Botulinum toxin type A (BOTOX) for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial

OBJECTIVE: The objective of this study was to evaluate the safety and efficacy of botulinum toxin type A (BoNT-A; BOTOX, Allergan, Inc.) for the prophylactic treatment of chronic daily headache (CDH). BACKGROUND: Several open-label and small controlled trials suggest that BoNT-A may be effective in the prophylactic treatment of headache. DESIGN AND METHODS: This was an 11-month, randomized double-blind, placebo-controlled study of BoNT-A for the treatment of patients aged 18 to 65 years old with 16 or more headache days per 30 days conducted at 13 North American study centers. Following a 30-day screening period and a 30-day, single-blind, placebo-response period to identify placebo responders, eligible patients from both the placebo responder and placebo nonresponder groups were injected with BoNT-A or placebo every 90 days and assessed every 30 days for 9 months, a period encompassing three treatment cycles. The primary efficacy measure was the change from baseline in the frequency of headache-free days in a 30-day period for the placebo nonresponder group at day 180, the chosen efficacy time point. The secondary efficacy measure was the proportion of patients with a decrease from baseline of 50% or more in the frequency of headache days per 30-day period for the placebo nonresponder group at day 180. The change from baseline in the frequency of headaches (per 30-day period), the proportion of patients with a decrease from baseline of 50% or greater in the frequency of headaches per 30-day period, acute medication use, and adverse events were also assessed. RESULTS: Of 571 patients assessed over the baseline period, 355 (mean age, 43.5 years; 300/355 [84.5%] female) were enrolled and randomized. At the end of the placebo run-in period, 279 patients (79%) were classified as placebo nonresponders and 76 patients (21%) as placebo responders. Subsequently, patients were randomized within each group to receive either BoNT-A or placebo. In the placebo nonresponder stratum, the mean number of headache-free days at baseline was 5.8 (+/-4.7) for BoNT-A- versus 5.5 (+/-4.7) for placebo-treated patients. At day 180, placebo nonresponders treated with BoNT-A had an improved mean change from baseline of 6.7 headache-free days per 30-day period compared to a mean change from baseline of 5.2 headache-free days for placebo-treated patients. The between-group difference of 1.5 headache-free days favored BoNT-A treatment, although the difference between the groups was not statistically significant. However, a statistically significant difference was observed at day 180 endpoint for the secondary efficacy measure. A significantly higher percentage of BoNT-A patients had a decrease from baseline of 50% or greater in the frequency of headache days per 30-day period at day 180 (32.7% vs. 15.0%, P=.027). Also, the mean change from baseline in the frequency of headaches per 30-day period at day 180 was -6.1 for BoNT-A patients vs. -3.1 for the placebo patients (P=.013). Only 4 of 173 BoNT-A patients (2.3%) discontinued the study due to adverse events. The majority of treatment-related adverse events were transient and mild to moderate in severity. CONCLUSIONS: BoNT-A treatment resulted in patients having, on average, approximately seven more (1 week) headache-free days compared to baseline. Although at the primary time point (day 180) the BoNT-A treatment resulted in a 1.5 between-group difference compared to placebo, this difference was not statistically significant. The treatment met secondary efficacy outcome measures, including the percentage of patients experiencing a 50% or more decrease in the frequency of headache days, in addition to statistically significant reductions in headache frequency. BoNT-A was also well tolerated in patients with CDH.     

Botulinum toxin type a prophylactic treatment of episodic migraine: a randomized, double-blind, placebo-controlled exploratory study

