Botulinum toxin type a for the prophylaxis of chronic daily headache: subgroup analysis of patients not receiving other prophylactic medications: a randomized double-blind, placebo-controlled study

OBJECTIVE: To assess the efficacy and safety of botulinum toxin type A (BoNT-A; BOTOX, Allergan, Inc., Irvine, CA) for the prophylaxis of headaches in patients with chronic daily headache (CDH) without the confounding factor of concurrent prophylactic medications. BACKGROUND: Several open-label studies and an 11-month, randomized, double-blind, placebo-controlled study suggest that BoNT-A may be an effective therapy for the prophylaxis of headaches in patients with CDH. DESIGN AND METHODS: This was a subgroup analysis of an 11-month, randomized double-blind, placebo-controlled study of BoNT-A for the treatment of adult patients with 16 or more headache days per 30-day periods conducted at 13 North American study centers. All patients had a history of migraine or probable migraine. This analysis involved data for patients who were not receiving concomitant prophylactic headache medication and who constituted 64% of the full study population. Following a 30-day screening period and a 30-day single-blind, placebo injection, eligible patients were injected with BoNT-A or placebo and assessed every 30 days for 9 months The following efficacy measures were analyzed per 30-day periods: change from baseline in number of headache-free days; change from baseline in headache frequency; proportion of patients with at least 30% or at least 50% decrease from baseline in headache frequency; and change from baseline in mean headache severity. Acute medication use was assessed, and adverse events were recorded at each study visit. RESULTS: Of the 355 patients randomized in the study, 228 (64%) were not taking prophylactic medication and were included in this analysis (117 received BoNT-A, 111 received placebo injections). Mean age was 42.4+/-10.90 years; the mean frequency of headaches per 30 days at baseline was 14.1 for the BoNT-A group and 12.9 for the placebo group (P=.205). After two injection sessions, the maximum change in the mean frequency of headaches per 30 days was -7.8 in the BoNT-A group compared with only -4.5 in the placebo group (P=.032), a statistically significant between-group difference of 3.3 headaches. The between-group difference favoring BoNT-A treatment continued to improve to 4.2 headaches after a third injection session (P=.023). In addition, BoNT-A treatment at least halved the frequency of baseline headaches in over 50% of patients after three injection sessions compared to baseline. Statistically significant differences between BoNT-A and placebo were evident for the change from baseline in headache frequency and headache severity for most time points from day 180 through day 270. Only 5 patients (4 patients receiving BoNT-A treatment; 1 patient receiving placebo) discontinued the study due to adverse events and most treatment-related events were transient and mild to moderate in severity. CONCLUSIONS: BoNT-A is an effective and well-tolerated prophylactic treatment in migraine patients with CDH who are not using other prophylactic medications.     

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.     

Botulinum toxin A for chronic daily headache: a randomized, placebo-controlled, parallel design study

Sixty patients with headaches of more than 15 days per month were recruited for this double-blind, placebo-controlled, parallel study of botulinum toxin type A (BTX) for chronic tension type and chronic migraine headaches. The primary efficacy point was the number of headache-free days as assessed by diary for 12 weeks after BTX injection. Secondary efficacy points included global impressions, the use of abortive headache medications, and palpation. After recruitment, subjects kept diaries for 4 weeks prior to randomization, at which time they received either 200 U of BTX or matching placebo and were followed. After the week-12 evaluation, patients were offered 200 U of BTX (open label), and were similarly followed for another 12 weeks. The mean days with headache of the 60 subjects (49 female, mean age 47 +/- 11 years) was 23 +/- 7 out of 30. Both groups were demographically similar (58 completed). Over a 12-week period after injections, headache-free days had improved in the BTX group from week 8 to 12 (P < 0.05), and strongly tended to improve over the entire 12-week period, 33 +/- 23 vs. 24 +/- 16 days without headache (P = 0.07), but did not meet the a priori significance criteria. The subject global impressions (P < 0.05), subject change in headache impressions (P < 0.005), and investigator global impressions (P < 0.001) all improved in the BTX group compared with placebo. Adverse events were mild and did not differ between groups. At week 24 (open label), headache-free days were less in the twice BTX injected group compared with the once injected group, 40 +/- 26 vs. 26 +/- 19 (P < 0.05). BTX may help chronic daily headache and appears to have a cumulative effect with subsequent injections. The treatment was very well tolerated.     

