Topiramate …

K K Jain MD†

Neuropharmacology & Neurotherapeutics

Updated 07.11.2021
Released 07.06.1999
Expires For CME 07.11.2024

Topiramate

Author: K K Jain MD†

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Topiramate

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Introduction

Historical note and terminology

Topiramate is a monosaccharide derivative with a sulfamate functionality. It has multiple putative mechanisms of action. It was developed as an antiepileptic as McN-4853 and showed effectiveness against maximum electroshock in rats with a potency equal to that of phenytoin. Topiramate was commercialized and has been available in the United Kingdom since mid-1995. The United States Food and Drug Administration approved it in 1997.

Pharmacology

Pharmacology. The exact mechanism of action as an antiepileptic is not established, but various explanations are as follows:

	• Topiramate induces an increase of brain GABA, homocarnosine (dipeptide of GABA and histidine), and pyrrolidine (an internal lactam of GABA) in human patients, and this contributes to seizure protection.
	• Topiramate suppresses voltage-sensitive sodium+ channels.
	• Topiramate blocks the kainate/alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid subtype of the glutamate receptor.
	• Topiramate inhibits abnormal firing of the CA3 pyramidal neurons of spontaneously epileptic rats by mainly blocking glutamate receptors in the neurons.
	• The anhydrase-inhibiting effect of topiramate may contribute to its antiepileptic properties.
	• The mechanism of action of preventive effect of topiramate in migraine is largely unknown. Results of a prospective, randomized, placebo-controlled, double-blind study on healthy participants using fMRI suggest that topiramate has a modulating effect on nociceptive processing in thalamo-cortical networks during trigeminal pain, which probably mediates its preventive effect on frequent migraine (16).

Pharmacokinetics. Topiramate has favorable pharmacokinetic characteristics and fewer drug interactions than some traditional antiepileptic drugs. The important points are as follows:

	• Topiramate is well absorbed from the gastrointestinal tract.
	• Topiramate has linear pharmacokinetics (ie, dose-proportional increase of plasma concentration that facilitates titration for "treatment-to-effect" approach).
	• Peak plasma levels are attained in 2 to 3 hours.
	• The drug is negligibly (9% to 17%) bound to plasma proteins.
	• Topiramate is not extensively metabolized when administered alone or in the absence of hepatic enzyme induction.
	• It is eliminated partly by renal excretion in unchanged form and partly by oxidation and hydrolysis.
	• In healthy volunteers, the half-life is about 19 to 23 hours in the absence of enzyme induction, but the time is reduced to 12 to 15 hours when topiramate is coadministered with enzyme-inducing antiepileptic drugs.

Formulations. An extended-release preparation of topiramate, compared with the immediate-release formulation, provides equivalent plasma exposure with an extended absorption profile (34). The extended-release formulation offers a once-daily alternative to twice-daily topiramate, with reduced fluctuations in blood levels of the drug. A study using computer simulations of population pharmacokinetics has shown that dosing irregularities with the once-daily extended-release formulation should pose no greater risk than with twice-daily immediate-release topiramate (03). In the event of a delayed or omitted extended-release dose, topiramate concentrations can be restored by administering the delayed/omitted dose at any time during the next dosing interval.

Pharmacogenetics. Heavy drinkers with alcohol dependence carrying the single nucleotide polymorphism rs2832407 in GRIK1 gene, which encodes the kainate GluK1 receptor subunit, are more likely to respond to treatment with topiramate, resulting in reduction of heavy drinking days (20). This finding will contribute to the personalized management of alcoholism.

Therapeutic drug monitoring. In addition to clinical observations, analysis of plasma concentration of topiramate is of importance for the individual adjustment of the administered dose to the patient. A liquid chromatography mass spectrometry–based validated method can simultaneously determine topiramate and its main metabolites in plasma over the selected analytical range (25). A bioanalytical method for the analysis of topiramate in plasma samples by capillary electrophoresis with capacitively coupled contactless conductivity detection of plasma samples has enabled the identification of 80% of undermedicated patients (18).

