TOPIRAMATE INCLINICALPRACTICE: EFFECT ON HEADACHESEVERITY, INTENSITY, ANDDISABILITY
Based on a poster presented by Kelman L Headache Center of Atlanta, Atlanta, Georgia
Several antiepileptic drugs are under investigation for use as migraine prophylaxis. They include topira-mate, zonisamide, lamotrigine, oxcarbazepine, and gabapentin. Valproate has an indication for migraine prophylaxis from the US Food and Drug Administration. As data are collected on antiepileptic agents in formal studies, the question most practitioners face is “How well will it work in my patients?” The benefits of controlled trials with specific patient populations free of concomitant medications or illnesses are clear, for initial studies. However, the practicing neurologist is faced with myriad patient types taking myriad med-ications. The patient’s lifestyle and demographics must be considered in choosing a therapeutic regi-men, along with prevention of drug-drug interactions with concomitant medications.
This study evaluated more than 200 patients in the Headache Center of Atlanta who were prescribed top-iramate for migraine, either during their first visit or dur-ing follow-up visits. Patient information was entered into a database and included demographics, family and social information, personal histories, women’s issues, headache characteristics, sleep issues, patient expecta-tions and satisfaction with their current therapy, and con-comitant medications, including any adverse effects and response. Women’s issues included severity ratings of postmenopausal symptoms, hormone use, oral contra-ceptive use, impact of hormones on headache, headache change during pregnancy (better, worse, or same), and headache change with menstruation (better, worse, or same). From these 200 patients, 78 new
patients just beginning topiramate therapy at their first visit were followed up to examine the effectiveness of topiramate in a “real-life” patient population.
Patients’ headaches were classified at the initial visit and at first follow-up (mean 44.27 days) using the International Headache Society (IHS) criteria with a modified definition of “chronic” defined as headaches on more than 14 days per month. At the initial visit, 70% had episodic migraine, 19% had chronic migraine, 7% had nonmigraine headaches, and 4% had atypical migraine (ie, lasting less than 4 hours or more than 72 hours or not fulfilling the IHS criteria of associated features [ie, nausea or vomiting, photo- and phonophobia]).
Topiramate had significant effects on the number of headache days per month and the number of headaches per month (Table). Significant effects were also observed in the number of severe headache days per month, number of moderate headache days per month, the headache index (duration x frequency x intensity), no housework days, fewer housework days,
POSTER PRESENTATIONS
—
The following are based on posters presented at the 44th Annual Meeting of the American Headache Society, held June 21-23, 2002, in Seattle, Washington.
Total Topiramate Episodic Chronic Population Migraine Migraine >50% reduction in
headaches/month 32.5% 25.9% 39.5% >50% reduction in
headache days/month 29.5% 18.5% 34.2%
Table. Effects of Topiramate on Headaches and Headache Days per Month
no work/school days, and fewer work/school days (P < .05). Anecdotally, from the patients’ headache diaries, these changes were considered to be more important to the patient than the actual number of headache days. Nonstatistical improvements were observed in headache duration and ability to function without medication, average headache intensity, and number of mild headache days per month.
Interestingly, the severity of headache type changed from the initial visit to the first follow-up. Many patients with chronic headache syndromes reverted to more episodic headaches. The proportion of patients with nonmigraine headaches increased 140% by the first follow-up. The proportion of patients with episodic migraine increased 40%, whereas chronic migraine cases decreased 47%.
Adverse events were rated as 0 or 1 on a scale of 0 to 3 by 71% of the patients. Overall, the severi-ty of adverse events was rated 1.06. Reported adverse events were typical of those reported in other studies (eg, tingling in the limbs, blurred vision, trou-ble concentrating, change in taste, decrease in appetite or libido, depression, drowsiness, mild word-finding difficulty, and weight loss). Weight loss occurred in a substantial number of patients, and weight loss was one of the deciding factors for many patients in choosing a migraine prophylactic therapy (from other antiepileptic or other classes of drugs).
Also, 125 concomitant medications were taken by the patients, none of which was used in a significant number of patients to affect results. No influence from the concomitant medications was observed.
