Rambo, a 7-year-old, neutered male golden retriever, was presented for evaluation of osteoarthritis (OA). The dog had been diagnosed with idiopathic epilepsy 4 years earlier, and his seizures were well controlled with phenobarbital at 5 mg/kg PO twice a day. On physical examination, the dog had difficulty rising and exhibited apparent pain on palpation of the hip joints. Results of a complete blood cell count were normal. Results of a serum chemistry panel, however, disclosed elevated levels of alkaline phosphatase (ALP) at 790 U/L (ie, 6 times normal; reference range, 5-131 U/L) and alanine aminotransferase (ALT) at 180 U/L (ie, 1.5 times normal; reference range, 12-118 U/L), with a decreased total thyroxine (T4) concentration of less than 0.5 µg/dL (reference range, 0.8-3.5 μg/dL). Pelvic radiography revealed degenerative joint disease. The serum phenobarbital level was 28 µg/mL (therapeutic range, 15-45 µg/mL).
Which of the following drugs would be appropriate in the management of this patient?
Based on the information provided, how would you grade the following drugs and why?
Correct ResponseSafe or Use CautionDifferentiating benign hepatic enzyme elevations attributed to enzyme induction from those attributed to mild hepatocyte change linked to drug-induced hepatotoxicity is important when determining whether ongoing phenobarbital treatment is safe. In dogs with benign liver enzyme elevations, the degree of elevated ALP level is typically higher than that of ALT. However, severely elevated ALT levels should prompt caution and further evaluation.1-5 Assessment of liver function (ie, albumin level, bile acid assay) may help predict impending hepatic failure.5,6 Risk for hepatotoxicity may be greater if the serum drug concentration approaches the maximum therapeutic range6; a proposed therapeutic trough of less than 35 μg/mL has been suggested.5
As noted in this patient, the ALT level was mildly elevated and the albumin was within normal range. Further evaluation of liver function with a bile acid assay would more completely assess the patient for hepatic dysfunction. If bile acid assay results were normal, phenobarbital therapy could be continued. If the results were abnormal, transition to another antiseizure medication would be recommended.
Correct ResponseSafePotassium bromide can be an effective single-agent antiseizure medication in dogs and is generally well tolerated, with minimal risk for hepatotoxicity.1,6 For this patient, transition to potassium bromide or another antiseizure medication should be considered in order to minimize the risk for phenobarbital- induced hepatotoxicity if (1) compromised hepatic function is evident based on results of a bile acid assay or (2) long-term NSAID therapy for OA is planned.
Potassium bromide has a long half-life in dogs and does not reach steady-state blood concentrations for approximately 2 to 3 months. Therefore, if immediate withdrawal of phenobarbital were desired and seizure control were marginal, potassium bromide may not be the best choice as an alternative antiseizure medication.
Correct ResponseSafeLevetiracetam is a well-tolerated antiseizure medication, with evidence of efficacy as adjunctive therapy that lowers seizure frequency in dogs.6-9 Levetiracetam has not been investigated extensively as monotherapy, but it may be effective.10
For this patient, transition to levetiracetam or another antiseizure medication should be considered in order to decrease the risk for phenobarbital-induced hepatotoxicity if (1) compromised hepatic function is evident based on results of a bile acid assay or (2) long-term NSAID therapy for OA is planned. In contrast to potassium bromide, levetiracetam has a short elimination half-life, so administration would result in steady-state blood concentrations more quickly.6-9 Because of cytochrome P450 enzyme induction by phenobarbital, higher doses of levetiracetam might be needed until the effects of phenobarbital on enzyme induction have subsided,11 which may be 3 to 5 weeks or longer after discontinuation of phenobarbital.12,13
Correct ResponseSafeIn some human studies,14-16 gabapentin has been shown to have analgesic properties, and although these properties have not been definitively documented in dogs, this drug may have analgesic effects.17 Gabapentin is also used as adjunctive medication for the control of partial seizures in humans and may have a role as adjunctive therapy for the control of seizures in dogs.7,18 Gabapentin is primarily eliminated by the kidneys. Although the liver also metabolizes gabapentin in dogs, there are no known reports of gabapentin-induced hepatotoxicity in dogs.7,19