Clinical trials

In double-blind, placebo-controlled trials, add-on therapy with topiramate given 400 mg daily to 1000 mg daily reduced the seizure rate by 50% or more in 35% to 52% of adult patients with resistant partial epilepsy (with or without secondarily generalized seizures) compared with 0% to 19% of placebo recipients. A 200 mg daily dosage was less effective. Randomized, double-blind clinical trials are listed in Table 1.

Table 1. Clinical Trials of Topiramate

Indication	Results
Lennox-Gastaut syndrome	Reduction of the number of drop attacks, major motor seizures, and seizure severity (27).
Adjunctive therapy for the treatment of primary generalized tonic-clonic seizures	The median percentage reduction in the rate of all generalized seizures was 42.1% for topiramate patients and 0.9% for placebo patients (01).
Adjunctive therapy for uncontrolled partial-onset seizures with or without secondarily generalized seizures in children	Topiramate-treated patients had a greater median percent reduction from baseline in average monthly partial-onset seizure rate than placebo-treated patients (33.1% vs. 10.5%) and a greater proportion of treatment responders (39% vs. 20%) (10).
Refractory partial-onset seizures in children, adolescents, and young adults	Topiramate was an overall effective and safe add-on drug both in cryptogenic and symptomatic childhood refractory partial seizures (07).
Adult patients with refractory partial epilepsy	Topiramate 300 mg/d was shown to be effective and well tolerated as treatment for refractory partial epilepsy in adults (36).
Randomized, concentration-controlled trial of topiramate in refractory focal epilepsy	Optimal treatment response is most likely at plasma concentrations higher than 6 micromol/L but no further increase in efficacy at concentrations above 31 micromol/L (06).
A 26-week, randomized, double-blind, placebo-controlled study of topiramate for prophylaxis of migraine	Topiramate was effective as a preventive therapy for patients with migraine (30).
A 16-week, randomized, double-blind, placebo-controlled trial of topiramate in chronic migraine	Topiramate at daily doses of 100 mg resulted in significant improvements compared with placebo in mean monthly migraine headache days (29).
A 26-week, multicenter, randomized, double-blind, parallel-group study of topiramate versus amitriptyline in migraine prevention	Topiramate was at least as effective as amitriptyline in terms of reducing the rate of mean monthly migraine episodes (08).
In a prospective study, neurosurgical patients with epilepsy were divided into monotherapy and add-on therapy groups, and both groups received topiramate via the dose-escalation method.	Dose-escalated topiramate monotherapy and add-on therapy demonstrate good efficacy in seizure control with fewer adverse events (22).

Indications

• Partial onset seizures in adults
• Prophylaxis of migraine

Off-label uses

	• Topiramate treatment may have antimanic effect in some patients with bipolar disorder.
	• Topiramate has been used for the control of Tourette syndrome.
	• Topiramate is useful for controlling essential tremor.
	• Topiramate is effective for the treatment of alcohol dependence, but side effects may limit widespread use.
	• Topiramate has been used successfully in relieving the pain of various neuropathies, including painful diabetic peripheral neuropathy.
	• Topiramate seems to be a relatively safe and effective agent in the treatment of chronic low back pain.
	• As add-on therapy in Dravet syndrome.
	• Cerebellar ataxia and tremor in multiple sclerosis.
	• A prospective study showed that topiramate followed by low-dose adrenocorticotropic hormone was effective for the treatment of infantile spasms (37).
	• Hypokalemic periodic paralysis (12).
	• As an adjunctive agent for the treatment of adult refractory status epilepticus (31).
	• Results of a double-blind randomized controlled trial showed that topiramate was effective in improving reexperiencing and avoidance/numbing symptom clusters in civilian patients with posttraumatic stress disorder (35).
	• Topiramate has been used for treatment-refractory schizophrenia with small to moderate benefits on psychopathology (14).
	• A meta-analysis of various studies has shown that topiramate can prevent or reduce weight gain associated with atypical antipsychotic drugs (24).
	• Cocaine addiction (19).
	• Treatment for adult obesity (15).
	• A systematic review of randomized clinical trials did not provide sufficient evidence to support topiramate for the treatment of patients with juvenile myoclonic epilepsy (23).
	• There is consistent evidence from randomized clinical trials to support the efficacy of topiramate in treating essential tremor, but a significant proportion of participants withdrew due to its adverse effects (04).
	• A systematic review of studies about topiramate for the treatment of generalized convulsive status epilepticus in adults found no statistically significant difference when comparing patients receiving topiramate as the last drug and achieving status epilepticus control with those receiving topiramate as the last drug but without termination of status epilepticus (02).
	• A metanalysis is reviewing all studies including clinical trials of the use of topiramate to reduce seizures in hypoxic encephalopathy (05).
	• A randomized controlled trial demonstrated efficacy of topiramate for treatment of sleep-related eating disorder (33).

