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 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   

A multicentre, double-blind, randomized, placebo-controlled, parallel group study of multiple treatments of botulinum toxin type A (BoNTA) for the prophylaxis of episodic migraine headaches

Our aim was to evaluate the safety and efficacy of botulinum toxin type A (BoNTA; BOTOX) for prophylaxis of episodic migraine. In this double-blind, placebo-controlled study, patients were randomized to 225, 150 or 75 U of BoNTA or placebo after a 30-day placebo run-in for three 90-day treatment cycles. The primary efficacy end-point was the mean reduction from baseline in the frequency of migraine episodes at day 180 in the placebo non-responder stratum. All groups (N = 495) improved, with no significant differences. At day 180, the frequency of migraine episodes was reduced from baseline means of 4.3, 4.7, 4.7 and 4.4 by 1.6, 1.7, 1.5 and 1.4 for BoNTA 225 U, 150 U and 75 U and placebo, respectively. The primary end-point was not met. Treatment-related adverse events were transient and mild to moderate. BoNTA treatment was safe and well tolerated but did not result in significantly greater improvement than placebo in this study. Several factors may have confounded the results.     

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.     

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 and divalproex sodium for prophylactic treatment of episodic or chronic migraine

OBJECTIVE: To compare the efficacy and safety of botulinum toxin type A (BoNTA; BOTOX: Allergan, Inc.) and divalproex sodium (DVPX; DEPAKOTE: Abbott Laboratories) as prophylaxis in reducing disability and impact associated with migraine. BACKGROUND: There is a need for effective, well-tolerated prophylactic treatment of migraine. DESIGN/METHODS: This was a randomized, double-blind, single-center prospective study. Fifty-nine patients received either BoNTA 100 U/placebo-DVPX bid or placebo-BoNTA/DVPX 250 mg bid. BoNTA/placebo injections were given at Day 0 and at Month 3. Patients were evaluated at Months 1, 3, 6, and 9. RESULTS: Both treatments showed significant improvements in migraine disability scores and reductions in headache days and headache index. A trend to decreased headache severity was observed with BoNTA. A greater percentage of DVPX patients reported adverse events possibly related to treatment (DVPX 75.8% vs BoNTA 50%, P = .04) and discontinued because of adverse events (DVPX 27.6% vs BoNTA 3.3%, P = .012). CONCLUSIONS: Both BoNTA and DVPX significantly reduced disability associated with migraine; BoNTA had a favorable tolerability profile compared with DVPX.     

Botulinum toxin type A as migraine preventive treatment in patients previously failing oral prophylactic treatment due to compliance issues