Botulinum toxin type A in the prophylactic treatment of chronic tension-type headache: a multicentre, double-blind, randomized, placebo-controlled, parallel-group study

We studied the safety and efficacy of 0 U, 50 U, 100 U, 150 U (five sites), 86 Usub and 100 Usub (three sites) botulinum toxin type A (BoNTA; BOTOX); Allergan, Inc., Irvine, CA, USA) for the prophylaxis of chronic tension-type headache (CTTH). Three hundred patients (62.3% female; mean age 42.6 years) enrolled. For the primary endpoint, the mean change from baseline in the number of TTH-free days per month, there was no statistically significant difference between placebo and four BoNTA groups, but a significant difference favouring placebo vs. BoNTA 150 was observed (4.5 vs. 2.8 tension headache-free days/month; P = 0.007). All treatment groups improved at day 60. Although efficacy was not demonstrated for the primary endpoint, at day 90, more patients in three BoNTA groups had >or=50% decrease in tension headache days than did placebo (P 相似文献   

Classical homeopathic treatment of chronic headaches

We conducted a randomized, placebo-cor rolled, double-blind clinical trial in order to determine the efficacy of classical homeopathic therapy in patients with chronic headaches. After 6 weeks of baseline observation, patients received either the prescribed individualized homeopathic medication or an indistinguishable placebo for 12 weeks. Outcome parameters were headache frequency, duration, and intensity, measured daily by diary. Use of medication for acure headache was also monitored. Of the 98 patients in the sample, 37 were randomized to receive placebo, 6l received individualized homeopathic remedies. Groups were comparable at the beginning of the treatment. The median age was 48.5 years; 76% suffered from migraine, 51% from tension-type headaches, and 94% were previously treated for headache. The median headache frequency was 3 days a week. Headaches were present for 23 years (median). In both groups, patients showed an improvement of one headache day less per month. The use of medication for acute headache was reduced. The headache frequency of 11 patients was reduced by more than 40%. Thirty-nine patients either did not improve or experienced aggravations. There was no significant difference in any parameter between homeopathy and placebo.     

Physical therapy and adjunctive botulinum toxin type A in the treatment of cervical headache: a double-blind, randomised, placebo-controlled study

We examined the efficacy of physical therapy and adjunctive botulinum toxin type A (BTX-A) injections in the treatment of cervical headache. We performed a doubleblind, randomised, placebo-controlled study over a 12-week period in a university clinic outpatients department. A total of 33 patients with cervical headache, diagnosed according to International Headache Society classification were enrolled. All patients received standardized physical therapy over a three-week period. Patients were randomised to receive either BTX-A (Botox) or placebo. The BTX-A group received a total dose of 90 mouse units (mu) BTX-A at six trigger points while the placebo group received saline. Pain characteristics were reported in a headache diary. Tenderness in the neck muscles, the sagittal range of motion and biofeedback measurement were also documented. Both groups showed significant improvement in terms of headache severity (p<0.05), number of headache-free days (p=0.005) and number of headache hours per day (p<0.05). Trends towards an increase in the number of headache-free days and a decrease in headache hours per day were observed in the BTX-A group. No major side effects were observed. Physical measures and BTX-A injections are safe and effective in the treatment of cervical headache. Received: 12 July 2001, Accepted in revised form: 1 July 2002 Correspondence to P. Schnider     

Treating chronic tension-type headache not responding to amitriptyline hydrochloride with paroxetine hydrochloride: a pilot evaluation