Correct ResponseUse Caution or Do Not UseNSAIDs can be effective treatment of OA and, in many dogs, may be well tolerated.20-22 Of note, however, idiosyncratic hepatotoxicity attributed to carprofen therapy has been reported.23 Other adverse effects associated with administration of an NSAID include dose-dependent GI and renal toxicities.24 If bile acid assay results in this dog were normal, carprofen therapy theoretically could be considered for treatment of this patient’s OA. However, although there is no documentation that concurrent use of phenobarbital and an NSAID may result in greater likelihood of hepatotoxicity in dogs, drug-induced hepatotoxicity in humans is more common when 2 or more hepatotoxic drugs are administered concurrently.25 If bile acid assay results were abnormal, NSAID therapy would not be recommended because of the increased risk for GI and renal toxicities.20
The best carprofen options for this patient would be either (1) regular use of other medications for OA, with carprofen used only as needed or not at all, or (2) transition to an alternative antiseizure medication, with administration of carprofen for treatment of OA after phenobarbital has been discontinued and the effects of phenobarbital enzyme induction have subsided.11-13 Regular monitoring of liver enzymes and function while the patient is being treated with carprofen would be recommended.20
Correct ResponseUse CautionThere is some evidence that oral tramadol may be an effective analgesic in dogs with OA.21 The opioid-like metabolite of tramadol is only produced in small amounts in dogs; thus, analgesic effects may occur from other metabolites that inhibit the reuptake of serotonin and norepinephrine. Tramadol is generally well tolerated by dogs,21,26-28 but it reportedly can result in seizures in humans, although it is unclear whether seizures only occur with overdosing or also occur with therapeutic dosing.29 Therefore, in dogs with concurrent epilepsy, tramadol should be used only with careful clinical monitoring.
Correct ResponseSafePolysulfated glycosaminoglycan (PSGAG) injections have been shown to decrease inflammatory mediators and improve signs of lameness in dogs.30,31 PSGAG is a safe, well-tolerated medication, and there would be no contraindications in this patient. PSGAG is a heparin analog, so caution should be taken when used concurrently with an NSAID.31 PSGAG injections have resulted in prolonged clotting times and buccal mucosal bleeding times in dogs,32 but clinically significant hemorrhage in dogs has not been documented.30 In one study in birds,33 severe hemorrhage was evident after injections of PSGAG.
Omega-3 fatty acids
Correct ResponseSafeOmega-3 fatty acids have been shown to be beneficial in humans with OA, are thought to be beneficial in dogs as adjunctive therapy for OA,34,35 and would not be contraindicated in this patient. Omega-3 fatty acids are generally well tolerated, although adverse effects potentially include decreased platelet function (which might be exacerbated by concurrent NSAID therapy), GI signs, and altered immune function.36
Correct ResponseSafeS-Adenosyl-methionine (SAMe) is an antioxidant supplement that increases glutathione levels and provides other cytoprotective effects for patients with a compromised hepatobiliary system.37-39 In addition, there is evidence that SAMe can be beneficial therapy for OA in humans.40 If this patient’s liver function were compromised, administration of this supplement may provide cytoprotective effects and serve as beneficial OA therapy.41
Correct ResponseDo Not UsePhenobarbital can alter thyroid hormone testing in dogs.12,42-44 Decreased levels of total and free T4 and eventual increased levels of thyroid-stimulating hormone (TSH) have been reported with phenobarbital use, but concurrent clinical hypothyroidism does not seem to develop.44 This patient had no clinical signs of hypothyroidism and was suspected to be euthyroid; because his low T4 level is attributed to phenobarbital therapy, L-thyroxine supplementation would not be recommended.
ALP = alkaline phosphatase, ALT = alanine aminotransferase, GI = gastrointestinal, NSAID = nonsteroidal antiinflammatory drug, OA = osteoarthritis, T4 = thyroxine
- Boothe DM, Dewey C, Carpenter DM. Comparison of phenobarbital with bromide as a first-choice antiepileptic drug for treatment of epilepsy in dogs. JAVMA. 2012;240(9):1073-1083.
- Gaskill CL, Miller LM, Mattoon JS, et al. Liver histopathology and liver and serum alanine aminotransferase and alkaline phosphatase activities in epileptic dogs receiving phenobarbital. Vet Pathol. 2005;42(2):147-160.
- Müller PB, Taboada J, Hosgood G, et al. Effects of long-term phenobarbital treatment on the liver in dogs. JVIM. 2000;14(2):165-171.
- Chauvet AE, Feldman EC, Kass PH. Effects of phenobarbital administration on results of serum biochemical analyses and adrenocortical function tests in epileptic dogs. JAVMA. 1995; 207(10):1305-1307.