Objective.— To examine the efficacy and safety of and satisfaction with botulinum toxin type A (BoNTA; BOTOX^®: Allergan, Inc., Irvine, CA) for prophylactic treatment of migraine headache in patients previously failing prophylaxis because of issues pertaining to compliance. Background.— Numerous factors (eg, adverse effects, tolerability, cost, frequency of dosage, hesitancy to take daily medication, failure to complete treatment) negatively influence compliance with the preventive pharmacology for migraine prophylaxis. BoNTA may offer benefit in improving compliance because of its long duration of action, injectable route of administration, and its tolerability (adverse event [AE]) profile. Methods.— This was a randomized, double‐blind, single‐center, placebo‐controlled study (months 1 to 3) of BoNTA with a cross‐over to open‐label BoNTA treatment (months 4 to 6). Criteria for enrollment included patients with disabling headache (International Headache Society, International Classification of Headache Disorders [ICHD‐I] diagnosis 1.1, 1.2, 1.7, or 2.2, and Headache Impact Test [HIT]‐6 scores ≥56) previously failing prophylaxis because of compliance, tolerability, or adherence issues. After baseline evaluation, subjects were randomized 2 : 1 to a single set of BoNTA (139 units [U] total; 17 sites/6 muscle groups) or placebo injections. After month 3, only placebo‐treated subjects were eligible to receive BoNTA in the open‐label continuation study. Treatment outcomes were evaluated by headache episodes and days and maximum headache severity. Headache impact was assessed by the HIT‐6, Migraine Disability Assessment (MIDAS) score, and Quality of Life (QoL) questionnaires. Treatment satisfaction was assessed with the Migraine Impact Questionnaire (MIQ), which included MIDAS and QoL. Results.— Of the 73 subjects screened, 61 (40 BoNTA; 21 placebo) with migraine headache diagnosis 1.1 and 1.2 who met all study criteria were enrolled in the 3‐month, blinded study, with 54 completing the study; 19 of 21 placebo‐treated subjects participated in the open‐label period (months 4 to 6), with 18 completing the study. Between‐group comparisons, demonstrated through analysis of the subjects' headache diaries, did not reach statistical significance at months 1 to 3 for the number of headache episodes or days (primary endpoint). At month 2, a decrease from baseline in the number of headache episodes (?0.99 ± 2.38; P = .0147 vs 0.42 ± 3.23; P = not significant [NS]) and headache days (?1.52 ± 3.84; P = .0194 vs 0.23 ± 4.67; P = NS) was noted in the BoNTA‐treated subjects but not in the placebo‐treated subjects, respectively. During the open‐label study, BoNTA‐treated subjects had a decrease in the number of headache episodes at months 5 and 6 (?1.58 ± 2.88 and ?1.58 ± 2.85, respectively; P < .05 vs baseline for both) and headache days at months 5 and 6 (?2.84 ± 4.47 and ?2.73 ± 4.86, respectively; P < .05 vs baseline for both). BoNTA did not affect maximum headache severity compared with baseline or placebo during the first 3 months of the study. A decrease in HIT‐6 scores was significantly greater for BoNTA‐treated subjects than for placebo‐treated subjects at month 3 (?7.77 vs ?3.58, P = .0466). Within‐group decreases in HIT‐6 scores were significant in BoNTA‐treated subjects during each month of the blinded trial (?5.10 ± 8.85, ?6.63 ± 7.49, ?7.77 ± 8.78 for months 1 to 3, respectively; P < .0001 for all vs baseline) and throughout the open‐label portion of the study (?7.89 ± 6.48, ?10.39 ± 10.81, ?9.00 ± 11.12 for months 4 to 6, respectively; P < .01 for all vs baseline). The within‐group decrease in placebo‐treated subjects was significant at months 1 and 3 (?3.35 ± 6.07 and ?3.58 ± 5.40, respectively; P < .05 for both). At 3 months, BoNTA was significantly better than placebo (P = .001) in the reduction of MIDAS total score. The change from baseline in the MIDAS total scores was significant in BoNTA‐treated subjects (?21.62 ± 38.70; P < .0001) but not in placebo recipients (4.76 ± 18.85; P = NS). BoNTA‐treated subjects showed improvement in 11 of 13 and 7 of 13 assessments of treatment satisfaction in MIQ at months 3 and 6, respectively, while the placebo group showed no improvement at any measured time interval in the study. At month 3 (blinded period), there were no treatment‐related AEs reported in both groups. However, there were 18 possible/probable occurrences of treatment‐related AEs in the BoNTA group. At month 6 (open‐label period), 4 treatment‐related AEs were reported, along with 2 possible occurrences. The majority of treatment‐related AEs were transient and mild to moderate in severity, with no subjects discontinuing the study because of AEs. Conclusions.— BoNTA‐treated subjects showed improvements from baseline in measures of headache frequency, and improvements from baseline and in comparison with placebo treatment in headache impact and treatment satisfaction at multiple time points in this study. However, BoNTA‐treated subjects did not differ from placebo‐treated subjects in measures of headache frequency and severity. BoNTA may be a useful treatment option for headache patients demonstrating poor compliance, adherence, or AE profile with oral prophylactic regimens.     

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.     

A series of three sequential, randomized, controlled studies of repeated treatments with botulinum toxin type A for migraine prophylaxis.