CONTEXT: In some individuals, chronic tension-type headache fails to respond to tricyclic antidepressant medications that often serve as first-line therapy. OBJECTIVE: To evaluate the clinical efficacy of paroxetine hydrochloride for chronic tension-type headache not responding to amitriptyline hydrochloride. DESIGN AND SETTING: Open-label trial of paroxetine conducted at 2 outpatient sites in Ohio. PARTICIPANTS AND INTERVENTION: Thirty-one adults (mean age, 37 years; 20 women) with chronic tension-type headache (mean, 25 headache days per month) who had failed to respond (less than 30% improvement) to treatment with either amitriptyline (n = 13) or matched placebo (n = 18). All participants were treated with paroxetine (up to 40 mg per day) in a 9-month protocol. OUTCOME MEASURES: Monthly headache index calculated as the mean of pain ratings (0 to 10 scale) recorded by participants in a diary 4 times per day, number of days per month with at least moderate pain (pain rating of 5 or greater), and analgesic medication use. RESULTS: In patients who had not responded to amitriptyline, paroxetine failed to reduce chronic tension-type headaches or analgesic medication use. In patients who had not responded to placebo, paroxetine produced modest reductions in chronic tension-type headaches and analgesic use. CONCLUSIONS: We found no evidence that chronic tension-type headaches that failed to respond to tricyclic antidepressant therapy with amitriptyline improved when subsequently treated with paroxetine. More support was found for the efficacy of paroxetine in patients with chronic tension-type headaches who had failed to respond to placebo.     

Efficacy and safety of topiramate for the treatment of chronic migraine: a randomized, double-blind, placebo-controlled trial

OBJECTIVE: To evaluate the efficacy and safety of topiramate (100 mg/day) compared with placebo for the treatment of chronic migraine. METHODS: This was a randomized, placebo-controlled, parallel-group, multicenter study consisting of 16 weeks of double-blind treatment. Subjects aged 18 to 65 years with 15 or more headache days per month, at least half of which were migraine/migrainous headaches, were randomized 1:1 to either topiramate 100 mg/day or placebo. An initial dose of topiramate 25 mg/day (or placebo) was titrated upward in weekly increments of 25 mg/day to a maximum of 100 mg/day (or to the maximum tolerated dose). Concomitant preventive migraine treatment was not allowed, and acute headache medication use was not to exceed 4 days per week during the double-blind maintenance period. The primary efficacy endpoint was the change from baseline in the mean monthly number of migraine/migrainous days; the change in the mean monthly number of migraine days also was analyzed. A fixed sequence approach (ie, gatekeeper approach) using analysis of covariance was used to analyze the efficacy endpoints. Assessments of safety and tolerability included physical and neurologic examinations, clinical laboratory parameters, and spontaneous reports of clinical adverse events. RESULTS: The intent-to-treat population included 306 (topiramate, n = 153; placebo, n = 153) of 328 randomized subjects who provided at least 1 efficacy assessment; 55.8% of the topiramate group and 55.2% on placebo were trial completers. The mean final topiramate maintenance dose was 86.0 mg/day. The mean duration of therapy was 91.7 days for the topiramate group and 90.6 days for the placebo group. Topiramate treatment resulted in a statistically significant mean reduction of migraine/migrainous headache days (topiramate -6.4 vs placebo -4.7, P= .010) and migraine headache days relative to baseline (topiramate -5.6 vs placebo -4.1, P= .032). Treatment-emergent adverse events occurred in 132 (82.5%) and 113 (70.2%) of topiramate-treated and placebo-treated subjects, respectively, and were generally of mild or moderate severity. Most commonly reported adverse events in the topiramate group were paresthesia (n = 46, 28.8%), upper respiratory tract infection (n = 22, 13.8%), and fatigue (n = 19, 11.9%). The most common adverse events in the placebo group were upper respiratory tract infection (n = 20, 12.4%), fatigue (n = 16, 9.9%), and nausea (n = 13, 8.1%). Discontinuations due to adverse events occurred in 18 (10.9%) topiramate subjects and 10 (6.1%) placebo subjects. There were no serious adverse events or deaths. CONCLUSIONS: Topiramate treatment at daily doses of approximately 100 mg resulted in statistically significant improvements compared with placebo in mean monthly migraine/migrainous and migraine headache days. Topiramate is safe and generally well tolerated in this group of subjects with chronic migraine, a burdensome condition with important unmet treatment needs. Safety and tolerability of topiramate were consistent with experience in previous clinical trials involving the drug.     