Adverse effects

A systematic review of antiepileptic drugs using the indication of epilepsy alone is not enough for the evaluation of adverse events of any antiepileptic drug; however, the addition of trials for nonepilepsy indications can improve the assessment (09).

Renal stones. One and a half percent of the patients in clinical trials with topiramate were reported to develop renal stones, but nonambulatory and neurologically impaired individuals in a long-term care facility appeared to be at higher risk of developing kidney stones with topiramate (13). The mechanism is that topiramate, like other carbonic anhydrase inhibitors, reduces urinary citrate excretion and increases urinary pH. Increased fluid intake, by increasing urinary output, reduces the concentration of substances involved in stone formation. A nationwide population-based cohort study in Taiwan, conducted between 1997 and 2008, concluded that the incidence of renal stones in patients treated with topiramate was no higher than in age- and gender-matched controls (28).

Oligohidrosis and hyperthermia. These have been reported as adverse effects associated with use of topiramate. Sweat production is decreased, as detected by a pilocarpine iontophoresis sweat test. The effect seems to be more significant in children than in adults.

Paresthesias. These are associated with the use of carbonic anhydrase inhibitors and can be controlled by supplemental potassium.

Drowsiness, psychomotor slowing, and cognitive impairment. These effects are dose-related and occur more frequently at higher doses. It is difficult to differentiate them from similar effects known to occur with concomitant antiepileptic drugs. Mental slowing and word-finding difficulties can be significantly reduced by using 25 mg dose increments fortnightly as opposed to 100 mg weekly. Topiramate at a dose of 100 mg is effective in the treatment of migraine, but electrophysiological studies have shown that cognitive functions are adversely affected (26).

Topiramate is known to cause language impairment. Neuropsychological studies and fMRI findings suggest a mechanism by which topiramate impairs cognitive processing in language network areas (34).

Visual adverse effects. The following adverse effects have been documented with topiramate therapy: abnormal vision, acute secondary angle-closure glaucoma, acute myopia, and suprachoroidal effusions. All findings are reversible if recognized early and if the drug is discontinued.

