Marc Kamin MD
Director, Clinical Research. Ortho-McNeil Pharmaceutical, Raritan, New Jersey
For many agents effective against seizures, the term anticonvulsant or antiepileptic drug (AED) does not reflect the full scope of their potential therapeutic effects in paroxysmal and other neuropsychiatric disorders. Beginning with the initial use of carbamazepine in trigeminal neuralgia to the now routine use of valproate in bipolar disorder and migraine prophylaxis and the more recent use of gabapentin in managing various pain syndromes, AEDs are proving to be of benefit in many disorders characterized by neuronal hyperexcitability centrally and peripherally. Thus, the broader label neuronal stabilizing agent may be a more accurate depiction of their therapeutic activity. Topiramate appears to be one of the newer AEDs to join the ranks of neuronal stabilizing agents with potential usefulness beyond antiseizure effects.
Topiramate is a structurally novel AED used in the treatment of partial-onset seizures and primary generalized tonic-clonic seizures. Electrophysiologic and biochemical studies have identified various mechanisms of action of topiramate, including sodium channel blockade, inhibition of kainate-α-amino-3-hydroxy-5-methyl-4-isoxazole priopionate (AMPA) glutamate receptors, and potentiation of γ-aminobutyric acid (GABA)-related neuroinhibition at GABAA receptors (1). In addition, topiramate is a weak carbonic anhydrase inhibitor (2), and it may have an inhibitory effect on certain calcium channels (3). Preliminary data suggest that, in addition to its use in epilepsy, topiramate may have therapeutic effects in various chronic pain syndromes, migraine and cluster headache prophylaxis, tremor, and certain psychiatric disorders.
DIABETIC NEUROPATHY AND OTHER PAIN SYNDROMES
Peripheral neuropathy is common in patients with diabetes. Altered nerve conduction and axonal structural alterations as a result of long-standing disease can produce acute, disabling pain in the legs and feet that is often resistant to treatment with nonsteroidal antiinflammatory drugs and opioids. Agents that block sodium channels or potentiate GABAergic inhibition may also be able to ameliorate neuropathic pain.
Animal studies suggest an effect of topiramate on neuropathic pain. In a spinal nerve ligation model (4), rats received 3, 10, or 30 mg/kg doses of topiramate (5). Topiramate exhibited a long-lasting dose-dependent antiallodynic effect that peaked at 1 to 2 hours and was maintained with long-term treatment. These experimental observations are supported by findings from open-label and doubleblind clinical studies. In a pilot study of eight patients with painful diabetic neuropathy, topiramate was added to baseline therapy of gabapentin, opioids, benzodiazepines, and/or tricyclic antidepressants (6). Topiramate treatment for ≤6 months at doses of 50 to 600 mg/day (mean, 258 mg/day) resulted in decreased pain intensity at the final study visit (p < .005). Topiramate was generally well tolerated and provided pain relief sufficient to discontinue concomitant gabapentin and benzodiazepine in all patients.
A subsequent double-blind, placebo-controlled study was conducted in 27 diabetic patients whose pain had persisted for >6 months (7). Baseline pain scores were recorded using the 45-point Short-Form McGill Pain Questionnaire (SF-MPQ) and the 100-mm visual analog scale of the SF-MPQ (Table 81.1). Topiramate was added to stable doses of existing therapy (serotonin reuptake inhibitors, tricyclic antidepressants, clonazepam) in 18 patients and was titrated over 9 weeks to the target dose of 400 mg/day. After 4 weeks of maintenance treatment, pain scores were again recorded. Patients on topiramate showed significant pain reduction in both SF-MPQ (p < .05) and visual analog scale
scores (p < .01), whereas patients receiving placebo had no pain reduction. Topiramate was generally well tolerated; four topiramate-treated patients and one placebo recipient withdrew because of side effects. The most common adverse events in patients receiving topiramate were asthenia, confusion, and weight loss. Average weight loss at the final visit was 9 pounds for 14 topiramate-treated patients versus 1 pound for eight placebo recipients.
TABLE 81.1. MEAN PAIN SCORES IN PATIENTS WITH DIABETIC NEUROPATHY
Topiramate-related weight loss has been associated with improvements in metabolic parameters such as glucose, insulin, and lipid levels (8). Further studies are needed to document whether topiramate has dual benefits in patients with diabetic neuropathy.