- Dayrell-Hart B, Steinberg SA, VanWinkle TJ, Farnbach GC. Hepatotoxicity of phenobarbital in dogs: 18 cases (1985-1989). JAVMA. 1991;199(8):1060-1066.
- Boothe DM. Anticonvulsants and other neurologic therapies in small animals. In: Boothe DM, ed. Small Animal Clinical Pharmacology & Therapeutics. 2nd ed. St. Louis, MO: Elsevier; 2012:932-993.
- Charalambous M, Brodbelt D, Volk HA. Treatment in canine epilepsy—a systematic review. BMC Vet Res. 2014;10:257.
- Muñana KR, Thomas WB, Inzana KD, et al. Evaluation of levetiracetam as adjunctive treatment for refractory canine epilepsy: a randomized, placebo-controlled, crossover trial. JVIM. 2012;26(2):341-348.
- Volk HA, Matiasek LA, Luján Feliu-Pascual A, Platt SR, Chandler KE. The efficacy and tolerability of levetiracetam in pharmacoresistant epileptic dogs. Vet J. 2008;176(3):310-319.
- Fryer KJ, Levine JM, Peycke LE, Thompson JA, Cohen ND. Incidence of postoperative seizures with and without levetiracetam pretreatment in dogs undergoing portosystemic shunt attenuation. JVIM. 2001;25(6):1379-1384.
- Moore SA, Muñana KR, Papich MG, Nettifee-Osborne JA. The pharmacokinetics of levetiracetam in healthy dogs concurrently receiving phenobarbital. J Vet Pharmacol Ther. 2011;34(1):31-34.
- Gieger TL, Hosgood G, Taboada J, Wolfsheimer KJ, Mueller PB. Thyroid function and serum hepatic enzyme activity in dogs after phenobarbital administration. JVIM. 2000;14(3):277-281.
- Fukunaga K, Saito M, Matsuo E, et al. Long-lasting enhancement of CYP activity after discontinuation of repeated administration of phenobarbital in dogs. Res Vet Sci. 2009;87(3):455-457.
- Bone M, Crichley P, Buggy DJ. Gabapentin in postamputation phantom limb pain: a randomized double-blind placebo- controlled cross-over study. Reg Anesth Pain Med. 2002;27(5):481-486.
- Dirks J, Fredensborg BB, Christensen D, Fomsgaard JS, Flyger H, Dahl JB. A randomized study of the effects of single-dose gabapentin versus placebo on postoperative pain and morphine consumption after mastectomy. Anesthesiology. 2002;97(3):560-564.
- Turan A, Karamanhoglu B, Memis D, et al. Analgesic effects of gabapentin after spinal surgery. Anesthesiology. 2004;100(4):935-938.
- Wagner AE, Mich PM, Uhrig SR, Hellyer PW. Clinical evaluation of perioperative administration of gabapentin as an adjunct for postoperative analgesia in dogs undergoing amputation of a forelimb. JAVMA. 2010;236(7):751-756.
- Platt SR, Adams V, Garosi LS, et al. Treatment with gabapentin of 11 dogs with refractory idiopathic epilepsy. Vet Rec. 2006;159(26):881-884.
- Radulovic LL, Turck D, Von Hodenberg A, et al. Disposition of gabapentin (neurotonin) in mice, rats, dogs and monkeys. Drug Metab Dispos. 1995; 23(4):441-448.
- Boothe DM. Antiinflammatory drugs. In: Boothe DM, ed. Small Animal Clinical Pharmacology & Therapeutics. 2nd ed. St. Louis, MO: Elsevier; 2012:1045-1118.
- Malek S, Sample SJ, Schwartz Z, et al. Effect of analgesic therapy on clinical outcome measures in a randomized controlled trial using client-owned dogs with hip osteoarthritis. BMC Vet Res. 2012;8:185.
- Mansa S, Palmér E, Grøndahl C, Lønaas L, Nyman G. Long-term treatment with carprofen of 805 dogs with osteoarthritis. Vet Rec. 2007;160(13):427-430.
- MacPhail CM, Lappin MR, Meyer DJ, Smith SG, Webster CR, Armstrong PJ. Hepatocellular toxicosis associated with administration of carprofen in 21 dogs. JAVMA. 1998;212(12):1895-1901.
- Monteiro-Steagall BP, Steagall PVM, Lascelles BDX. Systematic review of nonsteroidal anti-inflammatory drug-induced adverse effects in dogs. JVIM. 2013;27(5):1011-1019.
