JOURNAL. Improving seizure control in dogs with refractory epilepsy using gabapentin as an adjunctive agent. M GOVENDIR ab, M PERKINS a and R MALIK c

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1 Australian VETERINARY JOURNAL Improving seizure control in dogs with refractory epilepsy using gabapentin as an adjunctive agent CLINICAL SECTION EDITOR MAUREEN REVINGTON M GOVENDIR ab, M PERKINS a and R MALIK c ADVISORY COMMITTEE ANAESTHESIA LEN CULLEN AVIAN MEDICINE AND SURGERY GARRY CROSS EQUINE MEDICINE AND SURGERY JOHN BOLTON LABORATORY ANIMAL MEDICINE MALCOLM FRANCE OPHTHALMOLOGY JEFF SMITH PATHOLOGY CLIVE HUXTABLE PHARMACOLOGY / THERAPEUTICS STEPHEN PAGE PRODUCTION ANIMAL MEDICINE JAKOB MALMO RADIOLOGY ROBERT NICOLL REPRODUCTION PHILIP THOMAS SMALL ANIMAL MEDICINE BRIAN FARROW DAVID WATSON SMALL ANIMAL SURGERY GEOFF ROBINS GERALDINE HUNT WILDLIFE / EXOTIC ANIMALS LARRY VOGELNEST JOURNAL ABSTRACTS MAUREEN REVINGTON EDITORIAL ASSISTANT AND DESKTOP PUBLISHING ANNA GALLO CONTRIBUTIONS INVITED Practising veterinarians and others are invited to contribute clinical articles to the Australian Veterinary Journal. We will consider material in a variety of formats, including clinically orientated reviews, reports of case series, individual case studies, diagnostic exercises, and letters containing comments or queries. Contributors should consult instructions for authors on and recent issues of the journal for guidelines as to formatting. Over referencing should be avoided: authors should preferably quote only those articles they feel are most likely to be of interest and benefit to readers. Send all contributions to: Editor, AVJ Clinical Section AVA House, 272 Brunswick Road, Brunswick, Vic 3056 Phone: (03) Fax: (03) desktop@ava.com.au Authors, please note that from July 1st the manuscript handling fee will be $55, including GST. Objective To assess whether there is a change in seizure activity in dogs with refractory epilepsy that are receiving appropriate doses of phenobarbitone and/or potassium bromide, when gabapentin is added to the therapeutic regimen. Design A prospective study of 17 dogs with a refractory seizure disorder, 16 of which have idiopathic epilepsy. Procedure Patients were stabilised using phenobarbitone and/or potassium bromide to produce tolerable therapeutic serum concentrations and dosed additionally with gabapentin at 35 to 50 mg/kg/d (divided twice or three times daily) for 4 months. Owners recorded seizure activity and side effects during this period in a standardised diary. Patients underwent monthly physical examinations and venepuncture to assess selected serum biochemical analytes, as well as phenobarbitone and bromide concentrations. Patients were further monitored for long-term response to adjunctive gabapentin therapy. Results There was no significant decrease in the number of seizures over the study period for the entire cohort, however three dogs stopped seizuring completely. There was a significant increase in the number of patients who showed an increase in the interictal period (P > 0.001). Serum alkaline phosphatase activity and triglyceride concentrations were elevated at baseline. There were no significant changes in biochemical analytes during the course of the study period. Side effects observed initially on addition of gabapentin included sedation and hind limb ataxia. The former resolved spontaneously after a few days; the latter after a slight reduction in bromide dose. Long-term, a further two patients became seizure free and ten patients remained on gabapentin indefinitely. No long-term side effects have become apparent. Conclusion Addition of gabapentin to phenobarbitone and/or potassium bromide increased the interictal period and shortened the post-seizure recovery in some canine epileptics. In some dogs, seizures were prevented completely, while in others there was an increase in interictal period. The short-half life of gabapentin has advantages for seizure control, however its present high cost may prohibit therapy in large dogs. Aust Vet J 2005;83: AED ALP ANOVA CNS CSF EDTA IE GABA GP KBr MRI n/a NMDA PB TG SD RSD UVC-S Antiepileptic drug Alkaline phosphatase Analysis of variance Central nervous system Cerebrospinal fluid Ethylenediamine tetra-acetic acid Idiopathic epilepsy γ -amino butyric acid Gabapentin Potassium bromide Magnetic resonance imaging Not applicable N-methyl-D-aspartate Phenobarbitone Triglyceride Standard deviation Relative standard deviation University Veterinary Centre-Sydney a Faculty of Veterinary Science, Building B14, The University of Sydney, New South Wales 2006 b Author for correspondence M.Govendir@vetc.usyd.edu.au c Post Graduate Foundation in Veterinary Science, University of Sydney, New South Wales Australian Veterinary Journal Volume 83, No 10, October 2005