Anecdotal reports of topiramate use in other pain syndromes suggest that it may be a reasonable alternative treatment for patients in whom other therapies have failed. Open-label topiramate administered to 14 patients with histories of painful neuropathic symptoms resulted in significant pain reduction (9). Neuropathic pain syndromes included reflex sympathetic dystrophy in five patients and other forms of painful neuritis in nine (diabetic neuropathies were excluded). Before topiramate treatment, all patients reported substantial pain on a 10-point scale (mean, 8.8). After ≤6 months of topiramate treatment at doses of 100 to 800 mg/day, pain scores were significantly improved (mean, 3.1; p < .0001). Patients reported that pain relief first became apparent at doses of 50 to 600 mg/day (mean, 214 mg/day).
Patients undergoing thoracic surgery often develop an intense intercostal neuralgia that is refractory to treatment with antidepressants, AEDs, and opioid and nonopioid analgesics. In a case report of a 60-year-old patient with chronic postthoracotomy pain syndrome, various therapies failed to alleviate burning pain, either because of intolerable side effects (oral amitriptyline, mexiletine, carbamazepine, phenytoin, lidocaine, capsaicin) or because of suboptimal analgesia (nortriptyline, desipramine, paroxetine, gabapentin, lamotrigine) (10). A bedtime dose of 75 mg/day topiramate provided sufficient pain relief to allow the patient to sleep through the night. An additional morning dose of 75 mg/day provided consistent pain relief throughout the day and was maintained for >6 months without intolerable side effects.
In case reports of patients with chronic regional pain syndrome type 1, low doses of topiramate (50 to 125 mg/day) added to existing opioid analgesic therapy produced marked pain reduction, which was sustained for >1 year even though previous treatment with nonsteroidal antiinflammatory drugs, acetaminophen, tricyclic antidepressants, carbamazepine, gabapentin, and other pain therapies had failed to provide effective pain relief for these patients (6). Topiramate appeared to be especially helpful in relieving allodynia and improving sleep. A patient with postherpetic neuralgia also had persisting pain relief at a topiramate dose of 50 mg/day but discontinued treatment after 7 months because of dizziness and unsteadiness. A patient with atypical facial pain did not respond to topiramate at 400 mg/day.
Topiramate may also be effective against trigeminal neuralgia. Because this pain syndrome is more common in patients with multiple sclerosis than in the general population, open-label topiramate was administered to six patients with multiple sclerosis who had long-standing trigeminal neuralgia resistant to carbamazepine and other conventional therapy (11). Patients typically reported pain relief within the first week of topiramate therapy. Five patients reported complete disappearance of pain at 100 mg taken twice daily, and these patients were able to discontinue their concomitant medications. Pain also resolved completely for one patient who required 150 mg topiramate twice daily plus adjunctive carbamazepine. After 6 months, the therapeutic effect of topiramate was maintained with only minor side effects (mild nausea and dizziness) and no discontinuation of therapy.
MIGRAINE PROPHYLAXIS AND OTHER HEADACHE SYNDROMES
Migraine is a chronic neurologic disorder characterized by episodic attacks, occurring most frequently in women. Migraine therapy encompasses avoidance of triggers to prevent attacks, symptomatic treatment of acute attacks, and long-term prophylactic treatment.
Two relatively small, double-blind, placebo-controlled studies have evaluated topiramate prophylaxis in patients with
migraine. In one trial, 40 patients (39 female patients) were randomized to treatment with topiramate (n = 19) or placebo (n = 21) for 16 weeks (12). All patients had migraine, with or without aura, for >1 year and were experiencing at least two episodes every month. After a 4-week baseline phase, topiramate was started at 25 mg/day and was gradually increased over 8 weeks to a mean dose of 125 mg/day. Concomitant migraine prophylaxis was permitted at prestudy doses. After an 8-week maintenance phase, the mean 28-day headache rate calculated for the entire double-blind phase was compared with baseline. Topiramate prophylaxis significantly reduced headache frequency versus placebo (p < .005) (Figure 81.1). Mean headache frequency was reduced by 36% in topiramate-treated patients and by 12% in placebo recipients. In addition, 26% of topiramate-treated patients responded to treatment with a ≥50% reduction in headache frequency versus 10% of placebo recipients. Adverse events were generally mild and included paresthesia, taste alteration, weight loss, anorexia, memory impairment, dysarthria, abnormal vision, emotional lability, and urinary frequency. Two topiramate-treated patients discontinued the study because of adverse events (nausea, emotional lability).
