric ulceration, acidosis, hepatopathy, and coagulopathy. Decontamination of asymptomatic patients would include induction of emesis and administration of activated charcoal (repeat dosages with large exposures) and cathartic. Peritoneal dialysis can be effective in removing salicylates. Liver values, glucose, acid base status and electrolytes should be monitored. Maintain hydration and start GI protectants (sucralfate, H2 blockers, ± misoprostol, ± omeprazole) to help manage and/or prevent gastric ulcers. In the asymptomatic patient, gastric protectants should be continued for 5 - 7 days. Metoclopramide can be used to control vomiting. Bismuth subsalicylate antacid formulations and corticosteroids are contraindicated. Assisted ventilation and supplemental oxygen may be required if the animal is comatose. Seizures should be treated with diazepam. Fluids, whole blood, and electrolytes should be given to control hypotension and hemorrhage, manage acute bleeding ulcers, and correct electrolyte abnormalities. Acid base imbalances should be corrected. Hyperpyrexia should be treated conservatively as aggressive cooling (ice baths or cold water enemas) may result in hypothermia. Prognosis is good if the animal is treated promptly and appropriately.

Ibuprofen

Ibuprofen (Motrin®, Advil®, Midol®, etc.) is a nonsteroidal anti-inflammatory agent. Ibuprofen inhibits prostaglandin synthesis by blocking the conversion of arachidonic acid to various prostaglandins. Ibuprofen decreases secretion of the protective mucous layer in the stomach and small intestine and causes vasoconstriction in gastric mucosa. Ibuprofen inhibits renal blood flow, glomerular filtration rate, tubular ion transport, renin release and water homeostasis. Ibuprofen may also affect platelet aggregation and possibly hepatic function. Unlike salicylates, serious hepatotoxicosis does not appear to be a common problem with acute ibuprofen overdosages.

Absorption of ibuprofen is rapid (0.1 to 1.5 h). Plasma half-life in the dog has been reported to be 2-2.5 hours, but the elimination half-life is considerably longer.

Ibuprofen has a narrow margin of safety. Even at the therapeutic dog dosage of 5 mg/kg, ibuprofen may cause gastric ulcers and perforations with chronic use. In dogs, an acute exposure of 50-125 mg/kg can result in gastrointestinal signs (vomiting, diarrhea, nausea, abdominal pain, and anorexia), > 175 mg/kg can result in more severe GI signs (hematemesis, melena) plus renal damage (pu/pd, oliguria, uremia). Dosages of > 400 mg/kg in the dog may result in CNS signs (seizure, ataxia, coma, shock). Cats are about twice as sensitive to ibuprofen's toxic effects as dogs. Ferrets that ingest ibuprofen are at high risk for CNS depression and coma, with or without GI upset.

The onset of GI upset is generally within the first 2-6 hours after ingestion, with the onset of GI hemorrhage and ulceration occurring 12 hours to 4 days post ingestion. Lesions associated with ibuprofen overdose include perforations, erosions, ulcers, and hemorrhages in the upper (stomach and duodenum) and, on occasion, lower (colon) gastrointestinal tract. The onset of renal failure usually occurs within the first 12 hours after massive exposure to an NSAID but may be delayed until 3-5 days after exposure.

Decontamination of asymptomatic patients would include induction of emesis and administration of activated charcoal (repeat dosages with large exposures) and cathartic. In asymptomatic patients, gastric protection should be continued for 5-7 days. Animals should be started on IV fluids at twice maintenance for a minimum of 48 hours if renal failure is expected. Monitor BUN, creatinine, and urine specific gravity (baseline level, 24, 48, and 72 h). The animal may also need to be monitored for acidosis and electrolyte changes. Acid-base disturbances are rare and usually transient. Peritoneal dialysis may be necessary if unresponsive oliguric or anuric renal failure develops.

For symptomatic animals, GI protectants are very important. Mild gastrointestinal irritation may be treated symptomatically with antacids, such as magnesium or aluminum hydroxide. Misoprostol is helpful for treating or preventing gastric ulceration caused by NSAIDS as it stimulates mucus and bicarbonate secretion and increases gastric mucosal blood flow (contraindicated during pregnancy due to its abortifacient activity). H2 blockers, sucralfate and omeprazole can also be used to manage and/or prevent gastric ulcers. Assisted ventilation and supplemental oxygen may be required for comatose patients. Seizures should be treated with diazepam. Fluids, whole blood, inotropic agents, and electrolytes should be given to control hypotension and hemorrhage, maintain renal function, and correct electrolyte abnormalities.

Prognosis is good if the animal is treated promptly and appropriately. Gastrointestinal ulceration usually responds to therapy. Acute renal insufficiency resulting from ibuprofen administration has been considered reversible, however, the development of papillary necrosis is generally considered irreversible.

Other NSAIDs

Clinical signs and treatment are similar to ibuprofen. However, clearance of NSAIDS varies considerably between species, thus extrapolation of data across species is not reliable. For most NSAIDs the minimum toxic or lethal dosage is not clearly established. Treatment of acute overdosages of the NSAIDs follow the same treatment protocol as ibuprofen.