2 Accepted therapy for minimising the frequency and severity of seizures in dogs with IE is daily administration of PB and/or KBr. These older AEDs are popular with veterinarians because they are effective, affordable, have an acceptable therapeutic index and a long half-life that permit once or twice daily dosing. The good correlation between clinical efficacy and serum concentrations facilitates the provision of optimal therapy through therapeutic monitoring. Approximately 20 to 50% of epileptic dogs treated with PB alone continue to have unacceptable seizure activity, become refractory to this medication or develop unacceptable side effects. 1 Such patients require combination therapy incorporating KBr to achieve satisfactory control. However, even with optimised combination therapy, some dogs still seizure, despite achieving PB and KBr serum concentrations within target ranges. Since the early 1990s, a variety of new AEDs have been released for treating epilepsy in people, with the majority being available in Australia. 2 New AEDs have yet to find their way into conventional treatment regimes for canine epileptics because of adverse effects, unfavourable pharmacokinetics (too rapid metabolism), insufficient published canine clinical trials, or expense. This study was initiated to determine whether dogs with refractory epilepsy would achieve improved seizure control when a new AED, gabapentin, was used in the therapeutic regime. GP has a short half life, requiring dosing two or three times daily, but is reported to have very few adverse effects in dogs. 3,4 Although the patent for GP has recently expired and it is now available in a generic form, only one abstract is available 5 concerning the efficacy of GP as an adjunctive agent in reducing seizure activity in epileptic dogs. Materials and methods This study was approved by The University of Sydney Animal Care and Ethics Committee. Advertisements were placed in Australian veterinary publications requesting referral of dogs between 2 and 8 years-of-age with refractory IE, but which still had significant seizure activity (defined as at least one generalised motor seizure per fortnight) despite combination therapy with PB and KBr. If possible, dogs were managed by one of the authors at the UVC-S, however dogs outside the Sydney metropolitan area were included if they were treated by a veterinarian prepared to maintain regular contact with the investigators. All cases were treated as outpatients on a monthly basis over a 4 month study. Nineteen patients were initially recruited. Patient history was collected including: age of first seizure, description of seizure activity (generalised or partial motor activity), frequency, duration and severity of seizures, and previous and current anticonvulsant medication (including dose rates and frequency of administration). Patients underwent physical and neurological examinations. Blood (3 ml in a clot tube) was collected by jugular venepuncture for biochemical analyses and determination of serum PB and KBr concentrations. Blood samples were collected in the morning after a 12 h fast and prior to dosing with AEDs in order to determine trough serum concentrations. Neither cross-sectional imaging of the CNS nor collection of CSF were routinely performed. Owners were provided with a standard year diary with which to record the frequency, nature, duration, time of occurrence of seizures and any other significant events before and after any seizure. During the study period, the majority of patients were dosed with PB (Epiphen, Hi-Perform Veterinary Products, Wahroonga, NSW) and KBr (Epibrom, Hi-Perform Veterinary Products, Wahroonga, NSW). Doses of PB and KBr for each patient were titrated until serum concentrations for each agent were within accepted therapeutic ranges as determined by the respective laboratories using standardised validated methods: 65 to 150 μmol/l for PB (Mayne Vetnostics, North Ryde, NSW) and 8.8 to 25 mmol/l for KBr (Royal Prince Alfred Hospital, Camperdown, NSW). If the patient was still exhibiting unacceptable seizure activity after 2 or more months of optimised PB and KBr therapy then GP was added to the drug regimen at a dose of approximately 40 mg/kg/day in two or three divided doses (Neurontin [300 mg capsules], Pfizer Pty Ltd, West Ryde NSW; Gabapentin [400 mg capsules] David Bull Laboratories, Mulgrave, Vic). Two dogs (a German Shepherd and Great Dane) had greatly improved seizure control once their PB and KBr medication was optimised and took no further part in the study. Over a 4 month period, each patient underwent monthly rechecks that involved recording recent history, conducting a physical examination, scrutinising the seizure diary and collecting blood (3 ml) for serum biochemical analyses, PB and KBr determinations. Baseline TG concentrations were elevated in many patients; the owners of these patients were advised to feed a low fat diet during the subsequent study period. Owners of patients afflicted by severe cluster seizures were provided with liquid diazepam (Pamlin 5 mg/ml, Parnell Laboratories, Alexandria, NSW) to administer per rectum at a dose rate of 2 mg/kg via a catheter, if cluster seizures developed. 