We examined the effects of multiple treatments with low doses of botulinum toxin type A (BoNTA; BOTOX(R), Allergan Inc., Irvine, CA) versus placebo for prophylaxis of episodic migraine. This was a series of 3 sequential, randomized, controlled studies of 418 patients with a history of 4 to 8 moderate to severe migraines per month. In study I, patients were randomized to treatment with placebo or BoNTA (7.5 U, 25 U, or 50 U) in predetermined fixed injection sites on the front and sides of the head only. In study II, patients continued to receive, or were randomized to, 2 consecutive treatments with 25 U or 50 U. In study III, patients were randomized to placebo or continuation of 25 U or 50 U. Injection cycles were each 4 months long. BoNTA and placebo produced comparable decreases from baseline in the frequency of migraines at each time point examined (P >or= .201). No consistent, statistically significant differences were observed for any efficacy variable. Adverse events were similar among the groups within each study. In these exploratory studies of episodic migraine patients, repeated injections of low doses of BoNTA into fixed frontal, temporal, and glabellar sites were not more effective than placebo. BoNTA was safe and well tolerated. PERSPECTIVE: Beneficial effects of BoNTA in the treatment of migraine have been reported, but positive results are not universal, possibly because the optimal patient population and regimen are not yet definitively established. This study explores the effects of multiple injections of low BoNTA doses into fixed sites for episodic migraine.     

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.     

A randomized, double-blind, placebo-controlled study of venlafaxine XR in out-patients with tension-type headache

The aim of this study was to evaluate in a double-blind, randomized, placebo-controlled study the safety and efficacy of venlafaxine extended release (XR) in the prophylactic treatment of out-patients with tension-type headache (TTH) and no current depression or anxiety disorders. Sixty neurology and headache clinic out-patients meeting the International Headache Society diagnostic criteria for TTH were treated with venlafaxine XR (150 mg/day, n = 34) or placebo (n = 26) for 12 weeks. The primary efficacy variable was the decline in number of days with headache. At end-point, the venlafaxine XR group had a significantly greater decrease in the number of days with headache compared with placebo (P = 0.05). Differences with regard to secondary efficacy variables where not significant. The number needed to treat for responders (>or=50% reduction in days with headache) was 3.48. Six patients in the venlafaxine XR group interrupted therapy due to adverse events, while no patients in the placebo group did so for the same reason. The number needed to harm was 5.58. This study provides preliminary evidence for the efficacy and safety of venlafaxine XR 150 mg/day in reducing the number of days with TTH.     

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.     

Use of sibutramine in obese mexican adolescents: a 6-month, randomized, double-blind, placebo-controlled, parallel-group trial