- De Abajo FJ, Montero D, Madurga M, Garcia Rodriguez LA. Acute and clinically relevant drug-induced liver injury: a population based case-control study. Br J Clin Pharmacol. 2004;58(1):71-80.
- KuKanich B. Outpatient oral analgesics in dogs and cats beyond nonsteroidal antiinflammatory drugs: an evidence-based approach. Vet Clin North Am Small Anim Pract. 2013;43(5):1109-1125.
- Boothe DM. Control of pain in small animals: opioid agonists and antagonists and other locally and centrally acting analgesics. In: Boothe DM, ed. Small Animal Clinical Pharmacology & Therapeutics. 2nd ed. St. Louis, MO: Elsevier; 2012:994-1044.
- KuKanich B, Papich MG. Pharmacokinetics and antinociceptive effects of oral tramadol hydrochloride administration in greyhounds. Am J Vet Res. 2011; 72(2):256-262.
- Talaie H, Panahandeh R, Fayaznouri MR. Dose-independent occurrence of seizure with tramadol. J Med Toxicol. 2009; 5(2):63-67.
- De Haan JJ, Goring RL, Beale BS. Evaluation of polysulfated glycosaminoglycan for the treatment of hip dysplasia in dogs. Vet Surg. 1994;23(3):177-178.
- Fujiki M, Shineha J, Yamanokuchi K, Misumi K, Sakamoto H. Effects of treatment with polysulfated glyco-saminoglycan on serum cartilage oligomeric matrix protein and C-reactive protein concentrations, serum matrix metalloproteinase-2 and -9 activities, and lameness in dogs with osteo-arthritis. Am J Vet Res. 2007;68(8):827-833.
- Beale BS, Goring RL, Clemmons RM, Altman D. The effect of semi-synthetic polysulfated glycosaminoglycan on the hemostatic mechanism in the dog. Vet Surg. 1990;19(1):57 (abstr).
- Anderson K, Garner MM, Reed HH, et al. Hemorrhagic diathesis in avian species following intramuscular administration of polysulfated glycosaminoglycan. J Zoo Wildlife Med. 2013;44(1):93-99.
- Rousch JK, Dodd CE, Fritsch DA, et al. Multicenter veterinary practice assessment of the effects of omega-3 fatty acids on osteoarthritis in dogs. JAVMA. 2010;236(1):59-66.
- Fritsch DA, Allen TA, Dodd CE, et al. A multicenter study of the effect of dietary supplementation with fish oil omega-3 fatty acids on carprofen dosage in dogs with osteoarthritis. JAVMA. 2010;236(5): 535-539.
- Lenox CE, Bauer JE. Potential adverse effects of omega-3 fatty acids in dogs and cats. JVIM. 2013;27(2):217-226.
- Skorupski KA, Hammond GM, Irish AM, et al. Prospective randomized clinical trial assessing the efficacy of Denamarin for prevention of CCNU-induced hepatopathy in tumor-bearing dogs. JVIM. 2011;25(4):838-845.
- Wallace KP, Center SA, Hickford FH, Warner KL, Smith S. S-Adenosyl-l-methionine (SAMe) for the treatment of acetaminophen toxicity in a dog. JAAHA. 2002;38(3):246-254.
- Webster CRL, Cooper J. Therapeutic use of cytoprotective agents in canine and feline hepatobiliary disease. Vet Clin North Am Small Anim Pract. 2009;39(3): 631-652.
- De Silva V, El-Metwally A, Ernst E, Lewith G, Macfarlane GJ. Evidence for the efficacy of complementary and alternative medicines in the management of osteoarthritis: a systematic review. Rheumatology. 2001;50:911-920.
- Imhoff DJ, Gordon-Evans WJ, Evans RB, Johnson AL, Griffon DJ, Swanson KS. Evaluation of S-adenosyl- l-methionine in a double-blinded, randomized, placebo-controlled, clinical trial for treatment of presumptive osteoarthritis in the dog. Vet Surg. 2011; 40(3):228-232.
- Müller PB, Wolfsheimer KJ, Taboada J, et al. Effects of long-term phenobarbital treatment on the thyroid and adrenal axis and adrenal function tests in dogs. JVIM. 2000;14(2):157-164.
- Gaskill CL, Burton SA, Gelens HCJ, et al. Changes in serum thyroxine and thyroid-stimulating hormone concentrations in epileptic dogs receiving phenobarbital for one year. J Vet Pharmacol Ther. 2000;23(4):243-249.
- Daminet S, Ferguson DC. Influence of drugs on thyroid function in dogs. JVIM. 2003;17:463-472.
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