OBJECTIVE: This exploratory trial evaluated the safety and efficacy of multiple treatments of botulinum toxin type A (BoNTA; BOTOX, Allergan, Inc., Irvine, CA, USA) as prophylactic treatment of episodic migraine headaches. DESIGN AND METHODS: This was an 11-month randomized, double-blind, placebo-controlled, exploratory study. Patients were screened during a 30-day baseline period, and eligible patients with 4 or more migraine episodes and < or =15 headache days entered a single-blind 30-day placebo run-in period. Patients were classified as placebo nonresponders (PNR) if they had at least 4 moderate-to-severe migraine episodes and did not experience at least a 50% decrease from baseline in the frequency of migraine episodes following their placebo treatment. All other subjects were classified as placebo responders (PR). Patients were randomized within each stratum (PNR, PR) to 3 treatments with BoNTA (110 to 260 U of BoNTA per treatment cycle) or placebo at 90-day intervals using a modified follow-the-pain treatment paradigm. The primary efficacy outcome measure was the mean change from baseline in the frequency of migraine episodes for the 30 days prior to day 180 in the PNR group. Secondary efficacy measures included the proportion of patients with a decrease from baseline of 50% or more migraine episodes per 30-day period. Patients were allowed to take concomitant acute and prophylactic headache medications. Adverse events were reported. RESULTS: A total of 809 patients were screened and 369 patients (89.2% female; mean age, 45 years; range, 20 to 65 years) entered the placebo run-in period and were subsequently randomized to BoNTA or placebo. The mean total dose of BoNTA was 190.5 units (U) (range, 110 U to 260 U). The predetermined primary efficacy endpoint was not met. Substantial mean improvements of 2.4 and 2.2 fewer migraine episodes per month at day 180 in the PNR stratum treated with BoNTA and placebo, respectively, were observed (P > .999). From day 180 through the end of the study (day 270) at least 50% of all patients in each treatment group had a decrease from baseline of 50% or more migraine episodes per 30-day period. However, in the group of patients with > or =12 headache days at baseline (and < or =15 headache days), BoNTA patients experienced a mean change from baseline of -4.0 headache episodes at day 180 compared with -1.9 headache episodes in the placebo group (P= .048). The majority of treatment-related adverse events were transient and mild to moderate in severity. Only 7 patients (1.9%) discontinued the study due to adverse events (6 BoNTA, 1 placebo). CONCLUSION: There were no statistically significant between-group differences in the mean change from baseline in the frequency of migraine episodes per 30-day period. There were substantial, sustained improvements during the course of the study in all groups. Multiple treatments with BoNTA were shown to be safe and well tolerated over an active treatment period lasting 9 months.     

Botulinum toxin type A for the prophylactic treatment of chronic daily headache: a randomized, double-blind, placebo-controlled trial

OBJECTIVES: To identify a treatment-responsive population for botulinum toxin type A (BoNTA) and to evaluate the safety and efficacy of 3 different doses of BoNTA as prophylactic treatment of chronic daily headache (CDH). PATIENTS AND METHODS: A randomized, double-blind, placebo-controlled study of BoNTA in patients with CDH was conducted from July 6, 2001, through November 7, 2003, at 28 North American study centers. Eligible patients were injected with BoNTA at 225 U, 150 U, 75 U, or placebo and returned for additional masked treatments at day 90 and day 180. Patients were assessed every 30 days for 9 months. The primary efficacy end point was the mean change from baseline in the frequency of headache-free days at day 180 for the placebo nonresponder group. RESULTS: For this study, 702 patients were enrolled and randomized. The primary efficacy end point was not met. Mean improvements from baseline at day 180 of 6.0, 7.9, 7.9, and 8.0 headache-free days per month were observed in the placebo nonresponder group treated with BoNTA at 225 U, 150 U, 75 U, or placebo, respectively (P=.44). An a priori-defined analysis of headache frequency revealed that BoNTA at 225 U or 150 U had significantly greater least squares mean changes from baseline than placebo at day 240 (-8.4, -8.6, and -6.4, respectively; P=.03 analysis of covariance). Only 27 of 702 patients (3.8%) withdrew from the study because of adverse events, which generally were transient and mild to moderate. CONCLUSIONS: Although the primary efficacy end point was not met, all groups responded to treatment. The 225 U and 150 U groups experienced a greater decrease in headache frequency than the placebo group at day 240. The placebo response was higher than expected. BoNTA was safe and well tolerated. Further study of BoNTA prophylactic treatment of CDH appears warranted.     

Duration of migraine is a predictor for response to botulinum toxin type A

OBJECTIVE: To identify the clinical characteristics and/or injection parameters that predict a favorable response to botulinum toxin type A in patients with episodic and chronic migraine. BACKGROUND: There is emerging scientific and clinical evidence to support the utility of botulinum toxin type A (BoNT-A) in the prophylaxis of episodic and chronic migraine headache. However, the patient characteristics and injection strategies that predict a favorable treatment response are unknown. METHODS: We conducted a prospective, open-label study on 74 patients from our clinic receiving BoNT-A for episodic or chronic migraine. For all patients, migraine-related disability (Migraine Disability Assesment [MIDAS]), headache frequency, and average headache intensity were obtained at baseline and at 3 months post-BoNT-A. Information regarding demographic characteristics and injection parameters was also collected. RESULTS: Sixty-one patients met the study criteria and were available for 3-month follow-up. At the 3-month follow-up visit, the mean MIDAS scores of the 61 qualified study patients had decreased from 102 at baseline to 49 (52% decrease, P<.001). The mean number of headache days was reduced from 60 to 39 (P<.001), and the mean headache intensity decreased from 7.6 at baseline to 5.9 (P<.001). Frequency of migraine attacks, presence of analgesic overuse, total BoNT-A dose, and presence of underlying muscle tenderness were not predictive of treatment response. Age and duration of migraine were the only clinical factors significantly predictive of treatment response. Age likely was a predictor only as a consequence of duration of illness as subjects with migraine duration greater than 30 years were significantly less likely to respond to treatment with BoNT-A. CONCLUSION: BoNT-A may be effective in decreasing headache frequency, headache intensity, and headache-related disability in episodic and chronic migraine patients. Duration of illness emerged as a predictor of treatment response. Randomized controlled studies should evaluate headache-related disability as a primary endpoint in patients with episodic and chronic headache.     

