ADDITIONAL

DRUGS

Canine epilepsy is a challenging clinical problem and once treatment is started it is usually required lifelong. Treatment selection should always be based on a careful comparison of the individual risk-benefit ratio for the different treatment options. Proven efficacy, tolerability and safety are the main criteria for selection of any antiepileptic therapy. Standard therapy includes phenobarbital, imepitoin and bromide and there is much clinical evidence for their use.  Both phenobarbital and imepitoin are the only first line licensed veterinary drug for treating epilepsy. Bromide is licenced in dogs for treatment of refractory dog as an adjunct to Phenobarbital.  The advantage of a licensed canine product is that the pharmacodynamics of the veterinary formulation will be known in dogs. Generic human preparations of antiepileptic medication may have quite different properties in dogs than in man.

Treatment

Treatment options for epilepsy in man have improved dramatically since the early 1990s with the introduction of ten new generation antiepileptic drugs (AEDs) (felbamate, gabapentin, lamotrigine, levetiracetam, oxcarbazepine, tiagabine, topiramate, vigabatrin, zonisamide). In human medicine, a first line drug for patients with newly diagnosed epilepsy must demonstrate satisfactory efficacy as a monotherapy and few of the new anti-epileptics have achieved this. New generation AEDs are likely to become more important in the management of human epilepsy as experience with their use is gained (Tomson, 2004).

Management & research

To date published studies in dogs have looked primarily at the efficacy and pharmacokinetics of Phenobarbital, imepitoin and potassium bromide and most epileptic dogs are managed effectively with these “standard” antiepileptic drugs. However, approximately one-third are refractory to appropriate doses of these drugs and further increases in the dosage, in an effort to improve seizure control, can lead to unacceptable side-effects. Clinical trials have also been published investigating the use of felbamate for partial seizures, per rectum diazepam, zonisamide, pregabalin and primidone. Five human drugs that have been used as adjunctive antiepileptic medications in dogs are felbamate, gabapentin, zonisamide, levetiracetam and pregabalin.

 

Pregabalin is a new GABA analogue, similar to gabapentin. Its actions occur through similar mechanisms to gabapentin but it has a higher oral bioavailability and longer half life than gabapentin in people.

 

A study published in JAVMA (Dewey and others, 2009) investigated the efficacy of pregabalin as an adjunctive treatment for epilepsy in 11 dogs already receiving phenobarbital and/ or bromide. Nine of these dogs were suffering cluster seizures despite current regime. The dogs were given pregabalin at 3-4 mg/kg PO TID for 3 months. Two dogs had to be withdrawn from the study due to perceived lack of efficacy and side effects (and were both subsequently euthanased due to uncontrollable seizures). In the 9 dogs that completed the study seizure frequency reduced significantly. The most notably adverse events were sedation and ataxia which occurred in 10/11 dogs. Mild increases in liver enzymes were seen in 6 dogs.

 

This study suggests that pregabalin may be a useful adjunctive therapy in the management of refractory epilepsy in dogs, particularly in the presence of cluster seizures. However, as with many human drugs cost may be a significant barrier to use of this drug in dogs.

 

A study by clinicians at the Animal Health Trust in Newmarket looked at the efficacy of gabapentin as an adjunctive therapy for the management of refractory idiopathic epilepsy in dogs. Five of 11 dogs with refractory idiopathic epilepsy showed a significant reduction in seizure frequency when treated with gabapentin. However, many dogs still had cluster seizure activity on multiple days. Gabapentin was well tolerated - five dogs exhibited mild side effects (ataxia and sedation). This small study indicates that gabapentin may reduce seizure frequency in some dogs with refractory idiopathic epilepsy. A larger study is warranted to further evaluate the potential benefits of gabapentin in epileptic dogs. Like many human drugs gabapentin will be an expensive treatment for dogs.

 

The use of felbamate has been documented in 6 dogs which all showed an improved seizure frequency after a median duration of therapy of 9 months; potential side-effects in dogs include haematological abnormalities, keratoconjunctivitis sicca and hepatotoxity (as reported in man). Although sedation is not seen with this drug, excitability has been reported at high doses. The cost of treatment with felbamate will also be high.

 

In a study using zonisamide twice daily, in 12 dogs with refractory idiopathic epilepsy, 58% of dogs responded favourably, experiencing a mean reduction in seizures of 81.3%. Five of the twelve (42%) dogs actually had an increased seizure frequency and 50% of the dogs exhibited side-effects which included sedation, ataxia and vomiting. Zonisamide is not licensed for use in the UK.

