eMedExpert Home > Medications Facts > Topiramate (Topamax)

Topiramate has a singular chemical structure. This agent was synthesized during a research project to discover substances analogous to fructose 1.6-diphosphate inhibitors of the glyconeogenic process. Its structural chain resembles a chemical radical in the acetazolamide molecule, which raised the possibility that topiramate possessed antiepileptic properties.

The first studies demonstrating the efficacy and tolerability of topiramate in the migraine prevention emerged in the late 1990s 12. U.S. Food and Drug Administration (FDA) approved Topamax (topiramate) for the prophylaxis (prevention) of migraine headaches in adults in August 2004.

• Monotherapy or adjunctive therapy for partial onset seizures
• Monotherapy or adjunctive therapy for primary generalized tonic-clonic seizures
• Adjunctive treatment of seizures associated with Lennox-Gastaut syndrome
• Prophylaxis of migraine headache
  

• bipolar disorder 2, 3, 4, 10, 15
• weight loss and obesity 7, 13, 14, 21, 24
• alcohol dependence 8, 27
• binge eating disorder 5, 29
• cocaine dependence 28
• opiate withdrawal 41
• bulimia nervosa 6, 30
• cluster headaches 22, 23
• chronic daily headache 43
• infantile spasms 31, 32, 33
• smoking cessation 25, 34, 35
• post-traumatic stress disorder 20, 36
• neuropathic pain 37, 38
• sleep-related eating disorder (SRED) and nocturnal eating syndrome (NES) 9, 39
• scar therapy 40
• migraine prevention in children 19
• pathologic gambling 42
• painful diabetic neuropathy 44

Alcoholism
The putative efficacy of topiramate in the treatment of alcohol dependence is based on reversing chronic changes induced by alcohol resulting in dopamine-facilitated neurotransmission in the midbrain. Topiramate might antagonise alcohol's rewarding effects associated with abuse liability by inhibiting mesocorticolimbic dopamine release via the contemporaneous facilitation of GABA activity and inhibition of glutamate function.

Studies have shown that topiramate (up to 300 mg per day) is more efficacious than placebo as an adjunct to standardised medication compliance management in treatment of alcohol dependence. Topiramate can reduce consumption and craving in alcohol-dependent patients 8. Double-blind, randomized, controlled study indicated that topiramate also can increase overall well-being and quality of life and lessen dependence severity and its harmful consequences of alcohol-dependent individuals 27.

In the RCT topiramate showed potential as a safe and promising medication for the treatment of cigarette smoking in alcohol-dependent individuals 25.

Binge eating disorder associated with obesity
Topiramate is efficacious and relatively well tolerated in the short-term treatment of binge eating disorder associated with obesity 5. In the study topiramate was associated with a significantly higher rate of reduction in binge frequency, binge day frequency, body mass index, weight, and scores on the Clinical Global Impression severity scale and the Yale-Brown Obsessive Compulsive Scale (modified for binge eating) than placebo.

Bipolar disorder
Topiramate may represent a valuable alternative to existing mood stabilizers, either as an adjunct or as monotherapy in patients with bipolar disorder or schizoaffective disorder. Preliminary open observations suggest that it may have antimanic or anticycling effects in bipolar disorder 19.

Preliminary findings provide support for a modest efficacy of topiramate, especially as monotherapy, in the treatment of acute mania 16.

Results of four double-blind placebo-controlled trials do not support the efficacy of topiramate as monotherapy in acute mania or mixed episodes in adults with bipolar I disorder. Topiramate is not associated with mood destabilization measured as mania exacerbation or treatment-emergent depression 18.

Topiramate as adjunctive treatment appears to have efficacy for the manic and mixed phases of bipolar illness 17.

Topiramate lacks efficacy in the treatment of acute mania. Increasing evidence, based on controlled studies, supports the use of topiramate in bipolar disorders in depressive phase 15.

Results from these trials suggest topiramate may be efficacious in BD subtypes, particularly in rapid-cycling patients and those refractory to conventional treatment.

These preliminary results suggest that adjunctive topiramate may be useful in treating bipolar II disorder.

Weight loss and obesity
The evidence of a strong weight-reducing potential of topiramate is indisputable and clinically significant.

Randomised, double-blind, placebo-controlled study investigated the long-term efficacy and safety of topiramate in obese subjects 24. Topiramate treatment of obese subjects over the course of 1 year resulted in clinically significant weight loss. Improvements were also observed in blood pressure and glucose tolerance.