Long-term benefits of botulinum toxin type A (BOTOX) in chronic daily headache: a five-year long experience

Botulinum toxin type A (BoNT-A) has been recently suggested as prophylaxis therapy for the treatment of primary headache chronic forms. Several studies on its efficacy are available, but results are often contradictory and not univocal. The effects of BoNTA on chronic forms of both tension- type headache and migraine have been investigated. In this study we introduce our five-year long experience with BoNT-A (Botox, Allergan, Irvine, CA). The employed dosage was 100 U and the Fixed Sites-Fixed Doses (FSFD) protocol was used. The period of study was April 2001 to July 2006. A sum of 1347 patients suffering from chronic daily headache (CDH) were treated. We registered in these patients the number of headache days per month and observed their reduction in relation to the number of injections. The best results were found after 12 months of treatment, with patients being free of attacks 23 days per month. The BoNT-A treatment was safe and well tolerated, as only 1.6% of patients reported adverse events, and they were all mild and transient. In conclusion, BoNT-A therapy appears to be an efficacious new therapeutic choice in the prophylaxis of CDH, especially for patients not responding to previous prophylactic treatments.     

Somatic symptoms in headache patients: the influence of headache diagnosis, frequency, and comorbidity

BACKGROUND: Mood disorders of anxiety and depression are well known to be comorbid with primary headache disorders. Less is known of the comorbidity of other somatic symptoms with headache. METHODS: Headache Clinic patients were screened with the Primary Care Evaluation of Mental Disorders (PRIME-MD), a multidimensional psychiatric screening tool. The prevalence of somatic symptoms was compared by headache diagnosis, frequency of severe headache, and psychiatric diagnosis. Follow-up data were obtained 6 months after consultation. RESULTS: Clinical diagnoses and PRIME-MD data were available for 289 patients. Associated somatic symptoms were more frequent in patients with chronic migraine (mean 5.5, P<.001) and chronic daily headache (CDH) (6.3, P=.008) compared to episodic migraine (4.0); in patients with severe headache >2 days per week compared to 2 days per week had significantly higher somatic counts (P=.01). Six-month follow-up data were available for 140 patients. Associated symptoms decreased both for patients with and without decrease in severe headache frequency (mean reduction of 1.0, P=.01 and 0.8, P=.003, respectively). CONCLUSION: Associated somatic symptoms are more common in patients with chronic migraine and CDH, with more frequent severe headaches, and with associated anxiety or depression. Patients with episodic migraine have similar somatic prevalence as a previously studied primary care population. The spectrum of headache disorders may be characterized as showing increasing somatic prevalence as headaches, particularly severe headaches, become more frequent.     

Chronic daily headache prophylaxis with tizanidine: a double-blind,placebo-controlled,multicenter outcome study

OBJECTIVE: To assess the efficacy of tizanidine hydrochloride versus placebo as adjunctive prophylactic therapy for chronic daily headache (chronic migraine, migrainous headache, or tension-type headache). BACKGROUND: Tizanidine is an alpha2-adrenergic agonist that inhibits the release of norepinephrine at both the spinal cord and brain, with antinociceptive effects that are independent of the endogenous opioid system. Previous open-label studies have suggested the drug may be effective for treatment of chronic daily headache. METHODS: Two hundred patients completed a 4-week, single-blind, placebo baseline period, with 134 fulfilling selection criteria and then randomized to tizanidine or placebo. Ninety-two patients completed at least 8 weeks of treatment (tizanidine, n = 45; placebo, n = 47), and 85 patients completed 12 weeks of treatment (tizanidine, n = 44; placebo, n = 41). Most patients (77%) met the diagnostic criteria for migraine of the International Headache Society; 23% had either chronic migrainous headache or chronic tension-type headache. Tizanidine was slowly titrated over 4 weeks to 24 mg or the maximum dose tolerated (mean, 18 mg; SD, 6.4; median, 20.0; range, 2 to 24), divided equally over three dose intervals per day. Overall headache index ([headache days x average intensity x duration in hours]/28 days) was the primary end point. RESULTS: Tizanidine was shown to be superior to placebo in reducing the overall headache index (P =.0025), as well as mean headache days per week (P =.0193), severe headache days per week (P =.0211), average headache intensity (P =.0108), peak headache intensity (P =.0020), and mean headache duration (P =.0127). The mean percentage improvement during the last 4 weeks of treatment with tizanidine versus placebo was 54% versus 19% for the headache index (P =.0144), 55% versus 21% for severe headache days (P =.0331), 35% versus 19% for headache duration (P =.0142), 35% versus 20% for peak headache intensity (P =.0106), 33% versus 20% for average headache intensity (P =.0281), and 30% versus 22% for total headache days (P =.0593). Patients receiving tizanidine also scored higher ratings of overall headache improvement on a visual analog scale (P =.0069). There was no statistically significant difference in outcome for patients with chronic migraine versus those with only migrainous or tension-type headache. Adverse effects reported by more than 10% of the patients included somnolence (47%), dizziness (24%), dry mouth (23%), and asthenia (19%). Dropouts due to adverse events did not differ significantly between tizanidine and placebo. CONCLUSIONS: The results support tizanidine as an effective prophylactic adjunct for chronic daily headache, including migraine, migrainous headache, and tension-type headache. These results also suggest the possible importance of an alpha2-adrenergic mechanism underlying the pathophysiology of this spectrum of headache disorders.     

