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Clinical Journal of Pain for
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PainJournal.net Clinical Journal of Pain for Healthcare Professionals and Patients
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A study of patients’ perception of effectiveness
Jacob Green, M.D., Ph.D.; Sohail Kahn, P.A.C; Carlos M. Barth, M.D.; Joseph Warner, M.D.; Tim Lucey, D.O. Introduction: For fifty years, the utilization of anticonvulsants for migraine headache control has been an accepted and common neurological practice. Physicians, however, are always seeking better medications for patients afflicted with migraines. Clinically, migraine headaches do occur with greater frequency in families who also have members with seizure disorders, as both are episodic intermittent disorders. It is also a consideration that some of the anti-convulsants have objectively helped a great deal in amelioration in the severity and frequency of seizures and migraine attacks. Initially, when Dr. Houston Merritt introduced Dilantin for epilepsy in the 1930s, it did not take long until Dilantin was used by neurology practitioners (personal experience – 1960). Dilantin was a therapeutic agent in migraine headache disorders, as well. MATERIALS AND METHODS It was deemed appropriate by the authors to ascertain whether a migraine patient by their own perception alone receives a beneficial, deleterious, or no effect from some of the newer anti-convulsants. We selected Depakote (TM) and/or Topamax (TM) for use in patients in our private general neurology practice. Patients were admitted to the study if they met the clinical, published criterion for the diagnosis of migraine headaches. All our patients in this study had an MRI angiogram to rule out an intra-cranial aneurysm, noting that there is no way (in the opinion of the authors) to ascertain whether or not a patient with migraines has, or does not have a brain aneurysm. The differentiation cannot be based on the clinical characteristics of the headache alone. The two patient groups, named after their chosen start-up medication, consisted of a Topamax™ group and a Depakote™ group. All patients were continually re-assessed at each follow-up visit for the number of migraines. Patients made the initial choice of medication after a dedicated information and consent session with their own treating neurologist. Those patients that wished to switch medications at any point in time were allowed to do so. All participants were given complete information that this was a clinical study, and the recording of the outcome had nothing to do with which drug they chose. All patients were informed that we may publish the study outcome for informational purposes to other physicians. They can obtain a final copy of the report, post-publication. All medical records were kept in accordance with HIPAA regulations. Results: 85 migraine patients, 73 females, 12 males, from ages 17 to 74 were admitted into the study. The study began in January 2005. It is an open-ended study. All headache patients were referred to our 3-person neurologist group in northeast Florida. 85 patients were evaluated for a total of study months.
TOPAMAX VS DEPAKOTE IN-HOUSE STUDY Patients who took Topamax only (ages 21-63):
Patients who took Depakote only (Ages 26-65):
Patients who took both Depakote and Topamax (Ages 17-74):
RESULTS (Ages 17-74):
Patients were assessed periodically at each follow-up office visit as to whether or not, in their own opinion, they felt Topamax, if they started with this agent, was effective in the prevention of migraine headaches. We purposely did not count number of headaches. Results were based on the patient’s perception alone. Topamax patients were initially started on a dose of Topamax 25 mg, and increased 25 mg per week to 50 mg/day and then to 50 mg b.i.d. All those patients were informed that both the medications had potential side effects, causing tingling sensation and some weight loss, etc. All participants were fully familiarized with potential benefits and dangers of each of the medication (therapies) for migraine headache disorder, including, "none," as to any side effects. The Depakote™-treated group of migraine patients, those who initially chose Depakote™ as their initial therapy, were started on 500 mg Depakote ER daily. Some were increased to 500 mg, b.i.d. They were also fully informed as to the characteristic of the study and potential medication side effects (liver function abnormalities), or “none” side effects. All participants were assessed as to their own opinions, via a fixed written questionnaire, concerning the medication's overall migraine prevention effectiveness. All inquiries given for both Topomax™ and Depakote™ use were handled equally. The focus of this non-blinded, open clinical study was basically to assess the potential effectiveness of each of these two migraine-preventative medications, Depakote™ versus Topamax™. The outcome at the end of the