References

01: Biton V, Montouris GD, Ritter F, et al. A randomized, placebo-controlled study of topiramate in primary generalized tonic-clonic seizures. Topiramate YTC Study Group. Neurology 1999;52:1330-7. PMID 10227614
02: Brigo F, Bragazzi NL, Igwe SC, Nardone R, Trinka E. Topiramate in the treatment of generalized convulsive status epilepticus in adults: a systematic review with individual patient data analysis. Drugs 2017;77(1):67-74. PMID 28004305
03: Brittain ST, Wheless JW. Pharmacokinetic simulations of topiramate plasma concentrations following dosing irregularities with extended-release vs. immediate-release formulations. Epilepsy Behav 2015;52(Pt A):31-6. PMID 26409125
04: Chang KH, Wang SH, Chi CC. Efficacy and safety of topiramate for essential tremor: a meta-analysis of randomized controlled trials. Medicine (Baltimore) 2015;94(43):e1809. PMID 26512577
05: Chen G, Chen Y, Xie Y, et al. Topiramate for hypoxic ischemic encephalopathy: A systematic review protocol. Medicine (Baltimore) 2020;99(17):e18704. PMID 32332593
06: Christensen J, Andreasen F, Poulsen JH, Dam M. Randomized, concentration-controlled trial of topiramate in refractory focal epilepsy. Neurology 2003;61(9):1210-8. PMID 14610122
07: Coppola G, Caliendo G, Terracciano MM, et al. Topiramate in refractory partial-onset seizures in children, adolescents and young adults: a multicentric open trial. Epilepsy Res 2001;43(3):255-60. PMID 11248537
08: Dodick DW, Freitag F, Banks J, et al. Topiramate versus amitriptyline in migraine prevention: a 26-week, multicenter, randomized, double-blind, double-dummy, parallel-group noninferiority trial in adult migraineurs. Clin Ther 2009;31(3):542-59. PMID 19393844
09: Donegan S, Dixon P, Hemming K, Tudur-Smith C, Marson A. A systematic review of placebo-controlled trials of topiramate: how useful is a multiple-indications review for evaluating the adverse events of an antiepileptic drug? Epilepsia 2015;56(12):1910-20. PMID 26662191
10: Elterman RD, Glauser TA, Wyllie E, et al. A double-blind, randomized trial of topiramate as adjunctive therapy for partial-onset seizures in children. Topiramate YP Study Group. Neurology 1999;52:1338-44. PMID 10227615
11: Fechner A, Hubert K, Jahnke K, et al. Treatment of refractory and superrefractory status epilepticus with topiramate: a cohort study of 106 patients and a review of the literature. Epilepsia 2019;60(12):2448-58.** PMID 31713232
12: Fiore DM, Strober JB. Treatment of hypokalemic periodic paralysis with topiramate. Muscle Nerve 2011;43(1):127-9. PMID 21171065
13: Goyal M, Grossberg RI, O'Riordan MA, Davis ID. Urolithiasis with topiramate in nonambulatory children and young adults. Pediatr Neurol 2009;40(4):289-94. PMID 19302942
14: Hahn MK, Cohn T, Teo C, et al. Topiramate in schizophrenia: a review of effects on psychopathology and metabolic parameters. Clin Schizophr Relat Psychoses 2013;6(4):186-96. PMID 23302448
15: Harshman H, Kovach F. Clinical inquiries: is immediate-release topiramate an effective treatment for adult obesity? J Fam Pract 2014;63(12):745-6. PMID 25486315
16: Hebestreit JM, May A. Topiramate modulates trigeminal pain processing in thalamo-cortical networks in humans after single dose administration. PLoS One 2017;12(10):e0184406.** PMID 28991914
17: Hernandez-Diaz S. Evidence accumulates on the association between topiramate use early in pregnancy and the risk of oral clefts. Pharmacoepidemiol Drug Saf 2014;23(10):1026-8. PMID 25131848
18: Ishikawa AA, da Silva RM, Santos MSF, et al. Determination of topiramate by capillary electrophoresis with capacitively-coupled contactless conductivity detection: a powerful tool for therapeutic monitoring in epileptic patients. Electrophoresis 2018;39(20):2598-2604.** PMID 29577353
19: Johnson BA, Ait-Daoud N, Wang XQ, et al. Topiramate for the treatment of cocaine addiction: a randomized clinical trial. JAMA Psychiatry 2013;70(12):1338-46. PMID 24132249
20: Kranzler HR, Covault J, Feinn R, et al. Topiramate treatment for heavy drinkers: moderation by a GRIK1 polymorphism. Am J Psychiatry 2014;171(4):445-52. PMID 24525690
21: Le K, Yu D, Wang J, Ali AI, Guo Y. Is topiramate effective for migraine prevention in patients less than 18 years of age? A meta-analysis of randomized controlled trials. J Headache Pain 2017;18(1):69. PMID 28721545