      Naproxen (Naprosyn®, Aleve®)

OTC formulations of naproxen include 220, 250, 275, 375, 500 and 550 mg pills and 125 mg/tsp suspension. Half-life in the dog is 74 hours, as the drug undergoes extensive enterohepatic recirculation. Recommended dog dosage is 5 mg/kg PO initially, then 1.2-2.8 mg/kg q 24 h PO or 1.1 mg/kg q 12 h PO. Ulcerative gastritis is possible in dogs at 5 mg/kg/day for 7 days. Dog dosages of > 25 mg/kg are thought to cause acute renal failure. Due to the prolonged half-life, fluids need to be continued for at least 72 hours and GI protectants for 10-14 days.

      Carprofen (Rimadyl®)

In dogs, carprofen may cause GI signs at dosages exceeding 20 mg/kg and may induce renal injury at dosages over 40-50 mg/kg. Cats may develop GI signs at dosages > 4 mg/kg and renal injury has occurred at dosages > 8 mg/kg. Idiosyncratic hepatopathy may result from chronic exposure to carprofen (and other NSAIDs); generally signs occur after 2-3 weeks of exposure. Treatment includes discontinuation of the NSAID and supportive care (heptaoprotectants, dietary alteration, etc).

      Deracoxib (Deramaxx®)

Dosages of deracoxib > 15 mg/kg may produce GI signs and dosages > 30 mg/kg may result in renal injury in dogs; GI and renal dosages for cats are 4 and 8 mg/kg, respectively.

Acetaminophen

Acetaminophen (Tylenol®, non-aspirin pain reliever, APAP) is a synthetic non-opiate derivative of p-aminophenol. Acetaminophen's exact mechanism of action is unknown but it is believed to act primarily in the CNS to increase the pain threshold and it may also inhibit chemical mediators that sensitize the pain receptors to mechanical or chemical stimulation. The antipyretic activity of acetaminophen is achieved by blocking the effects of endogenous pyrogens by inhibiting prostaglandin synthesis.

Acetaminophen is rapidly and almost completely absorbed from the GI tract. Peak plasma levels are seen at 10-60 minutes for regular products and at 60-120 minutes for extended release forms. In dogs, the serum half-life after a dosage of 200 mg/kg of acetaminophen was 1.2 hours and increases to 3.5 hours after a dosage of 500 mg/kg. In cats after an oral acetaminophen dosage of 20 mg/kg serum half-life was 0.6 hour; but increases to 2.4 hours after a dosage of 60 mg/kg. Dog dosages of up to 500 mg/kg are 91% excreted in 24 hrs. Cat dosages of up to 120 mg/kg are 89.6% excreted in 24 hrs.

Acetaminophen itself is of low toxicity; it is the formation of toxic metabolites due to deficiency/absence of non-toxic metabolic pathways that is responsible for toxicity. Acetaminophen-induced hepatotoxicity and nephrotoxicity are due to the formation of the oxidative metabolite, N-acetyl-para-benzoquinoneimine (NAPQI), in the liver and to a lesser degree in the kidney. NAPQI binds covalently to sulfhydryl groups on tissue macromolecules leading to cell necrosis. Glutathione can conjugate and neutralize NAPQI, but when glutathione stores are depleted, NAPQI binds to the hepatic cell membrane and damages the lipid layer. Very large doses of APAP can cause nephrotoxicity characterized by proximal tubule necrosis. In general, dogs typically develop liver injury while cats develop methemoglobinemia. Although rare cases of cats developing liver injury without initial methemoglobinemia have been reported, generally cats succumb to methemoglobinemia before liver injury has a chance to develop.

Acetaminophen is deacetylated to p-aminophenol (PAP), which causes oxidative damage to red blood cells resulting in methemoglobinemia. Cats are more susceptible to acetaminophen-induced methemoglobinemia as they are deficient (relative to humans, dogs) in the enzyme that converts PAP back to acetaminophen, allowing buildup of high levels of PAP. Additionaly, PAP causes methemoglobinemia by binding to sulfhydryl groups on hemoglobin; as cats have more sulfhydryl groups on their hemoglobin (8 –SH compared to 4 in dogs and 2 in humans), making them more susceptible to oxidative injury to hemoglobin. For these reasons, cats exposed to acetaminophen generally develop signs at lower doses than dogs, and they usually present with methemoglobinemia, with liver injury being less common.

Methemoglobin values increase within 2-4 hours, followed by Heinz body formation. Clinical signs seen with acetaminophen toxicity include depression, weakness, hyperventilation, icterus, vomiting, methemoglobinemia, hypothermia, facial or paw edema, death, cyanosis, dyspnea, and hepatic necrosis. Other possible clinical signs include metabolic acidosis, renal insufficiency/damage, myocardial damage, coma, thrombocytopenia, and vomiting. Liver necrosis is less common with cats than with dogs. Clinical signs of methemoglobinemia may last 3-4 days. Hepatic injury may not resolve for several weeks. Hepatotoxicity has been reported in dogs at 100 mg/kg and 200 mg/kg caused clinical methemoglobinemia in 3 out of 4 dogs. Also in dogs, dosages of 40 mg/kg have resulted in keratoconjunctivitis sicca 72 hours after ingestion. In cats, methemoglobinemia has been reported at dosages as low as 10 mg/kg and hepatotoxicity is possible if doses exceed 40 mg/kg; ferrets appear to be as sensitive as cats.