4 At the time of writing, those patients remaining on GP in addition to PB and/or KBr for seizure control, continue to be monitored regularly to identify changes in seizure activity or development of long-term adverse effects. Statistical Analysis The number of observed seizures per month for patients was combined. The average number of seizures per month for each patient prior to GP administration, and for each month of GP administration thereafter (4 months) were compared by a one way ANOVA. For patients with cluster seizures, each day was considered a separate seizure event. The number of seizure free dogs and the number of patients that had an increase in interictal period after GP therapy were compared to the total number of patients by a two tailed Fisher s exact test. The serum ALP activity, cholesterol and TG concentrations for all patients were pooled, the mean ± SD for each of these analytes were calculated for both baseline and endpoint, which were compared by a paired t-test. For all statistical tests P values of < 0.05 were taken to be significant. To appreciate the stability of trough serum concentrations of PB and KBr for each patient over the course of the study period, the mean ± SD concentration of these agents were calculated (incorporating baseline and monthly concentrations). The RSD for each agent (SD/mean as a percentage; an indication of the variance with respect to the mean) were also calculated. Results In total, 17 dogs received GP as adjunctive therapy. At baseline, 14 of these received consistent PB and KBr doses resulting in therapeutic serum concentrations for both agents, but experienced seizures at an unacceptable frequency. Information concerning all patients: breed, weight, sex, age of first seizure, age at study entry, mean number of seizure episodes per month at baseline and endpoint, and length of time previously treated with Australian Veterinary Journal Volume 83, No 10, October

3 PB and KBr, is provided in Table 1. Phenobarbitone, KBr and GP dose rates for each patient during the study period, and observed side effects, are presented in Table 2 along with the mean ± SD and RSD of the serum concentrations of PB and KBr over the course of the study period and including baseline data as discussed below. PB was withdrawn slowly in three patients during the study period. One owner specifically requested this due to unacceptable sedation and obesity (case 4), another owner (case 7) was concerned by the presence of consistently elevated serum ALP activity ( > 4000 U/L; reference range < 120 U/L) and one patient (case 12) had developed a hepatopathy (determined by histological examination of liver biopsy specimens). One patient (case 2; a Miniature Schnauzer) did not have IE but acquired a seizure disorder subsequent to leakage of enilconazole through the cribiform plate during treatment of invasive nasal aspergillosis. This patient was given PB and GP only, as KBr had been previously withdrawn by the referring veterinarian subsequent to an episode of pancreatitis. As this patient experienced cluster seizures approximately every 6 months, the incidence of seizures was omitted from the statistical analysis. Another patient (case 3) had previously developed gastrointestinal side effects at therapeutic serum concentrations of KBr and thus was dosed at a standard conventional PB dose, but at a lower than recommended dose of KBr. The KBr serum concentration was consistent during the study period. Outcome after 4th month of GP administration Three patients (cases 1 to 3) became seizure free soon after commencing GP therapy and remained seizure free during the 4 month study period. The remaining 13 patients continued to display generalised motor seizures while receiving triple therapy, however in eight of these (cases 4 to 11) seizures tended to be less violent, occurring at a reduced frequency and lasting for a shorter time than prior to GP. Additionally, postictal depression and patient recovery time were reduced. In four patients (cases 12 to 15) there was no detectable change in any aspect of seizure activity. Two patients were euthanased during the study as a result of developing a severe episode of status epilepticus (case 16 during the 4th month; case 17 during the 1st month; see Table 1). Two patients initially demonstrated independent focal and generalised motor seizures (cases 9 and 15). Over Table 1. The effect of adding gabapentin to the therapeutic regimen for dogs with idiopathic epilepsy. Patient information prior to entering the study and number of seizure episodes per month at study end. Case Breed Weight (kg) Sex a Age at first Age at study No. of seizure No. of seizure Time on PB Time on KBr seizure (years) entry (years) episodes b /month episodes/month prior to prior at study entry at study end commencing commencing study (years) study (years) Patients with no seizures at end of study period 1 Maltese crossbred 10 M Miniature Schnauzer c 10 M (1 cluster d every 6 months) 3 Visla 28 F Patients with an increase in interictal period at end of study period 4 Maltese Poodle 10 M > 0.5 crossbred 5 Dalmatian 24 M Labrador crossbred 25 M German Short- 38 M Haired Pointer e 8 Golden Retriever e 40 M Golden Retriever f 47 M > Kelpie 28 F German Shepherd e 57 M Patients with no increase in interictal period at end of study period 12 Cattle Dog 20 F Staffordshire 23 M > 1 > 0.5 Bull Terrier 14 Dalmatian 33 F Cavalier King 9 F Charles Spaniel f Patients euthanased during study period 16 Dougue de Bordeaux e 54 M 1 18 months Beagle 15 F Median (25-75% (15-33) (1 4.5) (5-8) (1-4) (0.5-3) (1-2.5) (0.5-1) percentile) a all dogs neutered; b single seizures or as a cluster of seizures; c this case had acquired epilepsy (see text); d KBr had been withdrawn earlier as it was implicated in an earlier bout of pancreatitis; e denotes patient has clusters of seizure episodes over 24 h; f these cases also had several partial seizures per week prior to baseline. 