Chapter 229 New Maintenance Anticonvulsant Therapies for Dogs and Cats Curtis W. Dewey, Ithaca, New York Over the last 15 years the paradigm for treating dogs and cats with seizure disorders has changed, coincident with the introduction of several new anticonvulsant drugs. Although phenobarbital (dogs and cats) and bromide (dogs) remain valuable first-choice anticonvulsant drug options for pets with seizure disorders, a number of alternative drugs can be used as either adjunctive treatment (i.e., for refractory seizures) or sole therapy. The major impediments to widespread use of these newer anticonvulsant drugs have been principally higher cost compared with phenobarbital and bromide and clinical unfamiliarity with their usage. Since several of these drugs (gabapentin, zonisamide, levetiracetam) are now available in generic forms, cost is now less of a concern. Information is available concerning several newer anticonvulsant drugs for canine use. Unfortunately, much of the information regarding new anticonvulsant therapy for cats remains largely anecdotal, and the majority of clinical trials are neither randomized nor placebo controlled. This chapter provides information on some of these newer anticonvulsant drugs with recommendations based on published literature and my own clinical experience. Additionally, the next generation of some of these compounds is discussed briefly. Gabapentin Gabapentin, a structural analog of γ-aminobutyric acid (GABA), probably exerts its antiseizure effects via inhibition of voltage-gated calcium channels in the brain. Gabapentin is well absorbed in both dogs and people, with peak serum concentrations occurring within 1 to 3 hours after ingestion. In dogs 30% to 40% of the orally administered dose of gabapentin undergoes hepatic metabolism to N-methyl-gabapentin. Although gabapentin undergoes some hepatic metabolism in dogs, there is no appreciable induction of hepatic microsomal enzymes in this species. The half-life of elimination for gabapentin in dogs is between 3 and 4 hours. Because of its short half-life in dogs, gabapentin probably needs to be administered at least every 8 hours and possibly every 6 hours to maintain serum gabapentin concentrations within the therapeutic range. The potential need for dosing every 6 hours can make it difficult for some pet owners to administer gabapentin consistently. The recommended daily dosage range of gabapentin for dogs is 25 to 60 mg/kg of body weight in divided doses q6-8h. I recommend an initial dosage regimen of 10 mg/kg of body weight q8h. The suspected therapeutic plasma concentration for dogs is 4 to 16 mg/L. Gabapentin concentrations seldom are measured in dogs. The efficacy of gabapentin therapy in dogs has been evaluated in some small studies. In one prospective study evaluating gabapentin as an add-on treatment for dogs with refractory seizure activity, no significant decrease in overall seizure activity was seen over a 4-month evaluation period. Despite this, 3 of 17 dogs became seizure free, and 4 others experienced a reduction of 50% or more in seizure frequency during the evaluation period. In a similar study evaluating 11 dogs, an overall significant reduction in seizure frequency was found, and 6 dogs experienced a reduction of 50% or more in seizure frequency. Sedation and pelvic limb ataxia were the only reported adverse effects in these two studies. In my experience gabapentin occasionally is helpful as an anticonvulsant drug in dogs. In humans gabapentin appears to be much more effective in the treatment of focal seizure disorders than in the treatment of generalized seizures. Long-term canine toxicity trials for gabapentin have not been reported. However, the drug seems to be very well tolerated in this species, usually with few to no adverse effects. Sedation does not appear to be a major problem. However, I have had many clients report that their dog experienced mild sedation or mild polyphagia and weight gain in association with gabapentin use. Only anecdotal information is available regarding gabapentin use in cats. A dosage of 5 to 10 mg/kg of body weight q8-12h PO has been suggested but is not based on any published data. The elimination half-life of gabapentin in cats (approximately 3 hours) is similar to that in dogs, which suggests that a lower dose or longer dosing interval for this species is not necessary. A new gabapentin analog, pregabalin, has been approved recently for human use. Pregabalin has a greater affinity for the α2δ-subunit of voltage-gated calcium channels than gabapentin and purportedly is more effective in people than its predecessor as both an anticonvulsant and a pain-relieving drug. The elimination half-life of