22: Liu YT, Chen GT, Huang YC, et al. Effectiveness of dose-escalated topiramate monotherapy and add-on therapy in neurosurgery-related epilepsy: a prospective study. Medicine (Baltimore) 2020;99(52):e23771. PMID 33350762
23: Liu J, Wang LN, Wang YP. Topiramate for juvenile myoclonic epilepsy. Cochrane Database Syst Rev 2019;1:CD010008. PMID 30687937
24: Mahmood S, Booker I, Huang J, Coleman CI. Effect of topiramate on weight gain in patients receiving atypical antipsychotic agents. J Clin Psychopharmacol 2013;33(1):90-4. PMID 23277264
25: Milosheska D, Roškar R. A novel LC-MS/MS method for the simultaneous quantification of topiramate and its main metabolites in human plasma. J Pharm Biomed Anal 2017;138:180-8. PMID 28214451
26: Öztürk B, Övünç Özön A, Karadaş Ö. Evaluation of cognitive functions in migraineurs treated with topiramate. J Clin Neurosci 2019;59:89-92. PMID 30455137
27: Sachdeo RC, Glauser TA, Ritter F, et al. A double-blind, randomized trial of topiramate in Lennox-Gastaut syndrome. Topiramate YL Study Group. Neurology 1999;52:1882-7. PMID 10371538
28: Shen AL, Lin HL, Tseng YF, Lin HC, Hsu CY, Chou CY. Topiramate may not increase risk of urolithiasis: a nationwide population-based cohort study. Seizure 2015;29:86-9. PMID 26076848
29: Silberstein SD, Lipton RB, Dodick DW, et al. Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double-blind, placebo-controlled trial. Headache 2007;47(2):170-80. PMID 17300356
30: Silberstein SD, Neto W, Schmitt J, Jacobs D; MIGR-001 Study Group. Topiramate in migraine prevention: results of a large controlled trial. Arch Neurol 2004;61(4):490-5. PMID 15096395
31: Synowiec AS, Yandora KA, Yenugadhati V, Valeriano JP, Schramke CJ, Kelly KM. The efficacy of topiramate in adult refractory status epilepticus: experience of a tertiary care center. Epilepsy Res 2012;98(2-3):232-7. PMID 22000869
32: Westin AA, Nakken KO, Johannessen SI, Reimers A, Lillestolen KM, Brodtkorb E. Serum concentration/dose ratio of topiramate during pregnancy. Epilepsia 2009;50(3):480-5. PMID 19178558
33: Winkelman JW, Wipper B, Purks J, Mei L, Schoerning L. Topiramate reduces nocturnal eating in sleep-related eating disorder. Sleep 2020;43(9):zsaa060. PMID 32227216
34: Yasuda CL, Centeno M, Vollmar C, et al. The effect of topiramate on cognitive fMRI. Epilepsy Res 2013;105(1-2):250-5. PMID 23333471
35: Yeh MS, Mari JJ, Costa MC, Andreoli SB, Bressan RA, Mello MF. A double-blind randomized controlled trial to study the efficacy of topiramate in a civilian sample of PTSD. CNS Neurosci Ther 2011;17(5):305-10. PMID 21554564
36: Yen DJ, Yu HY, Guo YC, et al. A double-blind, placebo-controlled study of topiramate in adult patients with refractory partial epilepsy. Epilepsia 2000;41(9):1162-6. PMID 10999555
37: Zhu X, Chen O, Zhang D, et al. A prospective study on the treatment of infantile spasms with first-line topiramate followed by low-dose ACTH. Epilepsy Res 2011;93(2-3):149-54. PMID 21205578

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Topiramate …

Topiramate

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Clinical Trials of Topiramate

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview.
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Questions or Comment?

Also in This Category

Neurogenetics and genetic and genomic testing

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Topiramate

Introduction

Historical note and terminology

Pharmacology

Clinical trials

Table 1. Clinical Trials of Topiramate

Indications

Off-label uses

Contraindications

Goals and duration of treatment

Dosing

Special considerations

Interactions

Adverse effects

References

Contributors

Author

This is an article preview. Start a Free Account to access the full version.

Questions or Comment?

Also in This Category

Neurogenetics and genetic and genomic testing

Acute traumatic spinal cord injury

Tumors of the skull base

Photosensitive occipital lobe epilepsy

Toxic and nutritional deficiency optic neuropathies

Third nerve palsy

Nystagmus

Intermittent explosive disorder

This is an article preview.
Start a Free Account
to access the full version.