Topamax Review Article
Topamax (topiramate) is an anticonvulsant drug for patients with epilepsy who have certain types of seizures. It is a sulfamate - substituted monosaccharide with a molecular formula of C12H21NO8S and a structural formula of
Topamax for Migraine Prevention
Antiepileptic agents such as Topamax have been shown in several studies to be efficacious in migraine prevention. Storey, et al. (2001) conducted a single-center, double-blind, placebo-controlled trial to assess the clinical safety and efficacy of Topamax in the prophylaxis of migraine. After the study period, they concluded that prophylactic therapy with Topamax significantly reduced frequency of migraine episodes among patients. Similar studies by Brandes et al. (2004) and Silberstein et al. (2007) also reported highly desirable outcomes using Topamax prophylactic therapy. Continue reading...
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Mechanism of Action
Topamax acts by reducing electrical conduction on voltage – gated sodium channels in the cerebellum. Like phenytoin, another anticonvulsant, it effectively acts on both the activated and inactivated forms of the channel. Aside from this, Topamax also activates inhibitory potassium channels, potentiates the effects of the inhibitory neurotransmitter GABA, and also inhibits the action of AMPA-kinate subtype of the glutamate receptor.
Several clinical studies have been conducted to demonstrate the effectiveness of Topamax in several types of seizures. In a double – blinded study by Privitera et al., (2003) Topamax was found to be equally effective as valproic acid and carbamazepine in patients with newly diagnosed partial onset and primary generalized epilepsy. Topamax was also found to be an effective and well –tolerated monotherapy in both adults and children with newly diagnosed epilepsy or relapsed epilepsy (Glauser, et al. 2007). Other studies have also indicated the usefulness of Topamax as an adjunctive therapy in patients with refractory partial seizures (Sachdeo et al., 1997). In patients with refractory primary generalized tonic – clonic (PGTC) seizures, Topamax therapy resulted in a greater than 50 percent reduction in PGTC seizure rate (Biton et al. 1999).
In another study by Sachdeo et al., (1999) 98 patients with multiple seizure types associated with Lennox-Gastaut syndrome were treated with Topamax, resulting in significant reduction in drop attacks and major motor seizures, and in lessened overall severity of seizures. This is particularly important as most conventional antiepileptic drugs are usually ineffective against seizures associated with Lennox-Gastaut syndrome.
Epilepsy is a type of chronic brain disorder in which there is abnormal electrical activity in the brain leading to seizures, which are episodes of strange sensations, behavior, and sometimes muscle spasms, altered consciousness, or loss of control over body functions. Neurons in the brain, which are responsible for conducting electrical impulses, fire at an abnormally rapid speed, as many as 500 times a second. Worldwide, epilepsy affects three for every 1000 people, and in some areas up to 40 people for every 1000 is afflicted with the condition. Each year, 40 to 70 new cases for every 100,000 people occur worldwide.
Epilepsy can be due to a variety of causes, which may range from genetic predisposition to certain neurological diseases. There are also many types of seizures, which may vary according to manifestation, severity, and duration. Some people with epilepsy experience seizures only occasionally, while some experience seizures more frequently. Different types of seizures also differ in their management. Although epilepsy is a chronic condition, there is sufficient evidence that up to 80% of patients with epilepsy can still lead normal lives if properly treated. The ultimate goal of epilepsy management is to achieve maximum seizure control with the least side effects. For this reason, several drugs have been made available in the market.
Other Indications: Alcohol Withdrawal, Hyperhidrosis, Neuropathic Pain, Obesity
Topamax has also been found to be effective in treating alcohol dependence. One study has shown that compared to a placebo, Topamax therapy resulted in decreased alcohol craving among dependent individuals and a longer duration of abstinence (Johnson et al., 2003). The mechanism of Topamax in alcohol withdrawal is currently unknown, but it has been determined to be different from the mechanism of other drugs used in alcohol dependence. Topamax, therefore, appears to offer a new approach in assisting alcohol withdrawal.
Topamax may also be used in relieving neuropathic pain due to several etiologies. Zvartau-Hind, et al. (2000) reported six multiple sclerosis (MS) patients suffering from incapacitating trigeminal neuralgia who were successfully treated with Topamax. Another study by Raskin P, et al. (2004) conducted a placebo-controlled trial to assess the efficacy of Topamax in painful diabetic neuropathy, and concluded that Topamax monotherapy resulted in reduced neuropathic pain in diabetics. This conclusion was supported by an open-label extension study which established safety and efficacy in long-term therapy (Donofrio, et al. 2005)
One adverse effect of Topamax therapy, weight loss, has been investigated by studies for potential in the management of obesity. Kirov and Tredget (2005) and Khazaal, et al. (2007) reported that Topamax significantly reduced weight in psychotropic-drug induced weight gain. In another study, Topamax treatment of overweight diabetic patients was associated with reduced body weight and fat, and a significant improvement in glycemic control (Eliasson, et al. 2007).