The efficacy of divalproex sodium in the prophylactic treatment of children with migraine

OBJECTIVE: To determine the beneficial use of divalproex sodium as a prophylactic treatment for migraine in children. BACKGROUND: Previous studies for treatment of migraine in adults have shown a greater than 50% reduction in migraine attack frequencies. Few data exist, however, regarding the efficacy and safety of divalproex sodium use in children with migraine. METHODS: We studied the incidence of headache relief in our patients with migraine aged 16 years and younger treated with divalproex sodium prophylactically at our institution from July 1996 to December 1998 to determine medication dosage used, concomitant headache medications, and possible adverse effects. RESULTS: A total of 42 patients, ranging in age from 7 to 16 years (mean age, 11.3 years), were treated with divalproex sodium for headache. All had a history of migraine with or without aura. Baseline headache frequency during a minimum 6-month period was one to four headaches per month. Divalproex sodium dosage ranged from 15 mg/kg/day to 45 mg/kg/day. Of the 42 patients, 34 (80.9%) successfully discontinued their abortive medications. After 4 months' treatment, 50% headache reduction was seen in 78.5% of patients, 75% reduction in 14.2% of patients, and 9. 5% of patients became headache-free. CONCLUSION: These results indicate divalproex sodium to be an effective and well-tolerated treatment for the prophylaxis of migraine in children.     

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.     

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.     

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.     

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.     

Modified-release formulation of tizanidine in chronic tension-type headache

The efficacy of the modified-release formulation of tizanidine (Sirdalud) was compared with placebo in a randomized, double-blind, parallel-group study of 138 women and 47 men, aged 18 to 79 years, with a history of chronic tension-type headache (IHS categories 2.2 and 2.3). The treatment period was 6 weeks preceded by a 2-week prerandomization period. The patients were randomly assigned to receive 6-mg Sirdalud, 12-mg Sirdalud MR, or placebo. The study medication was taken once per day, orally in the evening. Efficacy was measured by visual analog scale, the number of headache-free days, the daily duration of headache, and the use of paracetamol. The primary end point was the severity of daily headache derived from visual analog scale scores covering the last 2 treatment weeks. One hundred sixty patients (56 in the 6-mg group, 49 in the 12-mg group, and 55 in the placebo group) completed the study. The severity of the headache decreased similarly in the treatment groups and the placebo group. The visual analog scale values decreased from the prerandomization values by 53% in the 6-mg group, 48% in the 12-mg group, and 52% in the placebo group. The modified-release formulation of tizanidine in doses up to 12 mg taken in the evening is not superior to placebo in the treatment of chronic tension-type headache. The placebo effect was unexpectedly strong in the present study, supporting the view that psychophysiological mechanisms are of considerable importance in sustaining chronic tension-type headache.     

Headache-Free Controls? Evidence of Headaches in Individuals Who Deny Having Headaches During Diagnostic Screening

In the course of two studies investigating whether individuals with recurrent tension headache differ from headache-free controls in the frequency and appraisal of stressful life events, subjects were asked to complete a headache diary for I week. Subjects in the headache-free control group were screened twice and reported having infrequent headaches (two or less per month). However, 13 of 38 control subjects reported multiple headache days on their headache diaries. These subjects also reported a greater frequency of stressful events and a greater stress impact score. These results suggest that a careful screening of control subjects may be necessary in studies theft examine differences between subjects with recurrent headache and headache-free controls. There is also some evidence that the inclusion of these subjects in a control group may bias the sample, making it less likely to find between-group differences.     