These results suggest that topiramate positively affects all categories of migraines in “real-world” patients in a headache clinic. Overall, the type of headache was reduced to a less severe form, and qual-ity of life, disabilqual-ity, and functioning were improved.
ZONISAMIDE ANDLAMOTRIGINE ASPROPHYLAXIS FOR
MIXEDMIGRAINE ANDPAINDISORDERS
Based on a poster presented by Krusz JC Anodyne Headache and PainCare, Dallas, Texas Zonisamide is a recently approved antiepileptic drug with multiple mechanisms of action thought to be potentially involved in migraine pathophysiology (eg,
inhibition of voltage-gated sodium channels, inhibition of T-type calcium channels, modulation of serotonin and dopamine centrally, and potassium-mediated inhibition of glutamate release). Lamotrigine is another antiepilep-tic drug that also shares mechanisms of action thought to be involved in migraine pathophysiology, specifically inhibitory effects on sodium- and calcium-channel sub-types. Other recently approved antiepileptic drugs, such as gabapentin, topiramate, tiagabine, oxcarbazepine, and levetiracetam, have been shown to be effective in controlling migraines and other headaches, as well as other painful disorders.1-14The preferred pharmacologic
term for these agents, when seizures are not the prima-ry focus, is a neuronal stabilizing agent.
ZONISAMIDESTUDY
This open-label study involved 50 headache patients (31 women, 19 men) from a headache clin-ic. A subset of these patients (n = 36) had concurrent pain disorders (lumbar and cervical radiculopathy pain primarily) and 42 of the 50 had failed at least 2 other prophylactic agents for their headaches. Almost all patients (n = 48) had tried at least 1 other prophylactic agent. The nature of their headache dis-orders also varied: 10 had migraine, and 40 had mixed migraine and tension-type headache.
The mean age of this study population was 45.2 years, and zonisamide was administered for a mean of 6.3 months. The mean zonisamide dosage was 230 mg daily. Zonisamide therapy was started at 100 mg every third or fourth night for 4 doses. During the following 4 to 6 doses, zonisamide was given every other night. Titration to at least 100 mg daily followed; dose adjustments occurred every 2 to 3 weeks based on patient response. Zonisamide was generally added to the patients’ existing prophylactic regimen. The maximal dose tolerated was main-tained for at least 3 months (after titration to 100 mg daily) to determine efficacy. Patients used headache diaries to record headache frequency and severity.
Of the 50 patients who enrolled in the study (40 of whom had mixed migraine and tension-type headache), efficacy data was obtained for 28 of the migraineurs and 40 patients with tension-type headache. A total of 28% of the migraineurs (n = 8) experienced greater than 50% reduction in migraine fre-quency; another 43% (n = 12) experienced 25% to 50% reduction. The remaining 28% had no response.
Migraineurs experienced a 60% reduction in mean migraine frequency after zonisamide treatment from 9 to 4 migraines per month. Those with tension-type headache saw a 62% reduction in mean headache fre-quency, from 16 to 6 per month.
Four patients were lost to follow-up and 4 patients withdrew because of zonisamide side effects, which included nausea (n = 2), hives (n = 1), and dizzi-ness/drowsiness (n = 1). Five other patients also reported drowsiness but did not discontinue therapy. Fourteen patients were just started on zonisamide and were being titrated to the effective dose at the time of the poster presentation.
LAMOTRIGINESTUDY
This open-label study involved 28 patients (13 women, 15 men) from a headache clinic with refracto-ry headache; 6 had migraine only, and 22 had migraine plus episodic tension-type headache. Twenty patients had neuropathic pain as well. All 28 patients had been taking antiepileptic drugs as migraine pro-phylaxis at the start of the study, and 80% had failed at least 2 antiepileptic drugs in previous drug trials.
The mean age of the study group was 46.5 years. Patients were asked to rate their headache pain severity on a scale of 0 to 10 (numeric rating scale [NRS]) and track the headache frequency using a headache diary.