Amitriptyline in the prophylactic treatment of migraine and chronic daily headache

(Headache 2011;51:33‐51) Objective and Background.— Amitriptyline is one of the most commonly used medications in migraine prophylaxis. There have been relatively few placebo‐controlled studies of amitriptyline in migraine prophylaxis or in treatment of chronic daily headache (CDH). This report deals with a large placebo‐controlled trial of amitriptyline vs placebo of 20 weeks duration that included subjects with intermittent migraine (IM) as well as CDH. The study was carried out between 1976 and 1979; however, results have never been fully reported. Methods.— Patients with a history of migraine as defined by the 1962 Ad Hoc Committee report were recruited for this study. Subjects had at least 2 headaches per month, and no limit was placed on the number of headaches per month that could be experienced. The study format included a 4‐week baseline period (Period A) in which all subjects received placebo in a dose of 2 pills per day for one week, 3 pills per day for one week and then 4 pills per day for 2 weeks. Subjects with at least 2 migraine headaches in this period were then entered into Period B and randomized into either amitriptyline or placebo tracks. Medication consisted of identical tablets containing either 25 mg amitriptyline or placebo. Period B was 4 weeks in duration with dose titration identical to Period A. The dose could be reduced if necessary to reduce side effects. The minimum dose was one pill per day. Period C was a 12‐week maintenance or stabilization period in which the patient continued the dose established by week 8 with visits at weeks 12, 16, and 20. Patients kept a headache calendar that was used for data collection. Headache frequency (per month), severity, and duration (hours) were the primary measurement parameters employed for data analysis. Results.— For the entire group, 391 subjects were entered into Period A, 338 were randomized into Period B, 317 (81%) subjects completed the first post‐randomization visit (8 weeks), 255 (65%) completed week 12, 210 (54%) completed week 16, and 186 (48%) completed week 20. Using headache frequency and evaluating parameters of (a) improvement, (b) no change, or (c) worsening relative to baseline, there was a significant improvement in headache frequency for amitriptyline over placebo at 8 weeks (P = .018) but not at 12, 16, or 20 weeks. When amitriptyline and placebo patients were compared for headache frequency at 8, 12, 16, and 20 weeks to their own placebo stabilization period at 4 weeks, statistically significant improvement vs worsening was seen in headache frequency at each evaluation point for both amitriptyline and placebo groups (P ≤ .01) reaching 50% reporting a decrease in frequency in each group and approximately 10% reporting worsening by week 20. There were no significant differences in headache severity or duration between amitriptyline and placebo groups at anytime during the study. Within the study sample, there were 36 amitriptyline and 22 placebo subjects who had headaches ≥17 days/month that fit the current definition of CDH by the Silberstein‐Lipton criteria. These were analyzed separately as a subgroup for comparison of amitriptyline vs placebo using a metric of (1) no change or worsening; (2) up to a 50% improvement; and (3) ≥50% improvement in headache frequency. Amitriptyline was superior to placebo in number with improvement in frequency of ≥50% at 8 weeks (25% vs 5% [P = .031]) and at 16 weeks (46% vs 9% [P = .043]). There was a trend for amitriptyline to be superior to placebo at 12 and 20 weeks but this did not reach significance. Conclusions.— In this study, using headache frequency as the primary metric, for the entire group, amitriptyline was superior to placebo in migraine prophylaxis at 8 weeks but, because of a robust placebo response, not at subsequent time points. For the subgroup with CDH, amitriptyline was statistically significantly superior to placebo at 8 weeks and 16 weeks with a similar but nonsignificant trend at 12 and 20 weeks. Compared with placebo amitriptyline is effective in CDH. Amitriptyline was also significantly effective in IM compared intragroup to its own baseline; however, placebo was equally effective in the same analysis. The reason for the robust placebo response in the IM group is not clear, but has been occasionally reported.     