pregabalin is approximately 7 hours in dogs and 11 hours in cats. In a small, prospective clinical trial involving epileptic dogs, administration of pregabalin (as an add-on therapy) was associated with an overall reduction in seizures of 57%. The response rate in this study was 78%, and the responding dogs had a mean 64% reduction in seizures. The main adverse effect of pregabalin appears to be sedation. The target dosage for canine epilepsy is about 3 to 4 mg/kg q12h. However, the starting dosage should be 2 mg/kg q12h for at least the first week to avoid severe sedation. I suspect the dosage range for cats (based on pharmacokinetic data) to be about half that for dogs (i.e., 1 to 2 mg/kg q12h). Felbamate Felbamate is a dicarbamate drug that has demonstrated efficacy in the treatment of both focal (partial) and generalized seizures in experimental animal studies and human clinical trials. Proposed mechanisms of action include blocking of N-methyl-d-aspartate (NMDA)–mediated neuronal excitation, potentiation of GABA-mediated neuronal inhibition, and inhibition of voltage-sensitive neuronal sodium and calcium channels. Felbamate also may offer some protection to neurons from hypoxic-ischemic damage. Approximately 70% of the orally administered dose of felbamate in dogs is excreted in the urine unchanged; the remainder undergoes hepatic metabolism. The half-life of felbamate in adult dogs typically is between 5 and 6 hours (range, 4 to 8 hours). Felbamate is well absorbed after oral administration in adult dogs, but bioavailability in puppies may be only 30% that in adults. The half-life of elimination also has been shown to be much shorter in puppies than in adult dogs (approximately 2.5 hours). For adult dogs I recommend an initial felbamate dosage regimen of 15 mg/kg of body weight q8h. Felbamate has a wide margin of safety in dogs, with serious toxic effects usually not apparent below a daily dose of 300 mg/kg of body weight per day. If the initial dose of felbamate is ineffective, the dose is increased by 15-mg/kg increments every 2 weeks until efficacy is achieved, unacceptable adverse effects are evident, or the cost of the drug becomes prohibitive. The therapeutic range for serum felbamate concentration in dogs is believed to be similar to that in people (20 to 100 µg/ml). Typically serum felbamate assays are costly. In addition, the wide therapeutic range and low toxicity potential of felbamate make routine serum drug monitoring of questionable clinical value. I do not routinely check felbamate levels in dogs. The limited published material regarding clinical efficacy of felbamate is similar to my experience with the drug. In one report of refractory epilepsy in dogs, 12 of 16 patients experienced a reduction of seizure frequency following initiation of felbamate therapy. In another report of six dogs with suspected focal seizure activity, all dogs experienced a substantial reduction in seizure frequency when felbamate was used as the sole anticonvulsant drug; two of these dogs became seizure free. I have used felbamate extensively in the treatment of dogs with seizure disorders. Felbamate appears to be very effective both as an add-on therapy and as a sole anticonvulsant agent for patients with focal and generalized seizures. Because of its lack of sedative effects, felbamate is particularly useful as monotherapy in dogs exhibiting obtunded mental status as a result of their underlying neurologic disease (e.g., brain tumor, cerebral infarct). I have found adverse effects from felbamate to be very infrequent, especially when it is used as the sole anticonvulsant drug. Hepatic dysfunction associated with felbamate use tends to resolve following discontinuation of the drug. In dogs with evidence of preexisting hepatic disease, felbamate should be avoided. Because of the potential for hepatoxicity, it is recommended that serum biochemistry analysis be performed every 6 months in dogs receiving felbamate, especially if the drug is given concurrently with phenobarbital. It also may be advisable to evaluate complete blood counts every few months in the unlikely event that a blood dyscrasia develops. Adverse effects are observed infrequently with felbamate use in dogs. Unlike other anticonvulsants, felbamate does not cause sedation. Because felbamate does undergo some hepatic metabolism, liver dysfunction is a potential adverse effect. In one study 4 of 12 dogs receiving felbamate as an add-on therapy developed liver disease; however, each of these dogs was also receiving high doses of phenobarbital. In humans felbamate has been shown to increase serum phenobarbital concentrations in some patients receiving combination therapy. It is unclear whether