Lamotrigine 12.5 mg daily or 25 mg daily was initiated as add-on therapy to their current antiepilep-tic-drug prophylaxis regimen. Lamotrigine was titrated up 25 mg weekly to reach the highest tolerable dose and best efficacy. The average lamotrigine dose dur-ing the study was 250 mg daily, usually given in 2 doses. Patients were treated on average more than 4 months after the titration period (4 to 6 weeks) to 100 mg to 125 mg daily.
Of the 28 patients who thus far have been entered in this ongoing study, 14 of 23 patients (5 having just been started on medication) were evaluable for this study. Six patients had no response to lamotrigine and were excluded from analysis. After lamotrigine therapy, headache frequency was reduced 71.4% on average in 14 patients who responded to therapy. Headache severity in the 14 responders was reduced 35% to 50% (using a 0 to 10 NRS), and in those patients with neuropathic pain, chronic pain was reduced by approximately 70%.
Only 2 patients discontinued therapy due to side effects (drowsiness, rash); however, both had achieved a response to lamotrigine, and their data was included in the responder category.
CONCLUSION
The results suggest that both zonisamide and lam-otrigine may be safe and effective antiepileptic drugs (neuronal stabilizing agents) to offer chronic migraine sufferers as prophylactic therapy. Larger, randomized, placebo-controlled trials are needed and are war-ranted, given the positive results from these open-label studies.
REFERENCES
1. Mathew NT, Rapoport A, Saper J, et al. Efficacy of gabapentin in migraine prophylaxis. Headache. 2001;41:119-128.
2. Tai Q, Kirshblum S, Chen B, Millis S, Johnston M, DeLisa JA. Gabapentin in the treatment of neuropathic pain after spinal cord injury: a prospective, randomized, double-blind, crossover trial. J Spinal Cord Med. 2002;25:100-105. 3. Rose MA, Kam PC. Gabapentin: pharmacology and its use
in pain management. Anaesthesia. 2002;57:451-462. 4. Tremont-Lukats IW, Megeff C, Backonja MM.
Anticonvulsants for neuropathic pain syndromes: mecha-nisms of action and place in therapy. Drugs. 2000; 60:1029-1052.
5. Rozen TD. Antiepileptic drugs in the management of cluster headache and trigeminal neuralgia. Headache. 2001; 41(suppl 1):S25-S32.
6. Storey JR, Calder CS, Hart DE, Potter DL. Topiramate in migraine prevention: a double-blind, placebo-controlled study. Headache. 2001;41:968-975.
7. Krymchantowski AV, Bigal ME, Moreira PF. New and emerging prophylactic agents for migraine. CNS Drugs. 2002;16:611-634.
8. Novak V, Kanard R, Kissel JT, Mendell JR. Treatment of painful sensory neuropathy with tiagabine: a pilot study. Clin Auton Res. 2001;11:357-361.
9. Zakrzewska JM, Patsalos PN. Long-term cohort study compar-ing medical (oxcarbazepine) and surgical management of intractable trigeminal neuralgia. Pain. 2002;95:259-266. 10. Beydoun A, Kutluay E. Oxcarbazepine. Expert Opin
Pharmacother. 2002;3:59-71.
11. Krusz JC. Zonisamide as a treatment for chronic pain. Presented at: 21st Annual Scientific Meeting of the American Pain Society; March 2002; Baltimore, Md. Poster 760.
12. Krusz JC. Zonisamide as a treatment for chronic pain. Presented at: 14th Migraine Trust International Symposium; September 2002; London, England. Poster PA 13.
13. Krusz JC. Lamotrigine in the treatment of neuropathic pain. Presented at: 21st Annual Scientific Meeting of the American Pain Society; March 2002; Baltimore, Md. Poster 758.
14. Krusz JC. Levetiracetam for chronic neuropathic pain treat-ment. Presented at: 21st Annual Scientific Meeting of the American Pain Society; March 2002; Baltimore, Md. Poster 759.