Analysis of the patients attending a specialist UK headache clinic over a 3-year period

OBJECTIVE: This study analyzed the profile of patients who attended a specialist UK headache clinic over a 3-year period. METHODS: An audit was conducted of the clinical records of patients attending the specialist headache clinic at King's College, London, between January 1997 and January 2000. Data were collected for diagnoses given, current medications taken, medications prescribed and recommended, and investigations conducted. Results were calculated as numbers and proportions of patients for the 3-year period and for the 3 separate 12-month periods. RESULTS: A total of 458 patients were included in the audit. Most patients were diagnosed as having chronic daily headache (CDH, 60%) or migraine (33%). Prior to the clinic visit, most patients with CDH and migraine treated their headaches with analgesics, and there was little use of prophylactic medication. In the clinic, 74% of patients with CDH and 85% of migraineurs were prescribed prophylactic medication, and 81% of migraineurs were given triptans for acute treatment. Diagnostic testing was performed in 12% of the patients, and all results were normal or negative. CONCLUSIONS: CDH and migraine were the most common headache types encountered in this UK secondary-care clinic. Review of treatment patterns used prior to the initial clinic evaluation suggests that management of CDH and migraine in UK primary care is suboptimal, and educational initiatives are needed to improve headache management.     

Botulinum neurotoxin type A in the preventive treatment of refractory headache: a review of 100 consecutive cases

OBJECTIVES: To review the efficacy of botulinum neurotoxin type A (BoNT-A) in the preventive treatment of refractory headache. BACKGROUND: Even after receiving expert care, some patients with refractory headache continue to have high disability and persistent headaches. METHODS: Clinical records and headache calendars of 100 patients fulfilling the following inclusion criteria were reviewed: (1) age from 18 to 65 years; (2) primary headache with previous failure of at least four preventive treatments; and (3) have received BoNT-A and have been followed for at least 6 months after the BoNT-A injections. BoNT-A (100 units) was diluted in 4-cc normal saline. The muscles injected included some or all of the following: frontalis, temporalis, corrugator, procerus, occipitalis, semispinalis, splenius capitis, trapezius, cervical paraspinalis, and sternocleidomastoid. Migraine-related disability was assessed using the Migraine Disability Assessment (MIDAS) questionnaire. RESULTS: There was a statistically significant reduction of the frequency of headache days 1 month after BoNT-A was administered (14.2 vs 28.2 days at the baseline, P <.001), which was maintained through the 3 months of study; similarly, a significant reduction in the headache index (22.3 vs 40.3, P <.001) and number of severe days with headache per month (2.6 vs 7.4, P <.001) were found at 1 month and maintained through the 3 months of study. MIDAS scores were reduced from 34.5 at baseline to 15.9 at 3 months (P <.001). A similar pattern was found in those overusing versus nonoverusing acute medication, though the response was more dramatic in the nonoverusing subgroup. CONCLUSION: BoNT-A may play a role in the preventive treatment of refractory headache. A significant number of patients showed decrease in clinically important measurements of their headaches as well as reduced headache-related disability with this treatment. Prospective, controlled studies must be considered for severely disabled, refractory patients.     

Divalproex extended-release in adolescent migraine prophylaxis: results of a randomized, double-blind, placebo-controlled study

Objective.— To evaluate the efficacy, tolerability, and safety of 3 different doses of divalproex sodium extended‐release vs placebo in the prophylaxis of migraine headaches in adolescents. Background.— Divalproex sodium has been approved for migraine prophylaxis in adults, and previous uncontrolled data suggest divalproex sodium may be effective in preventing migraine in children and adolescents with acceptable tolerability. Methods.— This was a 12‐week, phase 3, randomized, placebo‐controlled, double‐blind, parallel‐group, multicenter study in approximately 300 adolescents aged 12 to 17 years with migraine headaches. At the end of the baseline phase, subjects still meeting study criteria were randomized in a 1 : 1 : 1 : 1 ratio to receive divalproex sodium extended‐release 250 mg, 500 mg, or 1000 mg once daily, or placebo. The primary efficacy variable was reduction from baseline in 4‐week migraine headache rate for each active treatment group vs placebo. Standard safety assessments were conducted and testosterone and sex hormone‐binding globulin levels were collected for postmenarchal females. Results.— There was no statistically significant treatment difference between any divalproex sodium extended‐release dose group and placebo for the primary efficacy variable, reduction from baseline in 4‐week migraine headache rate. There were no statistically significant differences in adverse events between any active treatment group and placebo. A notable dose‐related decrease in platelets was observed, and individuals in all 4 treatment groups had increases in ammonia levels; treatment differences in other laboratory variables were generally small. Among postmenarchal female subjects who were not taking hormonal contraceptives or other steroids, there was no statistically significant change in testosterone levels, but a statistically significant dose‐related increase in sex hormone‐binding globulin was observed. Conclusions.— In the current study, divalproex sodium extended‐release did not differentiate from placebo in the prophylactic treatment of migraine headaches but was generally well‐tolerated in adolescents aged 12 to 17 years.     