felbamate, phenobarbital, or the combination of the two drugs is responsible for the reported hepatotoxicity in dogs. In humans serious hepatotoxicity rarely is associated with felbamate use and usually occurs in patients concurrently receiving other anticonvulsant drugs. Aplastic anemia (caused by bone marrow suppression) has been reported to occur in people receiving felbamate at a rate of 10 per 100,000 patients; this uncommon and severe adverse effect also usually is encountered in patients receiving combination anticonvulsant drug therapy. Fortunately this does not appear to occur in dogs. However, in one report reversible bone marrow suppression was suspected in two dogs receiving felbamate; one dog developed mild thrombocytopenia, the other mild leukopenia. Both of these abnormalities resolved following discontinuation of the drug. One patient in this report developed bilateral keratoconjunctivitis sicca; it is unknown whether this was related to felbamate use, although I have encountered several patients given felbamate that developed keratoconjunctivitis sicca. Generalized tremor activity in small-breed dogs receiving high dosages of felbamate also has been reported as a rarely encountered adverse effect. To my knowledge there is no clinical information regarding the use of felbamate in cats. Because of the potential for felbamate-associated hepatotoxicity and blood dyscrasias in dogs, felbamate is not likely to become a viable anticonvulsant option for cats. Because of the problems of hepatoxicity and blood dyscrasias occasionally associated with felbamate use in people, a new derivative of the drug—fluorofelbamate—has been developed and is undergoing clinical trials for human use. In experimental animal epilepsy models fluorofelbamate has been shown to have equal or superior anticonvulsant potency compared with felbamate. A reactive aldehyde intermediate that is formed from felbamate metabolism has been linked to the hepatic and hematologic adverse effects of this drug. This toxic intermediate is not produced from metabolism of fluorofelbamate.< div class='tao-gold-member'> Only gold members can continue reading. Log In or Register to continue Share this:Click to share on Twitter (Opens in new window)Click to share on Facebook (Opens in new window) Related Related posts: Ventilator Therapy for the Critical Patient Lawn and Garden Product Safety ASPCA Animal Poison Control Center Toxin Exposures for Pets Diabetic Monitoring Stay updated, free articles. Join our Telegram channel Join
Chapter 229 New Maintenance Anticonvulsant Therapies for Dogs and Cats Curtis W. Dewey, Ithaca, New York Over the last 15 years the paradigm for treating dogs and cats with seizure disorders has changed, coincident with the introduction of several new anticonvulsant drugs. Although phenobarbital (dogs and cats) and bromide (dogs) remain valuable first-choice anticonvulsant drug options for pets with seizure disorders, a number of alternative drugs can be used as either adjunctive treatment (i.e., for refractory seizures) or sole therapy. The major impediments to widespread use of these newer anticonvulsant drugs have been principally higher cost compared with phenobarbital and bromide and clinical unfamiliarity with their usage. Since several of these drugs (gabapentin, zonisamide, levetiracetam) are now available in generic forms, cost is now less of a concern. Information is available concerning several newer anticonvulsant drugs for canine use. Unfortunately, much of the information regarding new anticonvulsant therapy for cats remains largely anecdotal, and the majority of clinical trials are neither randomized nor placebo controlled. This chapter provides information on some of these newer anticonvulsant drugs with recommendations based on published literature and my own clinical experience. Additionally, the next generation of some of these compounds is discussed briefly. Gabapentin Gabapentin, a structural analog of γ-aminobutyric acid (GABA), probably exerts its antiseizure effects via inhibition of voltage-gated calcium channels in the brain. Gabapentin is well absorbed in both dogs and people, with peak serum concentrations occurring within 1 to 3 hours after ingestion. In dogs 30% to 40% of the orally administered dose of gabapentin undergoes hepatic metabolism to N-methyl-gabapentin. Although gabapentin undergoes some hepatic metabolism in dogs, there is no appreciable induction of hepatic microsomal enzymes in this species. The half-life of elimination for gabapentin in dogs is between 3 and 4 hours. Because of its short half-life in dogs, gabapentin probably needs to be administered at least every 8 hours and possibly every 6 hours to maintain