At 60 weeks, subjects in the placebo group lost 1.7% of their baseline body weight, while subjects in the topiramate 96, 192, and 256 mg/day treatment groups lost 7.0, 9.1, and 9.7%, respectively. Weight loss >/=5% of baseline weight was achieved by 18% of subjects in the placebo arm vs 54, 61, and 67% of subjects receiving topiramate 96, 192, and 256 mg/day, respectively. Weight loss >/=10% was achieved by 6 vs 29, 40, and 44%, respectively. Weight loss was accompanied by significant improvements in blood pressure (systolic/diastolic changes of +0.4/+1.0, -3.1/-1.3, -5.7/-3.4, and -4.6/-2.4 mmHg were observed for placebo, topiramate 96 mg/day, 192 mg/day, and 256 mg/day, respectively, P<0.001) and glucose and insulin. The most common adverse events more frequently observed in topiramate-treated subjects occurred mostly during the titration phase and were related to the central or peripheral nervous system and included paresthesia, difficulty with concentration/attention, depression, difficulty with memory, language problems, nervousness, and psychomotor slowing.

In a study 14 focusing on topiramate-related weight loss, 15 patients who had gained weight after using selective serotonin reuptake inhibitors for anxiety disorder received topiramate, starting at a dose of 50 mg and titrating up to a target daily dose of 100 mg to a maximum dose of 250 mg daily. Subjects' weights were measured at baseline and after 5 and 10 weeks of treatment. Before topiramate treatment, these subjects had gained a mean of 13.0 ± 8.4 kg (28.6 ± 18.5 lb). After the addition of a mean daily topiramate dose of 135.0 ± 44.1 mg for approximately 10 weeks, subjects lost a mean of 4.2 ± 6.0 kg (9.3 ± 13.3 lb).

However, Topamax (topiramate) is not considered a first choice for weight loss due to high rate of side effects, such as cognitive impairment, anxiety, memory loss or difficulty concentrating, which can make it difficult to tolerate the drug.

Neuropathic pain
Antiepileptic drugs are useful in the treatment of neuropathic pain. There are good theoretical explanations how topiramate can alleviate neuropathic pain. Topiramate acts on neuronal transmission in several ways: by modulating voltage-gated sodium ion channels, potentiating gamma-aminobutyric acid inhibition, blocking excitatory glutamate neurotransmission, modulating voltage-gated calcium ion channels, and by inhibiting carbonic anhydrase.

There are good reasons for a trial of topiramate in persons with neuropathic pain where conventional medical treatments have failed. Although not currently licensed for treating pain, topiramate should be considered before invasive methods of pain relief are contemplated 37.

Topiramate treatment may reduce chronic sciatica but causes frequent side effects 38.

In randomized, double-blind trial topiramate reduced pain visual analog score, worst pain intensity and sleep disruption in patients with painful diabetic neuropathy 44.

• Advantages:
• may be effective for patients who have failed to respond to antidepressants or mood stabilizers
• adjunctive topiramate effective for treatment-resistant bipolar-spectrum disorders 10
• potential for weight loss and a reduction in BMI (often, weight loss is highly desired by patients) 11
• one of the few FDA-approved medications for migraine prevention
• good tolerability
• probably works for all seizure types
• may be taken without regard to meals
• advantages over neuroleptic medications in that it carries no risk of tardive dyskinesia
• does not appear to destabilize mood in patients with comorbid bipolar disorder
• minimal interactions with other medications
• pharmacological advantages: low protein binding, high therapeutic index, minimal hepatic metabolism and mainly unchanged renal excretion
• blood pressure lowering effect 25
• Disadvantages:
• risk of developing kidney stones (about 1.5%); an explanation for this risk may lie in the fact that topiramate is a carbonic anhydrase inhibitor 1
• risk of acute myopia and angle-closure glaucoma 1, 3
• can decrease efficacy of oral contraceptives 1
• cognitive side effects 1

The precise mechanisms by which topiramate exerts its anticonvulsant and migraine prophylaxis effects are unknown. However, preclinical studies have revealed four properties that may contribute to topiramate's efficacy for epilepsy and migraine prophylaxis. Topiramate at pharmacologically relevant concentrations:

• blocks voltage-dependent sodium channels
• potentiates the activity of gamma-amino-butyric acid (GABA), an inhibitory neurotransmitter (activate GABA postsynaptic receptors)
• blocks the action of glutamate (excitatory neurotransmitter)
• inhibits the carbonic anhydrase enzyme, particularly isozymes II and IV (weakly inhibits carbonic anhydrase)

The mean plasma elimination half-life is 21 hours 1. Topiramate is excreted from the body within 4-5 days.

Steady state is reached in about 4 days in persons with normal renal function 1.

CNS side effects may be minimized by initial slow titration or small reductions in other medications with sedative effects. These effects ususally diminish over time.

Gradually withdraw therapy to minimize potential of increased seizure frequency.

• Topiramate (Topamax) versus Other Medications

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