A second double-blind, placebo-controlled study used a similar design with a slightly shorter titration phase (4-week baseline, 6-week titration, 12-week maintenance) (13). In this study, 30 patients (29 female patients) were randomized to topiramate prophylaxis (n = 15) or placebo (n = 15). Abortive migraine medication was permitted. Eleven patients reached a topiramate dose of 200 mg/day (mean, 173 mg/day). After 18 weeks of treatment, mean 28-day headache frequency was reduced by 29% in topiramate-treated patients and by 7% in placebo recipients (Figure 81.1). In addition, 47% of topiramate-treated patients had a ≥50% reduction in headache frequency versus 7% of placebo recipients. Topiramate also significantly reduced migraine severity and migraine disability. Therapy was well tolerated, and discontinuation rates were similar between study groups. Adverse events included paresthesia, diarrhea, altered taste, and somnolence. Weight loss was significantly greater with topiramate treatment (p = .01). Mean body weight in placebo-treated patients did not change, whereas topiramate-treated patients lost an average of 6.2 pounds; weight loss tended to correlate with baseline body weight.
FIGURE 81.1. Effect of topiramate prophylaxis in patients with migraine. Frequency of migraine episodes in a 28-day period was reduced from baseline by 36% and 29% with topiramate treatment versus 12% and 7% with placebo. (Data from Potter DL, Hart DE, Calder CS, et al. A double-blind, randomized, placebo-controlled, parallel study to determine the efficacy of topiramate in the prophylactic treatment of migraine. Neurology 2000;54[Suppl 3]:A15(abst); and Edwards KR, Glantz MJ, Norton JA, et al. Topiramate in the prevention of episodic migraine: a double-blind, placebo-controlled trial. Abstract presented at the 42nd annual meeting of the American Headache Society, Montreal, 2000.)
Anecdotal reports also support a prophylactic effect of topiramate in migraine management. In a retrospective chart review, 69 patients with migraine (56 female patients) who received topiramate prophylaxis ranging from 25 to 500 mg/day were followed-up for ≤24 weeks (14). Topiramate treatment significantly reduced the frequency of moderate to severe headaches by 30%. A subset analysis of 38 treatment-refractory patients in whom nine or more migraine preventive medications had previously failed showed that topiramate reduced moderate to severe headaches by 23%. Fifty patients experienced side effects, most commonly paresthesia, drowsiness, diarrhea, and decreased appetite. Twenty-seven patients discontinued topiramate, 21 because of adverse events.
A chart review of 34 patients (31 female patients) with intractable chronic migraine also found topiramate to be effective prophylaxis (15). All patients had chronic migraine (median, 20 years) unresponsive to various acute and preventive therapies, with at least three episodes of migraine per week and daily or near-daily migraines in 29 patients. Topiramate was added to existing therapy and was increased to a mean dose of 98 mg/day; patients were maintained on topiramate for ≤18 weeks (mean, 9 weeks). At the end of the maintenance period, 19 patients were improved or much improved with topiramate treatment, and 15 reported no change. Common adverse events were fatigue, paresthesia, and anorexia or weight loss. Fourteen patients lost between 1 and 26 pounds. Seven patients discontinued treatment because of adverse events.
In an open-label study of topiramate as migraine prophylaxis in patients with refractory migraine or chronic daily headache, Shuaib et al. found that low-dose topiramate reduced the frequency and severity of severe migraines or chronic daily headaches (16). Topiramate was administered to 68 patients with frequent (more than seven) headaches each month and in whom previous prophylaxis with two or more agents had failed. Patients received topiramate for ≤18 months, starting at 25 mg twice daily and increasing to a maximum of 200 mg/day over 6 to 8 weeks. A treatment effect was apparent within 8 to 10 weeks; 38% reported significant improvement (>60% reduction in headaches) and 24% reported moderate improvement (40% to 60% reduction). Headache severity was also reduced in most patients reporting improvement. Topiramate was well tolerated, with a few patients reporting drowsiness, concentration difficulty, paresthesia, and dizziness.