604 Australian Veterinary Journal Volume 83, No 10, October 2005

4 Table 2. Dose rates of PB, KBr and GP during study period, mean ± SD and RSD of monthly PB and KBr concentrations and over the course of the study period including baseline. Case PB dose during PB serum concentrations KBr dose during KBr serum concentrations GP dose during study period (recommended therapeutic study period (recommended reference study period Side effects mg/kg/d range μmol/l) a (mg/kg/d) range mmol/l) b (mg/kg/d) Mean ± SD RSD % Mean ± SD RSD % ± ± Initial hind limb ataxia, pancreatitis ± n/a n/a 32 None ± ± None ± ± None ± ± Initial hind limb ataxia ± ± None ± ± ALP > 4000U/L c ± ± Initial sedation ± ± Hind limb ataxia ± ± Occasional ataxia ± ± Initial hind limb ataxia, polyuria, polydipsia ± ± Initial ataxia ± ± Initial sedation ± ± Polyphagia ± ± Sedation ± ± Euthanased during 4th month 17 8 Insufficient data available 23 Insufficient data available 40 Euthanased during 1st month 8 (6-12) d n/a 24 (14-30) n/a 35 (32-40) a Mayne Vetnostics, North Ryde, NSW; b Royal Prince Alfred Hospital, Camperdown, NSW; c Normal ALP reference range < 120U/L (Mayne Vetnostics, North Ryde, NSW); d Median (25-75% percentile). the course of the study, the frequency of the focal seizures of case 9 decreased. The mean ± SD of seizure episodes for all patients except case 2 are presented in Table 3. Although the mean number of seizures was reduced during the first and last month of GP therapy, there was no significant difference in mean number of seizures between baseline or any month of the study period (P = 0.60). Despite three patients becoming seizure free there was no statistically significant difference between the number of seizure free patients after introduction of GP (P = 0.102) however eleven patients experienced an increase in the interictal period which was statistically significant (P > 0.001) Serum trough concentrations of PB and KBr were measured monthly to ensure that these concentrations did not rise throughout the course of the study period; corresponding mean ± SD and RSD are presented in Table 2. Omitting the PB data from cases 4, 7 and 12 whereby the PB dose was deliberately slowly reduced during the study, the RSD ranged from 4 to 32% and 4 to 31% for PB and KBr, respectively. Some biochemical analytes were elevated above the reference range at baseline (ALP, cholesterol and triglyceride), and are presented in Table 4, along with their concentrations at endpoint. During the study no biochemical analyte altered significantly between baseline and endpoint. Table 3 Pooled number of seizures (mean ± SD) of all patients at baseline and each month of the study. Baseline First month Second month Third month Fourth month No of seizures 3.0 ± ± ± ± ± 2.1 One way ANOVA P = 0.60 Table 4. Selected biochemical analyte concentrations (mean ± SD) at baseline and endpoint Baseline Endpoint Reference range Alkaline phosphatase ± ± (1-120 U/L) Cholesterol 7.1 ± ± 2.9 ( mmol/l) Triglyceride 4.9 ± ± 6.8 ( mmol/l) Longer-term outcomes Patients were checked periodically after the study period to ascertain i) whether owners had continued GP in addition to other AEDs, ii) the incidence of seizure activity and iii) whether any adverse side effects were observed during chronic dosing. This information is provided in Table 5. Long-term, one patient (case 3) became seizure free on GP, PB and low dose KBr until lapsing into status epilepticus 18 months after the trial and was euthanased. Another patient (case 14) was euthanased by the investigators 6 months after entering the study due to severe polyphagia, which likely contributed to biting of a child, that developed during triple therapy. Case 11 was euthanased January 2005 after two severe seizures. Australian Veterinary Journal Volume 83, No 10, October