TREATINGMIGRAINEPAINWITHOXCARBAZEPINE
Based on a poster presented by Jenson M*, Bhakta B†,
Royal MA‡, Movva V†, Ward S†
*Tulsa Pain Consultants, Tulsa, Oklahoma; †Pain
Evaluation and Treatment Center, University of Oklahoma College of Medicine, Tulsa, Oklahoma; ‡Elan
Pharmaceu-ticals, San Diego, California
Along with attack frequency, head pain (cepha-lalgia) is one of the most debilitating aspects of a migraine attack. Research into the mechanisms of migraine onset and perpetuation suggest common pathways with neuropathic pain.
Antiepileptic drugs are the most frequently used drug class for migraine prophylaxis. Traditional antiepileptic drugs have been valproate and carbamazepine. Newer agents, such as gabapentin and topiramate, are also showing efficacy in this treatment setting.
Carbamazepine has also been used to success-fully treat neuropathic pain. Its chemical cousin, oxcarbazepine, has been approved for use as monotherapy or adjunctive therapy for partial-onset seizures in adults and as adjunctive therapy in chil-dren for partial epilepsy. Oxcarbazepine is a keto analog of carbamazepine, which is rapidly metabo-lized to the active compound. It is not an inducer of hepatic enzymes and appears to have a better toler-ability profile than carbamazepine.1,2
Despite the wide range of therapeutic choices for prophylaxis, there remains a subset of patients who do not respond to any antiepileptic drug or other pro-phylactic choice (eg, beta blocking agents, calcium channel blocking agents, ergot alkaloids). The data reported here are from an open-label prospective study of 17 consecutive patients presenting to a pain clinic. All patients were nonresponders to the other prophylactic medications, including carbamazepine.
Each patient started the study taking 150 mg to 300 mg oxcarbazepine at bedtime. The dose was increased every 3 to 5 days by 150 mg to 300 mg until reaching a dose of 600 mg at bedtime. At that point, a 300-mg morning dose was introduced. The maximum dose allowed was 1200 mg, and oxcar-bazepine was given as adjunctive therapy to the patient’s medication regimen. Typical adjunctive med-ications included amlodipine, amitriptyline, citalo-pram, atenolol or metoprolol, and fluoxetine or paroxetine. The oxcarbazepine drug trial lasted 24 weeks, and patients were followed up with monthly office visits or telephone contacts.
Of the 17 patients, 14 were women, 9 had migraine with aura, 7 had migraine without aura, and 1 had chronic migraine with left-sided thoracic neuralgia. The average dose administered was 379 mg daily, ranging from 150 mg to 900 mg. Efficacy was measured using the McGill Short Form Pain Questionnaire, visual analog scale (VAS) score, patient and physician global response, and physical examination.
A decrease in the McGill and VAS scores was observed for 94% of study participants. One patient experienced a 7-point increase in the McGill score and no change in the VAS score after treatment and therefore discontinued. VAS scores decreased to 0 in 7 patients; McGill scores decreased by more than one half in all participants except the 1 patient who discontinued therapy. According to patient global subjective responses, 82% had at least 50% improve-ment in symptoms.
This study suggests that oxcarbazepine can be a useful adjunct to migraine prophylactic therapies because of its efficacy in reducing pain. Reducing pain quickly is one of the most important aspects of a migraine treatment to migraineurs.3 Oxcarbazepine
warrants further clinical investigation in migraine.
REFERENCES
1. Shorvon S. Oxcarbazepine: a review. Seizure.2000;9:75-79.
2. Beydoun A, Kutluay E. Oxcarbazepine. Expert Opin Pharmacother. 2002;3:59-71.
3. Lipton RB, Steward WF. Acute migraine therapy: do doctors understand what patients with migraine want from therapy? Headache. 1999;39(suppl 2):S20-S26.