Small, open-label investigations of topiramate in other headache syndromes have also been reported. Cluster headache, a relatively uncommon condition that is easily misdiagnosed, is characterized by episodes of severe pain several times a day for weeks or months, followed by long periods of remission. Low-dose topiramate was administered to 10 patients in an open-label study of cluster headache, including two patients with chronic cluster headache unremitting from onset and one patient with a cluster-tic syndrome (17). Topiramate treatment at doses of ≤125 mg/day (mean, 85 mg/day) was associated with rapid improvement in all patients, with remission of cluster episodes in nine patients within 1 to 3 weeks. Side effects of drowsiness, paresthesia, and word-finding difficulty were mild and were reported by only three patients.
Essential tremor is one of the most common movement disorders, but it is often confused with Parkinson's disease. Drug treatment strategies include propranolol and primidone, but adverse effects and drug interactions limit the usefulness of these agents in the elderly. Although results with GABAergic agents, carbonic anhydrase inhibitors, and calcium channel blockers have been inconsistent (18, 19, 20), topiramate's multiple mechanisms may offer a different approach to treatment. In a pilot, placebo-controlled crossover study (6), 24 patients received either 2 weeks of topiramate (≤400 mg/day) or placebo in addition to stable doses of existing therapy. After a 2-week washout period, patients were crossed over to the other study arm. Tremor rating scores that quantified tremor location/severity, specific motor tasks/functional disabilities, and tremor-resultant functional disabilities showed significant reduction with topiramate treatment (Table 81.2). The most common adverse events were appetite suppression or weight loss and paresthesia.
TABLE 81.2. MEAN CHANGE IN NORMALIZED TREMOR RATING SCORES
Two open-label studies of topiramate in essential tremor also suggested a treatment benefit. Eleven patients received 75 to 400 mg/day topiramate for ≤21 months (21). Results showed significant improvement in patients in whom who previous treatment with propanolol, primidone, and/or gabapentin had failed. Ten patients had ≥50% improvement and seven ≥75% improvement in tremors. Five patients were able to reduce or discontinue concomitant treatment with primidone, propanolol, and/or clonazepam. No serious adverse events occurred. Three patients reported weight loss, two experienced paresthesia, and one reported memory difficulty that resolved when the topiramate dose was reduced.
In another open-label study, nine patients in whom previous standard therapy for essential tremor had failed received an average topiramate dose of 144 mg/day (22). The study population included eight patients age ≥68 years, seven patients with long-standing tremor (>10 years), three with associated head tremor, and two with associated voice tremor. With topiramate treatment, there was a 60% improvement in the Archimedes Spiral average scores and a
53% improvement in the Activities of Daily Living average scores. Eight patients rated themselves as better and with less disability on a visual analog scale. There was no improvement in head or voice tremors. Topiramate was generally well tolerated, with fatigue and paresthesia as the most common side effects. One patient reported increased diuresis, and two patients discontinued treatment because of fatigue, despite improvements in tremor.
Bipolar disorder affects about 1% of the general population. Standard treatment for manic episodes includes lithium and the anticonvulsants valproate, which potentiates neuroinhibition by GABA, and carbamazepine, a sodium channel blocker. Alternative treatments include clonazepam and lorazepam, which enhance GABAergic neurotransmission by binding to the GABAA receptor, and acetazolamide, a carbonic anhydrase inhibitor. Topiramate has been used as an alternative treatment for bipolar disorder because of similar mechanisms, including potentiation of GABA-related neuroinhibition at GABAA receptors, sodium channel blockade, and weak carbonic anhydrase inhibition (1, 2, 3).