study, by and for each patient, was identified in their own judgment as to the amelioration or worsening of the migraine headache syndrome frequency, or no change in headaches at all. Medication crossover was permitted and duly recorded act the next office visit where the new prescription was given. Discussion Migraine headaches are an internationally significant medical problem. Random samples of 1,000 men and women from 25 to 64 years from the National Central Personnel Registry in Copenhagen utilizing the IHS criteria for migraine noted that there was an incidence of 5.8 new cases per 1,000 persons per year for women and 1.6 new cases per 1,000 persons in men. (Ref 1) One migraine study noted that the incidence was reported in 1,700 members of an HMO, ages 21 to 30, (where 98% of those patients who completed the study) rates were 5.5 per year new cases per 1,000 persons a year in women and 0.6 new cases in men. (Ref 2) Prevalence in migraine is easier to determine than incidence in the many previously published studies that exist. Larger studies more accurately tend to statistically reflect the prevalence of migraine in the general population. (Reference 3) A meta-analysis appearing in the Epidemiology of Primary Headache in Women reviewed a number of different studies, including a 20,000 persons study. They noted a variable incidence of men and women, but a clear, predominance of at least 3 to 1 in women over men. (Ref 4) The International Headache Society diagnostic criterion of migraine is. Five attacks of headaches that last four to 72 hours. Headaches with at least two of the following criteria: Unilateral pulsating, moderately severe pain. Aggravation occurs by routine physical activity. (Walking, climbing stairs, etc.) Headaches also have to have one of the criteria of nausea, vomiting, photophobia, phonophobia and these headaches were not due to any other disorder (migraine only). These criterion were used in order to qualify as migraine headache. We utilized the same definition. Reportedly, ninety percent of the women present to their primary care practice with recurrent, disabling headache will turn out to have migraine. The clinical diagnostic features of migraine are unilaterally at 70%, throbbing in 80%, moderate to severe in 70%, worse by physical activity in 76%, with nausea in 36%, vomiting 18%, photophobia 66% and phonophobia in 49%. It should be stated that migraine is not an equal opportunity disorder, noting that the annual days lost to bed rest because of migraine is 5.6 in women and 3.8 in men. The average duration of attack being over 24 hours is 71% in women and 48% in men. The proposed mechanism of action for the use of anticonvulsants in migraine appears to be neuronal cell "membrane stabilization" (Ref 1 and 2). Some authors, however, state the ACTUAL pathogenesis of migraine is still uncertain (Ref. 3). Abnormal EEGs were noted in migraine patients. Transcerebral magnetic stimulation was carried out showed a hyperirritability of brain cortex in patients with migraines (Ref. 5 & 6). Reversible physiological changes on serial MRI were also suggested as a finding in migraine patients (Ref. 7). Neurochemically, the brain hyperinstability in migraine is likely to be a gabaergic type of phenomenon (Ref. 8). The mechanism of action of the drugs used to treat migraines is to likely decrease cortical-hyperirritability (ref. 6). Some neurophysiologic tests suggest that “calming” of cortical neuronal irritability (Ref. 9) is a key mechanism of therapeutic action in migraine patients. It has been reported that between 47% to 82% reduction in attack frequency points to the effectiveness in the treatment of migraine with Depakote therapy (Ref.10, and 11). In several blind studies, Depakote was found to be effective and safe (Ref. 12, 13, 14, and 15). A decreased migraine frequency outcome was not dose-related (Ref. 16). Depakote should be considered as a first time, first line therapy said one author (Ref. 17). The short-term and long-term outcomes of migraine therapy are not necessarily the same with observed Depakote therapy (Ref. 18). The largest study and most quoted one suggests a 47% effectiveness of Depakote in aneloriating migraine headaches (Ref. 19). There was a strong statement published in the literature citing an “unprecedented” effect of Depakote on migraine (Ref. 20). A single study done comparing frequent classic migraine, transformation migraine, and tension-type headache noted the lowest rate of achievement of success using Depakote in decreasing the numbers of headaches was in those patients diagnosed with tension headache (Ref. 21). Bartolini did a comparison study between the drugs Sodium Valproate and Inderal for chronic migraine therapy. There was significant reduction of migraine in both treatment groups, thus, he stated that there were no substantial differences in efficacy or tolerability (Ref. 22). In another single study, there was no difference other than chance was noted in a comparison