Predictors of a negative response to topiramate therapy in patients with chronic migraine

OBJECTIVE: To identify variables predictive of a negative response to prophylactic therapy with topiramate in patients with chronic migraine. BACKGROUND: While certain of the newer antiepileptic drugs (AEDs) have emerged as promising or definitely effective therapies for migraine prevention, we continue to lack biologic or clinical variables predictive of treatment response to these or other widely used prophylactic therapies. METHODS: A consecutive series of 170 patients with IHS-defined migraine who were experiencing 15 or more days of headache per month were treated with topiramate according to a uniform dosing protocol. Variables examined for their potential value in predicting treatment response included age, gender, prior experience with prophylactic therapy, prior experience with divalproex sodium specifically, headache frequency and, if present, duration of chronic daily headache (CDH). A positive treatment response was defined as a 50% or greater reduction in headache days during the second treatment month relative to the patient's pretopiramate baseline. Only patients who completed the treatment phase and achieved the 50 mg BID target dose were analyzed (efficacy analysis). Each variable prospectively selected was evaluated in regards to treatment outcome via a paired t-test, and a multiple regression analysis of all variables subsequently was performed. RESULTS: A total of 116 patients completed at least 60 days of treatment and consequently were available for analysis. In the efficacy analysis, 45 (38.8%) of the 116 responded positively to topiramate. Neither age nor gender influenced treatment response. Those patients with CDH of more than 6 months duration, patients who previously had tried and failed more than three prophylactic agents and patients who previously had failed to respond to divalproex sodium were more likely to be nonresponders, but after multiple regression analysis the only statistically significant predictor of a negative treatment response was CDH of more than 6 months duration (P<.001). CONCLUSIONS: Patients with chronic migraine who are treated with topiramate may respond positively at a rate approaching that reported from placebo-controlled trials involving topiramate or other AEDs administered to less severely afflicted migraineurs. Our analysis suggests that patients with chronic migraine least likely to respond to topiramate would be those with extensive and negative previous experience with prophylactic therapy, previous failure to respond to divalproex sodium, CDH, and, most notably, CDH of more than 6 months duration.     

Topiramate in the treatment of chronic migraine

The purpose of this study was to evaluate the efficacy of topiramate in the treatment of chronic migraine. This was a double-blind, randomized, placebo controlled, parallel-group study. Patients suffering from chronic migraine with analgesic overuse were randomly assigned in a 1 : 1 ratio to receive topiramate or placebo. Following a baseline phase of eight weeks, the study drug was titrated in 25-mg increments over one week to 50 mg daily. Titration phase was followed by a 8-week maintenance phase. Number of days with headache during a 28-day period was the efficacy variable. At baseline, there was no difference in the number of days with headache between patients treated with topiramate and those treated with placebo (mean +/- SD: 20.9 +/- 3.2 and 20.8 +/- 3.2, respectively). During the last 4 week-maintenance phase, topiramate-treated patients experienced a significantly lower 28-day headache frequency in comparison to those treated with placebo (mean number of days with headache +/- SD: 8.1 +/- 8.1 vs. 20.6 +/- 3.4, P < 0.0007). Topiramate at low doses proved to be an effective therapeutic approach to reduce headache frequency in patients with chronic migraine and analgesic overuse.     

The prophylactic treatment of chronic daily headache

Chronic daily headache (CDH), a heterogeneous group of headache disorders occurring on at least 15 days per month, affects up to 4% to 5% of the general population. CDH disorders include transformed (or chronic) migraine, chronic tension-type headache, new daily persistent headache, and hemicrania continua. Patients with CDH have greater disability and lower quality of life than episodic migraine patients and often overuse headache pain medications. To date, only topiramate, gabapentin, tizanidine, fluoxetine, amitriptyline, and botulinum toxin type A (BoNTA) have been evaluated as prophylactic treatment of CDH in randomized, double-blind, placebo-controlled, or active comparator-controlled trials. The evidence supporting the use of BoNTA as prophylaxis of CDH is composed of larger and longer trials, as over 1000 patients were evaluated for up to 11 months duration. Compared with placebo BoNTA has significantly reduced the frequency of headache episodes, a recommended efficacy measure for headache trials and has been demonstrated to be safe and very well tolerated with few discontinuations due to adverse events. Side effects are generally transient, mild to moderate, and nonsystemic. The results of clinical trials using traditional oral pharmacotherapy, while supportive of their use as prophylactic treatment of CDH, are limited by several factors, including small numbers of patients, the choice of efficacy measures, and short treatment periods. The use of oral agents was associated with systemic side effects, which may limit their effectiveness as prophylactic treatment of CDH.     