In an open-label study, 56 outpatients with bipolar disorder who did not respond to or could not tolerate lithium, valproate, or carbamazepine therapy had topiramate added to their existing therapy (23). At baseline, 32 patients had manic, mixed, or rapidly cycling mood symptoms, 11 were depressed, and 13 were relatively euthymic. Topiramate was started at 25 to 50 mg/day and increased gradually over the course of treatment to a maximum dose of 1,200 mg/day. Mean dose was 291 mg/day at 6 months and 425 mg/day at 1 year. Two patients with manic symptoms at the start of treatment discontinued topiramate in the first week because of dizziness and hallucinations. Overall, patients with mania at baseline showed significant response to topiramate, but depressed and euthymic patients showed no significant changes. Clinical Global Impression scores showed that 55% of 30 initially manic patients were much or very much improved in their manic symptoms after a mean of 312 days of treatment; these patients also had significant decreases in Young Mania Rating scores. Topiramate was generally well tolerated, with mild and transient central nervous system- or gastrointestinal-related adverse effects, including reduced appetite, cognitive impairment, fatigue, and sedation.. Weight and body mass index were significantly reduced with topiramate treatment. Ten patients discontinued treatment because of side effects, including two because of weight loss.
In another open-label study, 45 patients with bipolar disorder, in all of whom previous treatment with at least two mood stabilizers had failed, were treated with topiramate for 6 months (24). Before topiramate treatment, all patients had moderately severe depression according to Hamilton Depression Rating scores (range, 18 to 29). Topiramate was added to existing therapy of mood stabilizers, antidepressants, and/or benzodiazepines and was increased every 2 days to a mean dose of 275 mg/day. Of the 31 patients completing the trial, 19 had a full response to treatment (scores of 3 to 7), and 12 responded partially (scores of 8 to 12). Response was seen within the first 4 weeks of therapy, with further mood stabilization after 8 weeks. Transient paresthesia and numbness occurred in three patients, which resolved with dose reduction. Fourteen patients discontinued treatment, nine because of adverse events of headache, tremor, dizziness, nausea, incoordination, sedation, or paresthesia. Seven patients lost weight previously gained while they were taking lithium and valproate.
An open-label trial of topiramate included 20 patients, including 18 patients with bipolar disorder and two patients with schizoaffective disorder, treated for an average of 142 days (25). All patients had responded poorly or not at all to combination therapy with mood stabilizers and/or antipsychotic agents, including recent treatment with lithium, valproate, carbamazepine, and gabapentin. Topiramate was added to stable doses of psychotropic drugs and was increased every 5 to 7 days to a maximum of 300 mg/day; mean dose at week 5 was 210 mg/day. Twelve patients responded positively to topiramate treatment, including one patient who discontinued treatment temporarily because of confusion and was successfully restarted on the drug after 2 weeks. Four patients had no response, and one patient worsened. Topiramate was generally well tolerated, with adverse events in nine patients during the first month of treatment. Three diabetic patients achieved good glycemic control with topiramate. All patients lost weight with topiramate treatment, with an average loss of 9 pounds over 5 weeks.
Open-label topiramate was given as a treatment for acute mania in 11 patients with bipolar disorder type 1 who were unresponsive to lithium and/or valproate (26). Topiramate was administered (with or without adjunctive lorazepam) for ≤29 days (mean dose, 313 mg/day). Mania was reduced in half of patients, with increased level of functioning and global improvement. Three patients had a >50% reduction in mania scores, and five patients had improved global impression scores. Treatment was generally well tolerated, with paresthesia as the most common side effect. Three of four patients completing the study lost weight.
Retrospective chart reviews also showed the potential of topiramate in bipolar disease. A chart review of 58 consecutive patients treated with open-label topiramate for various psychiatric disorders showed improvement in more than half (27). Diagnoses included 44 patients with rapidly cycling bipolar disorder, nine patients with schizoaffective disorder, three patients with dementia, and two patients with psychosis. In 18 patients, treatment with lamotrigine and/or gabapentin plus conventional mood stabilizers had previously failed. Topiramate was added to concomitant
medications and was gradually increased to doses ≤400 mg/day; 12 patients with rapidly cycling bipolar disorder had concomitant medications discontinued. Positive response to treatment—changes in sleep, appetite, mood, and concentration—were seen in 36 patients, often within 72 hours of the first dose and usually within days to weeks of topiramate initiation. Six patients were worse during topiramate therapy. Topiramate produced marked or moderate improvement in all five patients with dementia and psychosis, a finding suggesting an antipsychotic effect. Of the 18 patients in whom lamotrigine and/or gabapentin had previously failed, 50% had marked or moderate improvement with topiramate. Adverse events included delirium in one bipolar patient with a history of psychosis (the patient overmedicated with topiramate, tranylcypromine sulfate, and alcohol). One patient with epilepsy and mixed bipolar with panic attacks had an increase in panic attacks and a generalized tonic-clonic seizure. Other adverse events were generally minor gastrointestinal or central nervous system effects, including paresthesia, somnolence, fatigue, and concentration or memory difficulty; six patients treatment because of adverse events.