5 Table 5 Patient long-term response to anti epileptic drugs. Case Long-term outcome or Months on GP Long-term seizure Side effects thought medication (up to Dec 04) incidence specific to anticonvulsant medication 1 KBr & GP 15 Seizure free None 2 KBr & GP 18 Seizure free None 3 Euthanased after episode of n/a n/a n/a status epilepticus 12 months after starting GP medication 4 KBr & GP 11 Seizure free None 5 PB & KBr only n/a n/a n/a 6 PB, KBr & GP 11 Uncertain None 7 KBr & GP 12 No change a None 8 PB, KBr & GP 15 No change a None 9 PB, KBr & GP 15 No change a None 10 PB, KBr & GP 15 No change a None 11 PB, KBr & GP 15 No change a Ataxia 12 KBr & GP 10 Seizure free None 13 PB & KBr n/a n/a n/a 14 Euthanased due to severe polyphagia n/a n/a n/a resulting in biting 6 months after starting GP medication 15 PB (being reduced slowly), KBr & GP 14 No change a None a No change from data provided in no. of seizure episodes/month at study end in Table 1. On a more positive note, cases 4 and 12 have since become seizure free. Some patients no longer receive GP due to expense (case 5) or insufficient perceived response (cases 10 and 13). Ten patients continue to be medicated with GP and KBr (cases 1, 2, 4, 6 to 9, 11, 12 and 15) and there have been no noticeable adverse effects other than the development of persistent ataxia in case 11. Interestingly, five of these (cases 1, 2, 4, 7 and 12) no longer require PB including four (cases 1, 2, 4 and 12) that are almost seizure free (only a very occasional seizure is observed). Patient 15 is presently having PB withdrawn while being maintained on KBr and GP. In contrast to the short term outcome results, there is a statistically significant difference in long-term seizure free patients medicated with GP (P = 0.04). Discussion It has been stated that a mild, isolated seizure episode every 6 to 8 weeks is an acceptable therapeutic endpoint for canine epileptics 6 and that the aim of using AEDs for seizure control is to achieve a 100% increase in interictal time period, or a 50% decrease in seizure frequency, without drug toxicity. 7,8 However it is well recognised that some dogs receiving conventional anticonvulsant therapy at doses resulting in serum concentrations within recommended ranges still have unacceptable seizure activity and this is borne out by the present study. For some owners any residual seizure activity is considered unacceptable. It is therefore of great interest that addition of GP resulted in complete cessation of seizure activity in three patients (cases 1, 2 and 3) over the study period and two others subsequently (cases 4 and 12). Other patients (cases 5, 6, 7, 8, 9, 10 and 11) had fewer seizures per month and faster post-seizure recoveries to normality. PB and KBr are currently the mainstays of anticonvulsant therapy for dogs with epilepsy. PB has been available since 1912 and although KBr predates PB as an anticonvulsant, it was overlooked in veterinary medicine until being rediscovered by Schwartz- Porsche in the late 1980 s. 9 PB is the most commonly used therapeutic agent for the medical management of canine IE in Australia. It has generally acceptable side effects at low doses and is relatively inexpensive, an important consideration given that therapy is for the duration of a patient s life. However, approximately 20 to 50% of canine epileptics will eventually demonstrate inadequate seizure control using PB monotherapy, even when administered at high doses. 1 Another therapeutic agent, typically KBr, must therefore be added to improve seizure control in such patients. 10 Both PB and KBr have long half-lives in the dog (24 to 47 hours and 25 to 36 days, respectively) 4 and thus can be conveniently administered once or twice daily. The authors have noted, however, that twice daily administration of both agents is better tolerated and seemingly more efficacious (unpublished observations). Thirteen patients were receiving conventional doses of both, yet significant seizure activity persisted prior to enrolment. For this investigation, significant seizure activity was defined as at least one generalised motor seizure per fortnight. Four dogs experienced clusters of seizures (cases 7, 8, 11 and 16) prior to commencing the trial. Some dogs were more severely affected than others, for example cases 11 and 16 had such severe cluster seizures that hospitalisation was required prior to, and even during, the study period. Most other dogs had a major seizure approximately fortnightly prior to the study period, from which they recovered uneventfully, except cases 16 and 17. All patients except one were initially thought to have IE by considering the following factors at presentation: unremarkable interictal neurological examination, exclusion of a metabolic and toxic basis for seizure activity and lack of development of interictal signs over time. Thirteen patients had their first seizure before 6 years of age. Case 2 started to seize at 8 years immediately after treatment of nasal aspergillosis with a topical intranasal enilconazole infusion. It is reported that IE is more prevalent in large breeds, 11 however cases 1, 4, 15 and 17 weighed 15 kg. No cross sectional imaging was performed on any other patient 606 Australian Veterinary Journal Volume 83, No 10, October 2005