Symptomatic patients need initial stabilization, including oxygen if dyspneic. Treatment involves replenishing the glutathione stores and converting methemoglobin back to hemoglobin. N-acetylcysteine (Mucomyst®, NAC) is available in 10% and 20% solutions. An initial oral loading dosage for NAC would be 140 mg/kg of a 5% concentration (can be diluted in 5% Dextrose or sterile water) and then 70 mg/kg PO QID for generally 7 treatments. With ingestion of massive quantities some authors suggest using 280 mg/kg for a loading dosage and continuing treatment for 12 to 17 dosages. Adverse effects of the oral route of NAC include nausea and vomiting. Recently, an IV formulation of NAC (Acetadote®) has become available. A two-to-three hour wait between activated charcoal administration and PO administration of NAC is recommended, since activated charcoal could adsorb NAC as well as acetaminophen. Fluid therapy is used to correct dehydration and for maintenance needs, not for diuresis. Whole blood transfusions or oxyglobin may be necessary to increase oxygen carrying capacity.

Ascorbic acid provides a reserve system for the reduction of methemoglobin back to hemoglobin; however, ascorbic acid has questionable efficacy and may irritate the stomach. Cimetidine is an inhibitor of cytochrome p-450 oxidation system in the liver and may help reduce the metabolism of acetaminophen. Cimetidine is not recommended for cats, as it may increase the accumulation of p-aminophenol responsible for methemoglobinemia. For hepatic injury, a new therapy that shows potential is s-adenosylmethionine (SAMe, Denosyl-SD4®) at 20 mg/kg/day. Early studies and anecdotal reports show a positive effect for treatment of acetaminophen toxicosis. OTC formulations of SAMe have variable potency; use a prescription quality, enteric coated product (round the dosage to nearest whole pill and do not break pill). Steroids and antihistamines are contraindicated.

Decontamination of asymptomatic patients would include induction of emesis and administration of activated charcoal (repeat dosages with large exposures) and cathartic. Monitor liver values and for the presence of methemoglobinemia. ALT, AST and bilirubin may rise within 24 hours after ingestion and peak within 48 to 72 hours. Serum albumin concentrations decrease significantly after 36 hours and continue to decrease during liver failure, providing a true index of liver function. Prognosis is good if the animal is treated promptly. Animals with severe signs of methemoglobinemia or with hepatic damage have poor to guarded prognosis. Treatment may continue for weeks.

Opioids and opiates

There are many opioids and opiates used in human and veterinary medicine. Opioids and opiates are synthetic or natural compounds derived from the opium poppy, Papaver somniferum, and are generally classified (agonist or partial agonist) by their ability to exert effects at the different opioid receptors (mu, kappa, delta, sigma). Partial agonists are agonists at one (or more receptors) and antagonists at others. Opioids act centrally to elevate the pain threshold and to alter the psychological response to pain. Most of the clinically used opioids exert effect at the mu receptor (mu1 subtype mediates analgesic effects, mu2 mediates respiratory depression).

Most opioids are well absorbed from the GI tract. Metabolism varies, but opioids generally undergo hepatic metabolism with some form of conjugation, hydrolysis, oxidation, glucuronidation, or dealkylation. This glucuronidation may account for the sensitivity of cats (who are deficient in glucuronyl-S-transferase) to opioids.

In dogs, CNS signs include depression, ataxia, and seizures. Respiratory depression, vomiting, bradycardia, and hypotension may be seen. Cats may show excitatory behavior and urinary retention. Detection of opioids can be made from urine or serum samples.

Treatment in an asymptomatic animal may include emesis if the ingestion is recent. Activated charcoal with cathartic should be administered and the patient monitored for up to 12 hours. If the animal becomes symptomatic, respiratory support may need to be given. If severe respiratory depression is seen, naloxone (a pure competitive antagonist with activity at the mu receptors) at a dosage of 0.1-0.2 mg/kg IV, IM or SQ can be administered to reverse respiratory effects. As the duration of action of naloxone is much shorter than that of the opioids, repeat dosages may be necessary. Naloxone may not result in the animal regaining full consciousness. Partial agonists/antagonists (i.e. butorphanol) may be used to partially reverse pure agonists if no naloxone is available. Monitor temperature, cardiac function and blood gases. Treatment times will vary with the half-life of the opioid. If respiratory and cardiovascular function can be maintained then prognosis is good. For those cases that are seizuring, prognosis is guarded.

Fentanyl

Fentanyl suckers, lozenges and transdermal patches are becoming more frequently used in both human and veterinary medicine. The lozenges or suckers contain fentanyl citrate in a sucrose and liquid glucose base and are attractive to animals. The patches have poor absorption from the GI tract, but can be absorbed transmucosally while the animals are chewing on them. Signs are similar to other opioids with depression, bradycardia, hypotension, weakness, and pallor predominating. Treatment is as for other opioids.