of Depakote to Inderal (Ref. 23). In a Topamax-treated, dose-related migraine patient test treatment group, reports suggest outcome studies certainly suggest that effectiveness was greater than a comparison control group (Ref. 24). Various anti-convulsant drugs were tried for their therapeutic effects on various headaches, especially migraines of different types and degrees. (Ref. 25). Efficacy and tolerability were positively cited (Ref. 26 and 27) for Topamax in migraine therapy. There was a comment that Topamax was also effective in epilepsy. Recognizing the episodic nature of both, there was even a consideration presented by Harvard that Topamax’s successful migraine prophylaxis may modify the long-term total outcome of the migraine process (Ref. 26). Other authors noted migraine as a possible progressive disorder (Ref. 27). One study compared a number of different anticonvulsant agents used in treating migraines. It showed that there were some adverse effects such as fatigue, nausea, diarrhea, and mental confusion in some cases while on Topamax, but more frequently so with other agents tested (Ref. 28). It was initially cited that there was a lack of significant weight gain with Topamax (Ref. 29). Topamax was also cited as an effective anti-migraine compound even in children (Ref. 30). Topamax’s use to reduce migraine headaches was clearly better than placebo (Ref. 41). Topamax was stated to be migraine-effective in 100 mg doses (Ref. 31) In a quality of life study, stepwise treatment was suggested for the disorder noting that migraine is typically of various intensities (Ref. 32). Patients were treated with gabapentin and Depakote for migraine, and with other anti-convulsants including Topamax, were all evaluated equally for comparative outcomes (Ref. 33). Topamax did well. Urinary excretion was the primary mechanism of eliminating Topamax. (Ref. 34). Reportedly, there was good clinical response noted with the use of Topamax for migraine noted in two very large studies; one with 483 patients, (Ref. 35) and 469 patients in another study. Both showed similar good results for Topamax (Ref. 36). One small later study, however, found no difference between any headache-preventing medications used (Ref. 37). Topamax was very commonly reported to be a good therapy, efficacious, and better than placebo (Ref. 38, 39, and 40). The mild side effect of mental confusion was cited in another study of treatment with Topamax. Confusion was noted in only 11% (Ref. 41). In a long-term Topamax use study, there was an average 3.4 headaches/month. (Ref. 43) Headaches decreased to 2.5 in 408 subjects treated with Topamax. Overall, it appears in the recent literature that Topamax, the newer of the two drugs (Topamax and Depakote) is quite efficacious for migraine prophylaxis. Our study compared our results found in the literature to see if there was any difference other than chance in our unique open-label study with full patient choice. Patients were involved in a stakeholder-stockholder paradigm, in which they were able to choose and/or switch to the medicine they initially wanted, Topamax or Depakote. The study was under their personal control. SUMMARY: Our study showed that patients who voluntarily chose to switch from Depakote to Topamax, or vice-versa, regardless of start drug did not do as well as those using a single drug, be it Topamax or Depakote utilizing their own perception (non-numericals of efficacy). There was a 13 out of 20 failure of headache frequency improvement with either of these two medicines when with any switchover. The total of two medications used in any order, the “switch” occurred due to the patient's own wish regarding a lack of any decrease in headache frequency. Those who had switched seem did not seem to get much better in the majority of single medication use cases. In our study alone, the perception of Depakote improvement noted in the frequency of migraine headaches was 77.8% and with Topamax was 79.5%. The overall percentage, including switchovers, shows that initially, the Topamax-treated patients had significantly improved - 62.7%, and the overall percentage improvement with initial choice of Depakote was 47.4%, which appears to be a statistically significant outcome, noting our small 80-patient series. The number of patients in this voluntary study was not high. Patients in this non-blinded, participative study were parametric. The readers are left to make their conclusions as to the results of our study. References: 1. Palmer, JE, Chronicle, EP, Rolan P, Mulleners WM, Cortical hyperexcitability is cortical under-inhibition: evidence from a novel function test of migraine patients, Cephalagia, 2000 Jul;20 (6): 525-32. 2. Raskin, NH, Acute and prophylactic treatment of migraine: practical approaches and pharmacologic rationale, Neurology, 1993 Jun;43(6 Suppl 3):S39-42. 3. Solomon, GD, Therapeutic advances in migraine, J. Clin. Pharmacol 1993 Mar;33(3):200-9. 4. 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