6 during this study (other than case 12 by the referring veterinarian) because the investigators wanted to replicate the diagnostic workup most likely to occur in general veterinary practice. MRI, currently the diagnostic tool of choice for detecting structural lesions within the CNS, presently costs in the order of A$1200 per patient (including anaesthesia and transport fees) and is therefore beyond the financial resources of many owners and the grant supporting this study. The experimental design of this study set out to assess the efficacy of GP as an adjunctive AED during continued administration of therapeutic doses of PB +/or KBr in patients with refractory IE. A study similar to this one, reported in a research abstract, demonstrated that five of eleven dogs with IE exhibited a positive response when GP was added to PB and KBr, with a significant reduction in the seizure frequency. 5 The observation of similar benefit by two independent investigations supports the notion that GP as an adjunctive therapy provides benefit to some dogs with IE receiving PB +/or KBR. Another conceptually similar study has recently reported that zonisamide, another new AED, has a useful adjunctive role in some canine epileptics. 12 During the course of the 4 months of this study, PB and KBr were maintained at serum concentrations within their respective therapeutic ranges in 13 patients (Table 2). Mean concentrations for these patients were within the therapeutic range during the investigative period with variations in serum concentrations of PB and KBr varying by no more than 32%. This variation could be attributable to factors such as interassay variation, variable dosage administration times by owners, inconsistent blood collection time by the veterinarians, and daily variation in diet (which can influence bromide serum concentrations). The total daily doses of PB and KBr required to maintain recommended drug levels were remarkably variable, ranging from 6 to 26 mg/kg and 14 to 56 mg/kg, respectively. All patients had been medicated with PB longer than 6 months prior to study entry. It is recognised that PB administration is variably associated with sedation, ataxia, increased appetite and weight gain. 13 Weight gain is attributable to numerous factors including reduced activity, increased appetite and depression of the thyroid axis. 13 Bromide may also induce adverse effects including sedation, ataxia, vomiting, anorexia, diarrhoea or hind limb paresis 14 and be associated with pancreatitis. 4,15 ALP activity and TG concentration were elevated above reference ranges at the beginning of this study. Increased ALP activity during chronic PB dosing in dogs is well recognised and referable to enzyme induction. 15 This phenomenon also affects the cytochrome P450 oxidase system required for the metabolism of PB and numerous other drugs. It is of great interest that the mean fasting TG concentration at baseline was elevated in relation to the reference range. The development of fasting hypertriglyceridaemia during chronic PB administration (> 6 months) has been reported in children, 16 rats, 17 guinea pigs 18 and, briefly, in dogs. 19 During the course of the study, the owners of dogs with markedly elevated fasting TG concentrations were asked to feed their pet a low fat diet in order to minimise weight gain and, in the interest of the individual patient s well-being, to prevent any additional sequellae referable to increased serum TG developing during the study period (for example pancreatitis). PB and KBr are favoured over other drugs such as diazepam, phenytoin, carbamazepine and valproic acid for treating canine IE. These latter agents have been found to have a too short a half- life in the dog and thus fail to maintain effective serum levels, 4 unless sustained-release formulations are utilised. 20 Primidone, another older AED, undergoes metabolism to PB 4 but is thought to be hepatotoxic in its own right. 21 In the last decade many new AEDs have been developed for people, but as yet none have made in-roads into canine anticonvulsant therapy, probably a result of insufficient efficacy data and expense when compared to PB and KBr. The major advantages of new AEDs are the reduction of psychotropic, sedative and organ-toxic adverse reactions. 4 Unfortunately, newer agents are generally metabolised more rapidly in dogs than in people. Very few new AEDs have undergone clinical trials in dogs, with the exception of felbamate 22 which inhibits NMDA receptor-mediated cationic currents and potentiates GABA receptor chloride channel activity 23 and the sulphonamide derivative zonisamide 12 that blocks neuronal sodium and calcium channels. 24 Unfortunately neither of these are available in Australia. Many new AEDs produce side effects in dogs: chronic administration of the GABA transaminase inhibitor vigabatrin may lead to intramyelinic oedema in dogs; 25 felbamate can give rise to blood dyscrasias and liver disease; 22 the neuronal sodium channel blocker topiramate 26 may result in gastrointestinal irritability 4 and the neuronal sodium channel blocker lamotrigine 27 is converted to a cardiotoxic metabolite in dogs. 4 Additional drugs that have been shown to be useful or potentially useful in IE and induce minimal side effects include clorazepate (a long acting diazepam pro-drug), levetiracetam (mechanism of action unknown) 24 and gabapentin. Gabapentin has been used in people with intractable epilepsy including generalised tonic-clonic and partial seizures. 