 

The Royal Veterinary College, in association with the Animal Health Trust, has recently run completed a clinical trial to test the efficacy of Levetiracetam – the most well tolerated anti-epileptic drug in man, (with adverse reactions equivalent to placebo). In man this is a highly effective adjunctive therapy to control seizures refractory to standard treatment. The results of this trial suggest that levetiracetam is also well tolerated in dogs. Although the dogs in the trial were refractory to phenobarbital and bromide treatment levetiracetam produced a reduction in seizure frequency in around half the dogs. However, after around 4-8 months of treatment, seizure frequency increased again in many of these dogs.

 

Phenytoin has little place in the management of canine epilepsy due its rapid metabolism in dogs. A slow release formulation is now available but no trials have been published on slow release phenytoin and the presently available form should not be used with phenobarbital and has erratic gastrointestinal bioavailability It is essential that the use of any new treatment is properly documented to identify potential benefits and adverse effects. The anecdotal reports of success with any treatment must be interpreted with great caution. Benefit to the whole canine population can only be achieved by an evidence-based approach - so that the most efficacious treatments can be identified and made available to all; whilst time is not wasted repeating the mistakes of others with inefficacious treatment. In addition to the information on efficacy, safety and tolerance one of the main advantages of licensed (over non-licensed) veterinary products is the monitoring of suspected reactions to licensed products by an independent body. This monitoring is an ongoing process with an obligation on license holders to track, investigate and record reactions. This makes it possible to find out whether any suspected reaction has been reported for a particular product.

There are significant risks in the direct translation of results from human medicine to the veterinary field. It is important to study possible therapies in the species in which they are to be used. Contrary to the situation in humans (where gabapentin is excreted unchanged by the kidneys), gabapentin is metabolised by the liver in dogs and this puts this species at risk of hepatotoxicity (although this has not yet been documented). This risk may be increased when gabapentin is administered with phenobarbital.

 

There is a clear need for another antiepileptic drug for use in dogs with idiopathic epilepsy which are refractory to the combination of phenobarbital and bromide. It should be remembered that in human patients conventional treatments are always explored fully, and only if epilepsy is refractory to these treatments are other possibilities explored.

References:

Dewey CW, Cerda-Gonzalez S, Levine JM, Badgley BL, Ducoté JM, Silver GM, Cooper JJ, Packer RA, Lavely JA (2009) Pregabalin as an adjunct to phenobarbital, potassium bromide, or a combination of phenobarbital and potassium bromide for treatment of dogs with suspected idiopathic epilepsy. JAVMA 235(12):1442-9. - PubMed -

 

Jambroszyk M, Tipold A, Potschka H (2011) Add-on treatment with verapamil inpharmacoresistant canine epilepsy. Epilepsia. 52(2):284-91. doi: 10.1111/j.1528-1167.2010.02886.x. Epub 2011 Jan 10. - PubMed -

 

Mathie RT, Baitson ES, Hansen L, Elliott MF, Hoare J (2010) Homeopathic prescribing for chronic conditions in feline and canine veterinary practice. Homeopathy. 99(4):243-8. Review. - PubMed -

 

Matthews H, Granger N, Wood J, Skelly B (2011) Effects of essential fatty acid supplementation in dogs with idiopathic epilepsy: A clinical trial. Vet J. 2011 Jun 2. [Epub ahead of print] – PubMed -

 

Moore SA, Muñana KR, Papich MG, Nettifee-Osborne JA (2011) The pharmacokinetics of levetiracetam in healthy dogs concurrently receiving phenobarbital. J Vet Pharmacol Ther. 34(1):31-4. doi: 10.1111/j.1365-2885.2010.01188.x.- PubMed -

 

Schneider BM, Dodman NH, Faissler D, Ogata N (2009) Clinical use of an herbal-derived compound (Huperzine A) to treat putative complex partial seizures in a dog. Epilepsy Behav. 15(4):529-34. Epub 2009 Jul 17. – PubMed -

 

Scorza FA, Cavalheiro EA, Arida RM, Terra VC, Scorza CA, Ribeiro MO, Cysneiros RM (2009) Positive impact of omega-3 fatty acid supplementation in a dog with drug-resistant epilepsy: a case study. Epilepsy Behav. 15(4):527-8. Epub 2009 Jun 21. – PubMed -

 

Spinella M (2001) Herbal Medicines and Epilepsy: The Potential for Benefit and Adverse Effects. Epilepsy Behav 2 (6), 524-532 - PubMed -

 

Tomson T J (2004) Drug selection for the newly diagnosed patient: When is a new generation antiepileptic drug indicated? Neurol 251 (9), 1043-1049 - PubMed -

 

 

 

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