Twenty-seven women with rapidly cycling bipolar disorder were treated with open-label topiramate (28). Patients had long-standing disease (≤41 years) and were refractory to at least two previous mood stabilizers for >12 months; all 27 had significant weight gain from previous therapy. Patients received a mood stabilizer (lithium or valproate) for 3 weeks, then topiramate was added at 25 mg/day and was increased to a maximum of 150 mg/day. Fifteen of 23 treatment completers showed significant improvement in mood in <12 weeks. Therapy was well tolerated, with four discontinuations resulting from side effects, all before week 3 of treatment. One patient who discontinued treatment at week 3 had significant improvement in mood. Fourteen patients lost weight during the 16-week study (>5% body weight in nine), and 12 patients maintained baseline weight.
These preliminary observations suggest that topiramate may be an effective treatment for acute manic and mixed episodes associated with bipolar disorder. Pharmacokinetic studies show that topiramate has no clinically significant effect on haloperidol serum concentrations (29) and results in a modest decrease in lithium serum concentrations (30), findings suggesting that topiramate can be added to existing therapy without complication.
Anecdotal reports of topiramate use in other psychiatric conditions include patients with posttraumatic stress disorder (31) and binge-eating disorder (32). Topiramate was added to existing therapy in 17 patients with posttraumatic stress disorder (31). Symptoms included nightmares in 13 patients and flashbacks involving reexperience of trauma in all 17. Six patients also had bipolar disorder (including two with hallucinations), and 10 patients had major depressive disorder. Topiramate was started at 25 mg/day and was increased by 25 to 50 mg every 3 to 4 days. Nightmares were suppressed in 12 of 13 patients (completely in nine), and flashbacks were suppressed in 16 of 17 (completely in 10). All patients with nonhallucinatory disorder responded, usually within 2 to 3 days of reaching an effective dose. Three patients had a full response within the first week of treatment. Five patients discontinued treatment because of adverse events or the patient's choice. For those continuing treatment, topiramate remained effective, with no evidence of developing tolerance.
Topiramate was used as an open-label treatment for binge-eating disorder, characterized by recurrent episodes of binge eating not associated with compensatory behavior (e.g., bulimia) (32). Thirteen female patients with binge-eating disorder received ≤1,400 mg/day topiramate added to existing psychotropic therapy. The improved response in nine patients was maintained for 3 to 30 months. One patient had a mild response, one had no response, and two were lost to follow-up. Mean weight decreased from 99 to 88 kg, and mean body mass index dropped from 36.5 to 32.2. However, only seven patients accounted for this weight loss; one patient lost <5 kg, three patients lost no weight, and two patients gained weight. Mean topiramate dose for all 13 patients was 492 mg/day, but the mean dose in the seven patients losing >5 kg was 725 mg/day, significantly higher than in the six who lost <5 kg (mean, 221 mg/day). Of seven patients electing to continue topiramate after the study because of improvement of binge eating, response has continued for 21 months. Topiramate was well tolerated, with transient central nervous system side effects.
Topiramate has multiple mechanisms of action that may be important both in controlling seizures and in treating other neurologic conditions. Results of pilot controlled trials and open-label studies suggest that topiramate is a potential therapy for numerous disorders other than epilepsy. In patients with neuropathic pain, including painful diabetic neuropathy and trigeminal neuralgia, topiramate appears to provide consistent pain relief to patients in whom other analgesics, including other AEDs, have failed. At low doses, side effects are minor and tolerable. Initial experience in patients with chronic headache and migraine suggest that low-dose topiramate may be an effective prophylactic therapy, reducing the monthly frequency of episodes. Topiramate may be effective in controlling essential tremor in some patients, perhaps because of the combination of GABAergic and carbonic anhydrase inhibitory effects. Topiramate also appears to be effective in controlling manic episodes in bipolar patients and may find application as a neuronal stabilizing agent in other neurologic disorders as well. Further study in randomized controlled trials is needed to document these initial observations.