Preemptive Oral Treatment With Sumatriptan During a Cluster Period

This multinational, multicenter, randomized, double-blind, placebo-controlled study in 169 patients investigated the effect of a 7-day period of preemptive treatment with oral sumatriptan (100 mg tid) on the frequency and severity of cluster headache attacks occurring during an established cluster headache period. Safety and tolerability were also assessed.
Cluster headache patients who were not taking prophylactic medication and had experienced seven or more attacks in the preceding observation week, treated a cluster headache attack at home with subcutaneous sumatriptan 6 mg using an autoinjector device. Patients were then randomized to take sumatriptan 100 mg or placebo at 8-hourly intervals for a 7-day period. Cluster headaches occurring during this period could be treated 5 minutes after onset with rescue medication (100% oxygen or simple analgesics). Diary cards were used to record details of the cluster headache pattern during the observation and study treatment weeks.
Preemptive oral treatment with sumatriptan 100 mg tid for 7 days did not produce a significant reduction in the number or severity of cluster headache attacks occurring during an established cluster headache period. Oral treatment with sumatriptan 100 mg tid over a 7-day period was not associated with an increased or altered adverse event profile from that previously reported.     

Laser acupuncture in children with headache: a double-blind, randomized, bicenter, placebo-controlled trial

To investigate whether laser acupuncture is efficacious in children with headache and if active laser treatment is superior to placebo laser treatment in a prospective, randomized, double-blind, placebo-controlled trial of low level laser acupuncture in 43 children (mean age (SD) 12.3 (+/-2.6) years) with headache (either migraine (22 patients) or tension type headache (21 patients)). Patients were randomized to receive a course of 4 treatments over 4 weeks with either active or placebo laser. The treatment was highly individualised based on criteria of Traditional Chinese medicine (TCM). The primary outcome measure was a difference in numbers of headache days between baseline and the 4 months after randomization. Secondary outcome measures included a change in headache severity using a 10 cm Visual Analogue Scale (VAS) for pain and a change in monthly hours with headache. Measurements were taken during 4 weeks before randomization (baseline), at weeks 1-4, 5-8, 9-12 and 13-16 from baseline. The mean number of headaches per month decreased significantly by 6.4 days in the treated group (p<0.001) and by 1.0 days in the placebo group (p=0.22). Secondary outcome measures headache severity and monthly hours with headache decreased as well significantly at all time points compared to baseline (p<0.001) and were as well significantly lower than those of the placebo group at all time points (p<0.001). We conclude that laser acupuncture can provide a significant benefit for children with headache with active laser treatment being clearly more effective than placebo laser treatment.     

L-5-Hydroxytryptophan in the prophylaxis of chronic tension-type headache: a double-blind, randomized, placebo-controlled study. For the Portuguese Head Society

A parallel, randomized, double-blind trial is reported, in which 78 patients with chronic tension-type headaches were treated with L-5-hydroxytryptophan (5-HTP) (n = 43) or placebo (n = 35) for 8 weeks, after a washout period of 2 weeks and with a follow-up period of a further 2 weeks. Five patients dropped out (1 with placebo and 4 with 5-HTP), 1 was excluded due to noncompliance, and in 7 treatment was suspended due to adverse events (3 with placebo and 4 with 5-HTP), yielding a final number for evaluation of 65 patients. In comparison with the group treated with placebo, there was no statistically significant change in the number of days with headache or in headache intensity in the group treated with 5-HTP, 300 mg per day; however, there was a significant decrease in the consumption of analgesics. During the 2 weeks after treatment, there was a significant decrease in the number of days with headache. Subjective opinion during this latter period was also favorable to 5-HTP.     

Valproate in the Treatment of Persistent Chronic Daily Headache. An Open Label Study

Thirty patients with persistent chronic daily headache, unresponsive to various combinations of pharmacological and nonpharmacological treatment were selected for an open label study using divalproex sodium. All patients had normal liver function tests. After a baseline observation period of 1 month, patients were given divalproex sodium 1000 to 2000 mg per day, for a period of 3 months. Blood valproic acid levels were kept between 75 and 100 mcg/ml. Liver function studies and blood ammonia levels were obtained periodically. Based on weekly headache index, headache-free days, dysfunctional days and patients' general well-being rating and physicians' global assessment, two thirds of the patients improved significantly. The common side effects included weight gain, tremor, hair loss and nausea. Liver functions were unaffected by treatment. The possible mechanism of action of valproate in headache is discussed. Valproate appears to be a worthwhile addition to the prophylactic treatment of chronic recurrent headache.