serum gabapentin concentrations within the therapeutic range. The potential need for dosing every 6 hours can make it difficult for some pet owners to administer gabapentin consistently. The recommended daily dosage range of gabapentin for dogs is 25 to 60 mg/kg of body weight in divided doses q6-8h. I recommend an initial dosage regimen of 10 mg/kg of body weight q8h. The suspected therapeutic plasma concentration for dogs is 4 to 16 mg/L. Gabapentin concentrations seldom are measured in dogs. The efficacy of gabapentin therapy in dogs has been evaluated in some small studies. In one prospective study evaluating gabapentin as an add-on treatment for dogs with refractory seizure activity, no significant decrease in overall seizure activity was seen over a 4-month evaluation period. Despite this, 3 of 17 dogs became seizure free, and 4 others experienced a reduction of 50% or more in seizure frequency during the evaluation period. In a similar study evaluating 11 dogs, an overall significant reduction in seizure frequency was found, and 6 dogs experienced a reduction of 50% or more in seizure frequency. Sedation and pelvic limb ataxia were the only reported adverse effects in these two studies. In my experience gabapentin occasionally is helpful as an anticonvulsant drug in dogs. In humans gabapentin appears to be much more effective in the treatment of focal seizure disorders than in the treatment of generalized seizures. Long-term canine toxicity trials for gabapentin have not been reported. However, the drug seems to be very well tolerated in this species, usually with few to no adverse effects. Sedation does not appear to be a major problem. However, I have had many clients report that their dog experienced mild sedation or mild polyphagia and weight gain in association with gabapentin use. Only anecdotal information is available regarding gabapentin use in cats. A dosage of 5 to 10 mg/kg of body weight q8-12h PO has been suggested but is not based on any published data. The elimination half-life of gabapentin in cats (approximately 3 hours) is similar to that in dogs, which suggests that a lower dose or longer dosing interval for this species is not necessary. A new gabapentin analog, pregabalin, has been approved recently for human use. Pregabalin has a greater affinity for the α2δ-subunit of voltage-gated calcium channels than gabapentin and purportedly is more effective in people than its predecessor as both an anticonvulsant and a pain-relieving drug. The elimination half-life of pregabalin is approximately 7 hours in dogs and 11 hours in cats. In a small, prospective clinical trial involving epileptic dogs, administration of pregabalin (as an add-on therapy) was associated with an overall reduction in seizures of 57%. The response rate in this study was 78%, and the responding dogs had a mean 64% reduction in seizures. The main adverse effect of pregabalin appears to be sedation. The target dosage for canine epilepsy is about 3 to 4 mg/kg q12h. However, the starting dosage should be 2 mg/kg q12h for at least the first week to avoid severe sedation. I suspect the dosage range for cats (based on pharmacokinetic data) to be about half that for dogs (i.e., 1 to 2 mg/kg q12h). Felbamate Felbamate is a dicarbamate drug that has demonstrated efficacy in the treatment of both focal (partial) and generalized seizures in experimental animal studies and human clinical trials. Proposed mechanisms of action include blocking of N-methyl-d-aspartate (NMDA)–mediated neuronal excitation, potentiation of GABA-mediated neuronal inhibition, and inhibition of voltage-sensitive neuronal sodium and calcium channels. Felbamate also may offer some protection to neurons from hypoxic-ischemic damage. Approximately 70% of the orally administered dose of felbamate in dogs is excreted in the urine unchanged; the remainder undergoes hepatic metabolism. The half-life of felbamate in adult dogs typically is between 5 and 6 hours (range, 4 to 8 hours). Felbamate is well absorbed after oral administration in adult dogs, but bioavailability in puppies may be only 30% that in adults. The half-life of elimination also has been shown to be much shorter in puppies than in adult dogs (approximately 2.5 hours). For adult dogs I recommend an initial felbamate dosage regimen of 15 mg/kg of body weight q8h. Felbamate has a wide margin of safety in dogs, with serious toxic effects usually not apparent below a daily dose of 300 mg/kg of body weight per day. If the initial dose of felbamate is ineffective, the dose is increased by 15-mg/kg increments every 2 weeks until efficacy is achieved, unacceptable adverse effects are evident, or the cost of the drug becomes prohibitive. The