HEAD-TO-HEADCOMPARISON OFGABAPENTIN
ANDVALPROATE FORMIGRAINEPROPHYLAXIS
Based on a poster presented by Miranda-Delgado HS*†,
Peña D*, Echevarría S*, Guzmán J‡
*Centro Especializado en Dolor de Cabeza y Neurología;
†Associate Professor, Department of Neurology, School of
Medicine, University of Puerto Rico; ‡Department of
Biostatistics and Epidemiology, Graduate School of Public Health, University of Puerto Rico, San Juan, Puerto Rico
Valproate is the only antiepileptic agent approved for migraine prophylaxis, but several other antiepileptic drugs, such as gabapentin, top-iramate, oxcarbazepine, lamotrigine, and zon-isamide, have shown efficacy in small and large clinical studies. While many neurologists may choose to use one of the other antiepileptic drugs, there are limited head-to-head comparisons between these agents in migraineurs.
This randomized study of 63 migraineurs (9 men, 54 women) was designed to compare the efficacy of valproate to gabapentin in terms of migraine fre-quency, duration, intensity, and disability. Adverse events for both drugs were also monitored. Patients were recruited from the Centro de Estudios de los Dominicos de Caribe (CEDOC) Headache Center in San Juan, Puerto Rico, from October 2000 to May 2001. Each had migraine according to International Headache Society criteria, with at least 5 attacks per month with moderate or severe headaches. They were randomly assigned to receive either valproate (250 mg twice daily; n = 31) or gabapentin (300 mg twice daily; n = 32) for 20 weeks with visits at 2, 6, 12, and 20 weeks. Outcome measures were based on patient questionnaires provided at each visit.
The results show that migraine frequency decreased to almost 0 by 12 weeks of treatment, but the overall decrease was greater with valproate, though not statistically significant. Mean frequency rates after 20 weeks were 7.03 to 0.31 (gabapentin) and 5.71 to 0.45 (valproate).
Duration of headaches in the gabapentin group decreased to a mean of 0 hours from a mean of 8.50 hours and for valproate from a mean of 8 to 0 hours (P = .172). Of note, achieving 0 hours’ dura-tion occurred by week 6 for the gabapentin group and by week 12 of the valproate group.
Attack intensity was assessed on a scale of 1 to 4. Gabapentin patients had greater decreases in migraine intensity (from 4 to 1) than those in the val-proate group (from 4 to <2). They also experienced decreased intensity earlier (by 6 weeks) compared with the valproate group (first major decrease seen at 12 weeks).
To assess disability, patients were asked to rate their level of disability on a 0% to 100% scale, with 100% representing severe disability. Mean attack dis-ability was significantly lower in the gabapentin group compared with the valproate group (27.4% vs 42.9%, P = .0085).
Adverse effects were typical of those reported for the drugs: somnolence and dizziness with gabapentin, and alopecia, tremors, and weight gain with valproate. Only 2 patients discontinued therapy due to side effects, both in the valproate group.
This study provides insight into the differences between gabapentin and valproate as migraine pro-phylactic agents. Given that these agents are taken on a daily basis, therapy should be prescribed based on all factors that can affect a patient: migraine inten-sity, frequency, duration, disability from migraine, and drug tolerability. Studies to compare other antiepilep-tic drugs as migraine prophylaxis would be useful.
TWOYEARS’ EXPERIENCEWITHBOTULINUM
TOXINTYPEA INCAREFULLYSELECTED
CHRONIC-MIGRAINEPATIENTS
Based on a poster presented by Mathew NT, Kallasam J, Kaupp A, Meadors L
The Houston Headache Clinic, Houston, Texas Botinulinum toxin type A (Btx-A) is the latest devel-opment in prophylactic migraine treatments. It is a purified protein from the bacterium Clostridium botu-linum, which blocks the release of acetylcholine at the neuromuscular junction, preventing muscle contrac-tion along with having antinociceptive effects on nerve endings.1-4 Clinical studies to assess the safety
and efficacy of Btx-A have been performed and fur-ther, more in-depth studies are under way. The results
to date suggest that Btx-A is an effective prophylactic migraine therapy.5
The results reported here are the accumulation of 2 years’ experience with Btx-A in chronic migraine patients attending a specialty headache clinic. The results are from a retrospective study of 112 patients, each receiving at least 1 treatment and up to 6 treat-ments (n = 8) of Btx-A. Each treatment included intra-muscular injections of a total of 50 U to 100 U Btx-A at several predetermined sites on the head; “follow the pain” was also used in some patients to deter-mine injection sites. Treatments were given approxi-mately 3 months apart.