Botulinum toxin type-A in the prophylactic treatment of medication-overuse headache: a multicenter,double-blind,randomized, placebo-controlled,parallel group study

Medication-overuse headache (MOH) represents a severely disabling condition, with a low response to prophylactic treatments. Recently, consistent evidences have emerged in favor of botulinum toxin type-A (onabotulinum toxin A) as prophylactic treatment in chronic migraine. In a 12-week double-blind, parallel group, placebo-controlled study, we tested the efficacy and safety of onabotulinum toxin A as prophylactic treatment for MOH. A total of 68 patients were randomized (1:1) to onabotulinum toxin A (n = 33) or placebo (n = 35) treatment and received 16 intramuscular injections. The primary efficacy end point was mean change from baseline in the frequency of headache days for the 28-day period ending with week 12. No significant differences between onabotulinum toxin A and placebo treatment were detected in the primary (headache days) end point (12.0 vs. 15.9; p = 0.81). A significant reduction was recorded in the secondary end point, mean acute pain drug consumption at 12 weeks in onabotulinum toxin A-treated patients when compared with those with placebo (12.1 vs. 18.0; p = 0.03). When we considered the subgroup of patients with pericranial muscle tenderness, we recorded a significant improvement in those treated with onabotulinum toxin A compared to placebo treated in both primary (headache days) and secondary end points (acute pain drug consumption, days with drug consumption), as well as in pain intensity and disability measures (HIT-6 and MIDAS) at 12 weeks. Onabotulinum toxin A was safe and well tolerated, with few treatment-related adverse events. Few subjects discontinued due to adverse events. Our data identified the presence of pericranial muscle tenderness as predictor of response to onabotulinum toxin A in patients with complicated form of migraine such as MOH, the presence of pericranial muscle tenderness and support it as prophylactic treatment in these patients.     

Intravenous dexamethasone vs placebo as adjunctive therapy to reduce the recurrence rate of acute migraine headaches: a multicenter, double-blinded, placebo-controlled randomized clinical trial

Objectives

Some physicians prescribe corticosteroids as adjunctive therapy for patients with migraine headaches to decrease the rate of rebound headache. The efficacy of this practice has not been tested. Our objective is to determine the efficacy of single-dose dexamethasone as adjunctive therapy for emergency medicine patients with migraine headache in preventing headache recurrence at 3 and 30 days posttreatment.

Methods

From November 2004 to November 2005, we conducted a multicenter, double-blinded, placebo-controlled randomized clinical trial of adult patients who met the International Headache Society definition of migraine headache. After informed consent, patients were randomly assigned to one of two groups: receiving either placebo or 24 mg dexamethasone intravenously. To ensure generalizability, all other aspects of patient care were left to the discretion of the emergency physician. Clinical and demographic information was obtained; and patients were subsequently contacted at both 3 and 30 days to determine headache recurrence, current functional disability, and need for return to the ED. Our primary outcome measures were the recurrence of migraine headache at 3 and 30 days. We used Fisher exact to test for statistical significance.

Results

A total of 115 patients were enrolled, with 16 patients lost to follow-up at 3 days and 3 additional patients lost at 30 days. Baseline characteristics as well as adverse event profiles were equivalent in both study groups. At 3-day follow-up, 45% (95% confidence interval [CI] 31%-60%) of the placebo group had recurrence of their migraine compared with 35% (95% CI 24%-48%) in the dexamethasone group (P = .68). At 30-day follow-up, this relative reduction in migraine recurrence decreased to a 4% difference between the 2 groups (P = .68). Limitations include small sample size and significant proportion lost to follow-up.

Conclusion

A single dose of dexamethasone as adjunctive therapy for migraine headache does not decrease the recurrence of migraines at 3 or 30 days.     

MEDICATION OVERUSE HEADACHE AND OTHER CHRONIC DAILY HEADACHES

The purpose of this study was to evaluate the efficacy of topiramate in the treatment of chronic migraine. This was a double-blind, randomized, placebo controlled, parallel-group study. Patients suffering from chronic migraine with analgesic overuse were randomly assigned in a 1:1 ratio to receive topiramate or placebo. Following a baseline phase of eight weeks, the study drug was titrated in 25-mg increments over one week to 50 mg daily. Titration phase was followed by a 8-week maintenance phase. Number of days with headache during a 28-day period was the efficacy variable. At baseline, there was no difference in the number of days with headache between patients treated with topiramate and those treated with placebo (mean ± SD: 20.9 ± 3.2 and 20.8 ± 3.2, respectively). During the last 4 week-maintenance phase, topiramate-treated patients experienced a significantly lower 28-day headache frequency in comparison to those treated with placebo (mean number of days with headache ± SD: 8.1 ± 8.1 vs. 20.6 ± 3.4, P < 0.0007). Topiramate at low doses proved to be an effective therapeutic approach to reduce headache frequency in patients with chronic migraine and analgesic overuse.
Comment: This is a fascinating study for a number of reasons. Topiramate (TPM) received a Food and Drug Administration (FDA) approvable letter for an indication for migraine in late 2003. In the large, randomized, controlled studies for episodic migraine, 100 mg was superior to 50 mg and placebo, and 200 mg was not significantly different from 100 mg, but had more adverse events associated with use. See the following :     

