Topiramate is used alone or with other medications to treat certain types of seizures including primary generalized tonic-clonic seizures (formerly known as a grand mal seizure; seizure that involves the entire body) and partial onset seizures (seizures that involve only one part of the brain). It is also used with other medications to control seizures in people who have Lennox-Gastaut syndrome (a disorder that causes seizures and developmental delays). Topiramate is also used to prevent migraine headaches but not to relieve the pain of migraine headaches when they occur in adults and children 12 years of age and older. Topiramate is in a class of medications called anticonvulsants. It works by decreasing abnormal excitement in the brain. Although appropriate studies on the relationship of age to the effects of which have not been performed in the geriatric population, geriatric-specific problems are not expected to limit the usefulness of topiramate in the elderly. However, elderly patients are more likely to have age-related kidney problems, which may require caution and an adjustment in the dose for patients receiving this medicine.

Topiramate in the prevention and treatment of migraine

Migraine is the second most common form of headache after episodic tension-type headache. Epidemiological studies have documented its high prevalence and high socioeconomic impacts. It is ranked by the World Health Organization as number 19 among all diseases worldwide causing disability. In general, a timely start of preventive treatment has to be considered in patients suffering from migraine with high impact on daily activities and overall functioning. Many different substances were tested in regard to their prophylactic effects on migraine. Topiramate is a sulfamate-substituted monosaccharide, related to fructose. It is rapidly absorbed (peak plasma concentrations about 2 hours after intake) with a high bioavailability (81% to 95%). The major fraction of topiramate is eliminated primarily as unchanged drug. It shows linear steady-state pharmacokinetics, and its elimination half-life in monotherapy ranged from 19 to 25 hours in healthy volunteers after single-dose oral administration.  Topiramate blocks voltage-dependent sodium and calcium channels. It also inhibits the excitatory glutamate pathway while enhancing the inhibitory effect of GABA.[1]

The focus will be directed on recent randomized, controlled, clinical trials on the efficacy and safety of topiramate in prophylactic treatment of migraine in general and treatment of chronic migraine in particular. There is sufficient scientific evidence that topiramate is effective in reducing migraine frequency at a dose of 100 mg/day in patients suffering from episodic migraine with or without aura. Topiramate 100 mg/day also appears to be effective in the treatment of CM. A lower dose of 50 mg/day may also be effective. General treatment effects appear to be independent from medication overuse in CM, and thus it may not be necessary to withdraw patients from medication overuse prior to attempting treatment with topiramate. Data on treatment periods longer than 14 months are still unavailable, but the trials performed give no reason to raise concern about efficacy or safety in long-term treatment. Topiramate is generally well tolerated with moderate side effects in migraine patients. Common side effects were paresthesias, fatigue, nausea, anorexia and weight loss within the first 8 weeks of treatment. Treatment in pediatric migraine (age 6 to 17 years) was proven safe and effective. Assessment of safety in pregnancy requires further investigations and cannot be recommended at this time.

Topiramate: Safety and Efficacy

Headache is a common disorder, with an estimated prevalence of 5 to 12% based on data obtained from an international survey conducted in five countries. Migraine headache occurs in 9% of the general population. From both a clinical and economic perspective, data also support the need to prevent the progression of episodic migraine to chronic migraine. Interventions can be taken to decrease the risk for progression of migraine from episodic to chronic. Topiramate was originally developed and marketed for epilepsy. It is proposed that epilepsy and migraine share some of the same pathophysiological mechanisms including abnormal function of voltage-gated sodium and calcium channels, reduced GABA- mediated inhibition, and increased glutamate-mediated excitation. The efficacy of topiramate as an antiepileptic drug (AED) was proven in controlled trials in the United States and Europe. Since that time, various trials have proven the efficacy and safety of topiramate in migraine prevention and treatment. It is approved for prophylactic treatment of migraine by the United States Food and Drug Administration (FDA). The exact mechanism of topiramate is unknown, but several activities are theorized to contribute to its efficacy for migraine prophylaxis. Migraine and epilepsy are thought to share various pathophysiologic properties.[2]

Cost-effectiveness of medication plays an important role in establishing its use in clinical practice for many patients. A study was conducted to examine the cost-effectiveness of topiramate in migraine prevention. Since migraine often affects young individuals, the economic burden to employers, health systems, and society can be significant. The investigators used a decision-analytical model to simulate model outcomes for patients taking topiramate over a specific duration. Depression, obesity, anxiety, stroke, epilepsy, sleep disorders, ulcer disease, asthma and other pain disorders are commonly associated comorbidities in patients with migraine.Migraine headache is a prevalent, disabling condition worldwide. In 2004, the number of migraine suffers worldwide was reported to be 324.1 million people. Clinical evidence indicates that topiramate is an effective agent in the prevention of migraine headache in patients with headaches that affect quality of life or who are intolerant to rescue medications. It has a number of clinically significant side effects, however few patients discontinue therapy as a result. It has gained popularity over other agents in the prophylaxis and treatment of migraine headache. Relative to other agents, side effects are bothersome, but not disabling.

Topiramate for treatment of psychiatric disorders

The use of mood stabilizing antiepileptic drugs has increasingly been explored for the treatment of different psychiatric conditions. Topiramate is a novel neurotherapeutic agent approved in more than 75 countries for adjunctive treatment for refractory partial-onset seizures or primary generalised tonic-clonic seizure in adults and children over 2 years of age and migraine prophylaxis in USA. Several mechanisms of action of it support the hypothesis for its putative actions in bipolar affective disorders, unipolar depression, schizophrenia, posttraumatic stress disorder, disordered eating behaviour. This article reviews the pharmacology of it and describes adverse events and the outcomes observed in published and unpublished studies. Particular interest is focused on topiramate related weight loss and its clinical implications. The use of topiramate in bipolar spectrum disorders is based on the putative shared biological mechanism between epilepsy and bipolar disorders suggested by the amygdala-kindled seizures in animal models and the high rate of co-morbid psychiatric conditions in epilepsy. However, there is inadequacy of current treatment strategies. The efficacy of lithium, valproate, and carbamazapine in prophylaxis of bipolar spectrum disorders is rather modest.[3]

The role of topiramate in the treatment of rapid cycling bipolar disorders, and as adjunctive treatment in refractory bipolar disorder in adults and children, is limited by the open label nature of the published studies: lack of randomisation and blindness, heterogeneous patient, population resistant to conventional treatment regimes, incomplete information on current or past treatment for illness, concomitant medications with possibly inflating side effects profile and therapeutic effect, self-reported weight and side effects, qualitative assessment of response to treatment, various settings and variegated level of symptoms, co-morbid psychiatric and medical conditions.

References

[1]Naegel S, Obermann M. Topiramate in the prevention and treatment of migraine: efficacy, safety and patient preference. Neuropsychiatr Dis Treat. 2010 Feb 3;6:17-28. doi: 10.2147/ndt.s6459. PMID: 20169042; PMCID: PMC2951059.

[2]Minton GC, Miller AD, Bookstaver PB, Love BL. Topiramate: safety and efficacy of its use in the prevention and treatment of migraine. J Cent Nerv Syst Dis. 2011 Jun 23;3:155-68. doi: 10.4137/JCNSD.S4365. PMID: 23861645; PMCID: PMC3663617.

[3Arnone D. Review of the use of Topiramate for treatment of psychiatric disorders. Ann Gen Psychiatry. 2005 Feb 16;4(1):5. doi: 10.1186/1744-859X-4-5. PMID: 15845141; PMCID: PMC1088011.