Of the 112 patients participating in the study, 94 were women; the age range for all participants was 18 to 77 years. Patients were included if they had con-traindications to acute therapies, had failed and/or had severe and intolerable adverse events with prophylactic therapies, refused to take daily medications, or were elderly patients with chronic migraine (and therefore were more likely to have adverse events [eg, loss of bal-ance and dizziness] with daily medications). Patients could continue taking the following acute therapies: nonsteroidal anti-inflammatory drugs, isometheptene, triptans, or ergotamine. Any medications for comorbid psychiatric or medical conditions were also continued. Participants were asked to keep a headache diary to record the headache frequency, the number of
headache days after each treatment, and acute migraine therapy use. Participants were also assessed using the Migraine Disability Assessment Scale (MIDAS). The results show significant reductions in mean MIDAS scores, mean number of headache days after treatment, and acute migraine medication use for the first 3 treatments. In those receiving 4 or more treat-ments, the degree of improvement remained high but the changes from the immediate previous treatment were not significant (Table). The mean duration of beneficial effect with Btx-A was 12.5 ± 2.2 weeks.
Btx-A also had a greater effect on severe episodes of migraine compared with low-grade headaches, and emergency room visits decreased with Btx-A treatments, based on the patients’ headache diaries.
The number of participants who received Btx-A treatment dropped dramatically after the fourth treat-ment, from 60 to 36, primarily due to financial limi-tations. Btx-A treatments were well tolerated, with no episodes of tachyphylaxis, 1 report of injection-site pain for 3 weeks, and 1 report of ptosis. Scalp pares-thesia was experienced by 2 patients.
The results confirm previous reports of Btx-A as an effective prophylactic strategy and suggest that it may alter the course of chronic migraine in selected patients—both headache disability and frequency were reduced. Clearly, larger, randomized studies will be required to more accurately assess Btx-A as a prophylactic treatment in the wider migraine population. The results reported here after 2 years of experience with this product suggest fur-ther research is warranted.
REFERENCES
1. Mathew NT, Kaup AO. The use of Botulinum toxin type A in headache treatment. Curr Treat Options Neurol. 2002;4:365-373.
2. Aoki KR. Pharmacology and immunology of botulinum toxin serotypes. J Neurol. 2001;248(suppl 1):3-10. 3. Binder WJ, Brin MF, Blitzer A, Schoenrock LD,
Pogoda JM. Botulinum toxin type A (BOTOX) for treat-ment of migraine headaches: an open-label study. Otolaryngol Head Neck Surg. 2000;123:669-676. 4. Silberstein SD. Review of botulinum toxin type A and its clinical applications in migraine headache. Expert Opin Pharmacother.2001;2:1649-1654.
5. Silberstein S, Mathew N, Saper J, Jenkins S. Botulinum toxin type A as a migraine preventive treat-ment. For the BOTOX Migraine Clinical Research Group. Headache. 2000;40:445-450.
Before After 3rd Btx-A After 6th Btx-A Treatment Treatment Treatment Mean MIDAS score 85.8 ± 12 26.2 ± 8.2* ~11†
Mean headache days 64.4 ± 2.2 29.3 ± 7.1* ~15†
Mean reduction in acute therapy use (# tablets)
Oral triptans 16.5 ± 4.8 ... 4.2 ± 1.9‡
NSAIDs, isometheptenes,
ergotamine 58.9 ± 11.2 ... 16.3 ± 1.9‡
Table. Outcomes of Btx-A Treatment in Chronic Migraine Patients
*P< .001 compared with before treatment.
†Not significant compared with 3rd treatment or immediate previous treatment but
sig-nificant compared with before treatment.
‡Reduction in acute migraine medication use after Btx-A treatment overall.
Btx-A = botulinum toxin type A; MIDAS = Migraine Disability Assessment Scale; NSAID = nonsteroidal anti-inflammatory drug.