Transformed or Evolutive Migraine

SYNOPSIS
630 (39%) of 1600 patients seen in a Headache Clinic over a three year period had chronic daily headaches (CDH). In 78% of these CDH patients, the daily headaches evolved out of a prior history of episodic migraine; these patients we designate as having "transformed" or "evolutive" migraine. The other 12% had migraine headaches which were daily from the start.
Patients with transformed migraine, in contrast to those with daily headaches from the start, have a significantly higher incidence of positive family history of migraine, menstrual aggravation of migraine, identifiable trigger factors, associated G.I. and neurological symptoms, and early morning awakening with headache.
The CDH group in general over-used symptomatic medication and exhibited abnormalities on behavioral scale testing. Withdrawal of daily symptomatic medication, institution of a low tyramine low caffeine diet, initiation of prophylactic anti-migraine therapy, and biofeedback and behavioral therapy, gave worthwhile improvement in 76% of chronic daily headache patients.
Factors which promote "evolution" of migraine from intermittent to chronic daily occurrence are not well-defined but may include medication abuse, medication withdrawal, and psychiatric disturbances.     

Treatment of mild headache in disabled migraine sufferers: results of the Spectrum Study

OBJECTIVE: To evaluate the effectiveness of sumatriptan, 50-mg tablets, versus placebo for early intervention while head pain was mild in patients with disabling migraine. METHODS: A post hoc analysis was performed in a subgroup of patients from a large, randomized, placebo-controlled study of patients with disabling headache who treated while pain was mild. Pain-free response 2 and 4 hours postdose, headache recurrence, and safety were examined. Significance tests were performed only for the first-treated attacks. RESULTS: Twenty-six patients with disabling headache treated 46 mild and 166 moderate or severe headaches. For the first-treated headaches while pain was mild, pain-free rates were significantly higher for sumatriptan than placebo 4 hours postdose (78% versus 0%, P =.02), but not 2 hours postdose (52% versus 0%, P =.22). Across all headaches treated while pain was mild, pain-free responses were higher for sumatriptan than placebo 4 hours (85% versus 17%) and 2 hours (50% versus 0%) postdose compared with placebo. When the same patients treated headaches while pain was moderate or severe, pain-free rates were lower than that reported for treatment during mild pain. There was a trend toward lower headache recurrence in headaches treated while pain was mild compared with moderate or severe pain (13% versus 18%). No drug-related adverse events were reported in the headaches treated while pain was mild. CONCLUSIONS: Patients with disabling migraine may benefit from early intervention with sumatriptan, 50 mg, while pain is mild.     

Behavioral and nonpharmacologic treatments of headache

Cognitive-behavioral analysis and the multiaxial assessment of relevant behavioral domains (headache frequency and severity, analgesic and abortive use and misuse, behavioral and stress-related risk factors, comorbid psychiatric disorders, and degree of overall functional impairment) help set the stage for CBT of headache disorders. Controlled studies of CBTs for migraine, such as biofeedback and relaxation therapy, have a prophylactic efficacy of about 50%, roughly equivalent to propranolol. Cluster headache responds poorly to behavioral treatment. The persistent overuse of symptomatic medication impedes the effectiveness of behavioral and prophylactic medical therapies. Behavioral treatment can help sustain improvement after analgesic withdrawal, however, and prevent relapse in cases of analgesic overuse. Cognitive factors (e.g., an enhanced sense of self-efficacy and internal locus of control) appear to be important mediators of successful behavioral treatment. Patients with CDH are more likely to overuse symptomatic medication (and in some cases abuse analgesics), have more psychiatric comorbidity; have more functional impairment and disability, and are at least as likely to experience stress-related intensification of headache as patients whose episodic headaches occur less than 15 days per month. Despite the significance of these behavioral factors, patients with CDH (particularly those with migrainous features) are less likely to benefit from behavioral treatment without concomitant prophylactic medication than is the case for episodic TTH and migraine sufferers. Continuous daily pain may be more refractory to behavioral treatment as a solo modality than CDH marked by at least some pain-free days or periods of time. The combination of behavioral therapies with prophylactic medication creates a synergistic effect, increasing efficacy beyond either type of treatment alone. Compliance-enhancement techniques, including behavioral contracts for patients with severe personality disorders, can increase adherence to behavioral recommendations. CBT has earned an important place in the comprehensive treatment of patients with episodic migraine/TTH and severe, treatment-resistant chronic daily headache.