therapeutic range for serum felbamate concentration in dogs is believed to be similar to that in people (20 to 100 µg/ml). Typically serum felbamate assays are costly. In addition, the wide therapeutic range and low toxicity potential of felbamate make routine serum drug monitoring of questionable clinical value. I do not routinely check felbamate levels in dogs. The limited published material regarding clinical efficacy of felbamate is similar to my experience with the drug. In one report of refractory epilepsy in dogs, 12 of 16 patients experienced a reduction of seizure frequency following initiation of felbamate therapy. In another report of six dogs with suspected focal seizure activity, all dogs experienced a substantial reduction in seizure frequency when felbamate was used as the sole anticonvulsant drug; two of these dogs became seizure free. I have used felbamate extensively in the treatment of dogs with seizure disorders. Felbamate appears to be very effective both as an add-on therapy and as a sole anticonvulsant agent for patients with focal and generalized seizures. Because of its lack of sedative effects, felbamate is particularly useful as monotherapy in dogs exhibiting obtunded mental status as a result of their underlying neurologic disease (e.g., brain tumor, cerebral infarct). I have found adverse effects from felbamate to be very infrequent, especially when it is used as the sole anticonvulsant drug. Hepatic dysfunction associated with felbamate use tends to resolve following discontinuation of the drug. In dogs with evidence of preexisting hepatic disease, felbamate should be avoided. Because of the potential for hepatoxicity, it is recommended that serum biochemistry analysis be performed every 6 months in dogs receiving felbamate, especially if the drug is given concurrently with phenobarbital. It also may be advisable to evaluate complete blood counts every few months in the unlikely event that a blood dyscrasia develops. Adverse effects are observed infrequently with felbamate use in dogs. Unlike other anticonvulsants, felbamate does not cause sedation. Because felbamate does undergo some hepatic metabolism, liver dysfunction is a potential adverse effect. In one study 4 of 12 dogs receiving felbamate as an add-on therapy developed liver disease; however, each of these dogs was also receiving high doses of phenobarbital. In humans felbamate has been shown to increase serum phenobarbital concentrations in some patients receiving combination therapy. It is unclear whether felbamate, phenobarbital, or the combination of the two drugs is responsible for the reported hepatotoxicity in dogs. In humans serious hepatotoxicity rarely is associated with felbamate use and usually occurs in patients concurrently receiving other anticonvulsant drugs. Aplastic anemia (caused by bone marrow suppression) has been reported to occur in people receiving felbamate at a rate of 10 per 100,000 patients; this uncommon and severe adverse effect also usually is encountered in patients receiving combination anticonvulsant drug therapy. Fortunately this does not appear to occur in dogs. However, in one report reversible bone marrow suppression was suspected in two dogs receiving felbamate; one dog developed mild thrombocytopenia, the other mild leukopenia. Both of these abnormalities resolved following discontinuation of the drug. One patient in this report developed bilateral keratoconjunctivitis sicca; it is unknown whether this was related to felbamate use, although I have encountered several patients given felbamate that developed keratoconjunctivitis sicca. Generalized tremor activity in small-breed dogs receiving high dosages of felbamate also has been reported as a rarely encountered adverse effect. To my knowledge there is no clinical information regarding the use of felbamate in cats. Because of the potential for felbamate-associated hepatotoxicity and blood dyscrasias in dogs, felbamate is not likely to become a viable anticonvulsant option for cats. Because of the problems of hepatoxicity and blood dyscrasias occasionally associated with felbamate use in people, a new derivative of the drug—fluorofelbamate—has been developed and is undergoing clinical trials for human use. In experimental animal epilepsy models fluorofelbamate has been shown to have equal or superior anticonvulsant potency compared with felbamate. A reactive aldehyde intermediate that is formed from felbamate metabolism has been linked to the hepatic and hematologic adverse effects of this drug. This toxic intermediate is not produced from metabolism of fluorofelbamate.< div class='tao-gold-member'> Only gold members can continue reading. Log In or Register to continue