26 It is also effective in alleviating neuropathic pain. 26 Although its exact mechanism of action in the CNS is uncertain, it may indirectly enhance GABA receptor activation or GABA synthesis 14,27 thereby increasing chloride conductance and preventing neuronal excitation. The dose rate administered here was extrapolated from other publications concerning canine IE 14 with a previous study using a dose rate of 10mg/kg/d every 8 h. 5 In dogs, its elimination half-life is 3 to 4 hours, compared to 5 to 6 hours in humans. 4,27 Gabapentin is well absorbed orally, with peak serum levels occurring within 2 h of dosing. 27 In people, bioavailability is inversely related to dose rate. 27 An oral dose of 50mg/kg has a bioavailability of 80% in dogs. Approximately 34% of the dose is metabolised to N-methylgabapentin, although the principal route of excretion is by the kidney. 28 As yet, side effects apart from sedation have not been documented 4 although it has been reported that one dog developed a sterile panniculitis after 18 months of GP therapy which resolved when the drug was withdrawn. 5 Upon adding GP to on-going PB and KBr therapy, some dogs were more sedated than usual for 3 to 4 days. Another common initial side effect was the development of hind limb ataxia. We found empirically that the hind limb paresis resolved within 24 to 48 hours by slightly reducing the KBr dose. During the course of the study, patient 11 developed polyuria and polydipsia, while patient 1 developed pancreatitis; these adverse effects have been well documented to occur during PB, KBr and PB/KBr therapy. 4 In the majority of cases GP was administered twice daily, although in one patient (case 11) it was administered at the same total dose but divided three times daily. Two cases were given 50mg/kg/d (divided twice daily); this was based on the owner s requests (case 10) and rounding up the dose using the available 300 or 400mg capsules (case 5). Because of its rapid onset of action, GP was found to be of specific benefit in those patients Australian Veterinary Journal Volume 83, No 10, October

7 prone to multiple seizures on a given day, as dogs who regained consciousness between seizures could be dosed orally with GP in the postictal period, providing an alternative or adjunct to rectal diazepam. GP may also prove to be useful in the prevention of withdrawal seizures in dogs being weaned off PB. For example, cases 4 and 12 appeared to experience an increase in seizure frequency during PB-withdrawal; transient escalation in the GP dose to 40mg/kg/d (divided, given three times daily) prevented further seizures. As GP is not principally metabolised by the liver, it may be useful in dogs with hepatic dysfunction, such as patients with PB-associated hepatopathy or congenital porto-systemic shunts. With regard to the latter, GP s short half-life makes it a theoretically superior choice to KBr, which is renally excreted but encumbered by very slow pharmacokinetics. The therapeutic serum concentration of GP has not been addressed here, as the drug has a very high therapeutic index and minimal interactions with other drugs, thus serum monitoring provides little additional information for the considerable expense. 4 GP as an adjunctive therapy appeared to further decrease the frequency and severity of seizures in some dogs. Importantly, three of 17 patients (cases 1, 2 and 3) stopped seizuring completely after 4 months of triple therapy and at the time of writing continue to be seizure free. In six additional patients (cases 5 to 12), the interictal period was increased and over the longer term two of these (cases 4 and 12), subsequently became seizure free. A common feature of these two cases was that PB was gradually withdrawn during the study period; this drug withdrawal and a corresponding reduction in triglyceridaemia took longer than 6 months. Presently a generic GP tablet (400 mg) costs A$0.60 (wholesale); therefore the cost of dosing a 20 kg dog daily is $1.20. Gabapentin was provided at no cost to owners during this study, however owners were informed at commencement that they would have to pay for further GP at the completion of the trial. Interestingly, 10 owners elected to continue GP at the end of the study period despite the ongoing cost of medication. This suggests that many owners thought GP provided a substantial benefit to their pet. Certainly in the smaller dogs, GP does not represent a large financial burden. For many owners of larger dogs, GP offered some welcome respite from seizure activity, further improvement in their dog s perceived quality of life and reduced ongoing veterinary fees for management of severe seizure episodes. GP thus appears to have several useful benefits as an adjunctive drug for some dogs with refractory epilepsy. GP may provide an alternative drug for use in combination therapy when the patient is sensitive to the effects of PB and/or KBr and may have additional benefits resulting from its short half-life such as rapid action and the prevention of