Adverse effects and Precautions
The most common adverse effects associated with the use of Topamax include impaired concentration and coordination, confusion, dizziness, drowsiness, and paresthesia. Other reported effects are anxiety, mood changes, abdominal pain, weight loss, asthenia, and visual disturbances. In predisposed patients, Topamax may result in renal calculi formation. Thus, in these cases, adequate hydration is recommended. Reduced sweating, which may be accompanied by hyperthermia, has been observed particularly in children. Because of this, it is recommended that children should be monitored closely for these symptoms, especially during warm weather.
Because it is structurally related to the carbonic anhydrase inhibitor class of diuretics, Topamax treatment has been associated to a 23-67% risk of metabolic acidosis which is secondary to a moderate decrease in serum bicarbonate levels. Because of this, US licensed product information for Topamax recommends that baseline and periodic serum bicarbonate levels should be monitored during therapy. Should metabolic acidosis develop, alkali therapy or an adjustment of the dose may be done to correct the problem (Janssen-Ortho Canada, 2004; Garris & Oles, 2005).
Other anti-epileptic drugs have been reported to interact with Topamax, resulting in toxicity. Because of this, plasma monitoring is often advisable when using combination anti-epileptic therapy.
Valproic acid, for instance, when used concomitantly with Topamax resulted in reversible hepatic impairment (Longin, et al. 2002; Bumb, et al. 2003). Drug-induced hyperammonemia and encephalopathy has also been observed (Latour, et al. 2004). There have also been reports of increased carbamazepine toxicity upon combination therapy with Topamax, which was easily resolved upon reduction in the dose of carbamazepine (Mack et al, 2002).
Anti-epileptics which are also hepatic enzyme inducers such as carbamazepine, phenobarbital, and phenytoin have also been observed in pharmacokinetic studies to decrease the plasma concentration of Topamax (Bourgeois, 1996).
Biton, V., Montouris, G. D., Ritter, F., et al., 1999, A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures: Topiramate YTC Study Group
Bourgeois, B. F. D., 1996, Drug interaction profile of topiramate
Brandes, J. L., et al., 2004, Topiramate for migraine prevention: a randomized controlled trial.
Bumb, A., et al., 2003, Adding topiramate to valproate therapy may cause reversible hepatic failure.
Donofrio, P. D., et al., 2005, Safety and effectiveness of topiramate for themanagement of painful diabetic peripheral neuropathy in an open-label extension study.
Eliasson, B., et al., 2007, Weight loss and metabolic effects of topiramate in overweight and obese type 2 diabetic patients: randomized double-blind placebo-controlled trial.
Garris, S. S., and Oles, K. S., 2005, Impact of topiramate on serum bicarbonate concentrations in adults.
Glauser, T. A., et al., 2007, Topiramate monotherapy in newly diagnosedepilepsy in children and adolescents.
Janssen-Ortho Canada, 2004, Important drug safety information: Topamax (topiramate) use is associated with metabolic acidosis.
Johnson, B. A., Ait-Daoud, N., Bowden, C. L., et al., 2003, Oral topiramate for treatment of alcohol dependence: A randomized, controlled trial.
Khazaal, Y., et al., 2007, Long-term topiramate treatment of psychotropic drug-induced weight gain: a retrospective chart review.
Kirov, G., and Tredget, J., 2005, Add-on topiramate reduces weight in overweight patients with affective disorders: a clinical case series.
Latour, P., et al., 2004, Drug induced encephalopathy in six epileptic patients: topiramate? valproate? or both?.
Longin, E., et al., 2002, Topiramate enhances the risk of valproate-associated side effects in three children.
Mack, C. J., et al., 2002, Interaction of topiramate with carbamazepine: two case reports and a review of clinical experience.
Privitera, M. D., Brodie, M. J., Mattson, R. H., et al., 2003, Topiramate, carbamazepine and valproate monotherapy: double-blind comparison in newly diagnosed epilepsy.
Raskin, P., et al., 2004, Topiramate vs placebo in painful diabetic neuropathy: analgesic and metabolic effects.
Sachdeo, R. C., Leroy, R. F., Krauss, G. L., et al., 1997, Tiagabine therapy for complex partial seizures: a dose-frequency study: the Tiagabine Study Group.
Sachdeo, R. C., Glauser, T. A., Ritter, F., et al. 1999, A double-blind, randomized trial of topiramate in Lennox-Gastaut syndrome: Topiramate YL Study Group.
Silberstein, S. D., et al., 2007, Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double-blind, placebo-controlled trial.
Storey, J. R., et al., 2001, Topiramate in migraine prevention: a double-blind, placebo-controlled study.
Sweetman, S. C. ed., 2009, Martindale, The complete drug reference 36th ed, London: Pharmaceutical Press, 1433
Zvartau-Hind, M., et al., 2000, Topiramate relieves refractory trigeminal neuralgia in MS patients.
Topamax Review Article