ongoing clusters of seizures. Further work is clearly justified to determine whether GP represents effective monotherapy for dogs with uncomplicated IE. Acknowledgments The investigators thank the Canine Research Foundation (Victoria) who financed the study. A donation was provided by the NSW Beagle Club. We express our thanks to Dr David Snow and Mayne Vetnostics who performed biochemical analyses and drug monitoring; Hi-Perform Veterinary Products for provision of PB and KBr at cost; Pfizer Australia Pty Ltd who generously supplied the 300mg Neurontin gabapentin capsules; Post Graduate Foundation in Veterinary Science of the University of Sydney, The Veterinarian and The Australian Veterinary Journal for publicising the study. Thanks to Dorothy Lewis for assistance with sample processing and Brian Farrow who provided neurological assessment of some patients. We thank Geraldine Hunt, Jody Braddock and Rhonda Foreman for UVC-S support. Also thanks to the following veterinarians: Linda Abraham, Carolyn and Andrew Bissett, Darren Fry, Robert Labuc, Kay McIntosh, Victoria Onus, Suzanne Payne, Steve Saunders, Nick West, and Kate Wingate and the many other colleagues who referred patients to this study. References 1. Podell M, Fenner WR. Bromide therapy in refractory canine idiopathic epilepsy. J Vet Intern Med 1993;7: Sachdeo R. Challenging our past paradigm in the management of epilepsy. Neurology 2000;55 (3 Suppl):S1-S4. 3. Booth DM. Anticonvulsant therapy in small animals. Vet Clin N Am Small Anim Pract 1998;28: Podell M. Antiepileptic drug therapy. Clin Tech Small Anim Pract 1998;13: Platt SR, Adams V, Garosi LS et al. Gabapentin as adjunctive therapy for refractory idiopathic epilepsy in dogs. 16th Annual European College of Veterinary Neurologists Symposium, Prague, Knowles K. Idiopathic epilepsy. Clin Tech Small Anim Pract 1998;13: Farnbach GC. Seizures in the dog. Part 1; Basis classification and predilection. J Am Anim Hosp Assoc 1984;24: Fenner WR. Seizures. In: Kornegay JN, editor. Neurological Disorders. Contemporary Issues in Small Animal Practice. Churchill Livingston, New York, 1986;5: Schwartz-Porsche D, Jurgens U. Wirksamkeit von Bromide bei den Therpieresistent epilesein de Hundes. Tierarzt Prax 1991;19: March PA, Podell M, Sams RA. Pharmacokinetics and toxicity of bromide following high-dose oral potassium bromide administration in healthy beagles. J Vet Pharmacol Therap 2002;25: Podell M, Fenner WR, Powers JD. Seizure classification in dogs from a nonreferral-based population. J Am Vet Med Assoc 1995;206: Dewey CW, Guiliano R, Boothe DM et al. Zonisamide therapy for refractory idiopathic epilepsy in dogs. J Am Anim Hosp Assoc 2004;40: Müller PB, Wolfsheimer KL, Toboada J et al. Effects of long-term phenobarbitone treatment on the thyroid and adrenal axis and adrenal function tests in dogs J Vet Intern Med 2000;14: Podell M. Strategies of antiepileptic drug therapy Proceedings of the American College of Veterinary Internal Medicine, Denver, CO 2001: Taylor SM. Seizures. In: Nelson RW, Couto CG, editors. Small Animal Internal Medicine. 3rd edn. Mosby, St Louis, 2003: Eiris J, Novo-Rodriguez MI, Del Rio M et al. The effects on lipid and apolipoprotein serum levels of long-term carbamazepine, valproic acid and phenobarbitone therapy in children with epilepsy. Epilepsy Res 2000;41: Farombi EO, Akinloye O, Akinmoladun CO et al. Hepatic drug metabolizing enzyme induction and serum tricyglycerol elevation in rats treated with chlordiazepoxide, griseofulvin, rifampicin and phenytoin. Clin Chim Acta 1999;289: Goldberg DM, Yu A, Roomi MW et al. Effects of phenobarbitone upon triglycerol metabolism in the guinea pig. Can J Biochem 1981;59: Foster SF, Church DB, Watson ADJ. Effects of phenobarbitone on serum biochemical tests in dogs. Aust Vet J 2000;78: Derkx-Overduin LM. Slow-release phenytoin in canine epilepsy. [Thesis] Faculty of Veterinary Medicine, Utrecht, Netherlands: Krebs-Breuer B. Hepatotoxicity of the anticonvulsant primidone in dogs. Clinical chemical and pathological findings during a long-term study. [Thesis] Fachbereich Veterinarmedizin, Freie Universitat, Berlin,Germany: Ruehlmann D, Podell M, March P. Treatment of partial seizures and seizurelike activity with felbamate in six dogs. J Small Anim Pract 2001;42: Palmer KJ, McTavish D. Felbamate. A review of its pharmacodynamic and pharmacokinetic properties, and therapeutic efficacy in epilepsy. Drugs 1993; 45: Willmore LJ. Clinical pharmacology of new antiepileptic drugs Neurology 2000;11: (3 Suppl) S17-S Loscher W. Basic aspects of epilepsy. Curr Opin Neuro Neurosurg 1993;6: LaRoche SM, Helmers SL. The new antiepileptic drugs: scientific review. J Am Med Assoc 2004; 291: Matar KM, Nicholls PJ, Bawazir SA et al. Effect of vigabatrin and gabapentin on phenytoin pharmacokinetics in the dog. Pharmacol Res :6; Radulovic LL, Turck D, von Hodenberg A et al. Disposition of gabapentin (Neurontin) in mice, rats, dogs and monkeys. Drug Metab Dispos 1995;24: (Accepted for publication 7 February 2005) 608 Australian Veterinary Journal Volume 83, No 10, October 2005