BACKGROUND: The prevalence of overweight and obesity in children and adolescents is increasing in both the United States and Mexico. OBJECTIVE: The goal of this article was to assess the efficacy and safety of sibutramine in obese Mexican adolescents. METHODS: This was a 6-month, randomized, double-blind, placebo-controlled, prospective clinical trial of sibutramine QD. Male and female patients aged 14 to 18 years with sex-specific body mass index (BMI) for age and sex >85th percentile were eligible. The primary end points for the trial were the baseline versus end point absolute values for body weight, BMI, and percentage of the initial BMI (%BMI); secondary end points were waist circumference and percentage of the initial waist circumference (%waist). These were measured at days -15, 0, 30, 60, 90, 120, 150, and 180 of the study. Quality of life was assessed at the study start and end using the 36-Item Short-Form Health Survey (SF-36) questionnaire. Blood pressure and heart rate were assessed, and adverse events (AEs) were recorded. Both groups received individually tailored diet and exercise programs. RESULTS: Forty-six patients (age range, 14-18 years) with a BMI >95th percentile for age were included (sibutramine group, n = 23 [14 females, 9 males]; placebo group, n = 23 [12 females, 11 males]). Twenty-one patients in the sibutramine group and 19 patients in the placebo group completed the 6-month trial. Using the intent-to-treat data, weight (mean [SD]) in the sibutramine group changed from 92.5 (14.6) kg to 85.7 (14.4) kg, for a net weight loss of 7.3 kg (95% CI 4.6-9.9), a waist circumference loss of 8.0 cm (95% CI, 4.7-11.3), and a % BMI loss of 9.2% (95% CI, 6.9-11.6). In the placebo group, weight changed from 98.9 (22.7) kg to 94.6 (22.5) kg, a weight loss of 4.3 kg (95% CI, 1.7-6.9), a waist circumference loss of 3.8 cm (95% CI, 0.7-7.0), and a %BMI loss of 5.2% (95% CI, 2.4-7.9) (P < 0.05 for all intragroup comparisons; P > 0.05 for the intergroup comparisons). Mean (SD) scores on the SF-36 scale in the sibutramine group changed from 78.0 (13.3) at baseline to 84.8 (7.4) at study end (P < 0.05); the respective values in the placebo group were 82.8 (10.3) and 87.3 (7.6) (P < 0.05). At base-line, systolic blood pressure (SBP) was 116.7 (5.9) mm Hg in the sibutramine group and 118.3 (7.6) mm Hg in the placebo group; at end point, the respective SBPs were 112.4 (9.6) mm Hg and 112.6 (6.5) mm Hg. At baseline, diastolic blood pressure (DBP) was 78.9 (4.5) mm Hg in the sibutramine group and 79.5 (5.2) mm Hg in the placebo group; at end point, the respective DBPs were 73.5 (6.3) mm Hg and 76.6 (6.2) mm Hg. At baseline, heart rate was 76.3 (6.4) beats/min in the sibutramine group and 81.1 (9.5) beats/min in the placebo group; at end point, the respective findings were 79.8 (8.8) beats/min and 77.6 (8.6) beats/min (P > 0.05 for all preceding intergroup comparisons). One patient in the sibutramine group had increased blood pressure (at month 3) and 3 had increased heart rate (at months 1, 2, and 4); 2 patients receiving placebo had increased blood pressure (month 3) and 2 had increased heart rate (at months 1 and 3). These changes disappeared in 1 week and did not require treatment or trial suspension. Additionally, in the sibutramine group, 3 patients experienced 4 mild AEs: headache, dry mouth, headache with nausea, and headache with weakness and paleness (P > 0.05). In the placebo group, 3 patients experienced 4 mild AEs: 2 cases of headache, as well as 1 case of headache with somnolence and 1 case of headache with dry mouth (P > 0.05). CONCLUSION: Sibutramine 10 mg QD in addition to diet and exercise was effective and generally well tolerated in this population of obese Mexican adolescents.     

Factors associated with the onset and remission of chronic daily headache in a population-based study

The etiology and prognosis of chronic daily headache (CDH) are not well understood. The aim of this study is to describe factors that predict CDH onset or remission in an adult population. Potential cases (180+ headaches per year, n=1134) and controls (two to 104 headaches per year, n=798) were interviewed two times over an average 11 months of follow-up. Factors associated with CDH prevalence at baseline were evaluated. The incidence of CDH and risk factors for onset were assessed in controls whose headache frequency increased to 180+ per year at follow-up. Prognostic factors were assessed in CDH cases whose headache frequency fell at follow-up. CDH was more common in women, in whites, and those of less education. CDH cases were more likely to be previously married (divorced, widowed, separated), obese, and report a physician diagnosis of diabetes or arthritis. At follow-up, 3% of the controls reported 180 or more headaches per year. Obesity and baseline headache frequency were significantly associated with new onset CDH. In CDH cases, the projected 1-year remission rate to less than one headache per week was 14% and to less than 180 headaches per year was 57%. A better prognosis was associated with higher education, non-white race, being married, and with diagnosed diabetes. Individuals with less than a high-school education, whites, and those who were previously married had a higher risk of CDH at baseline and reduced likelihood of remission at follow-up. New onset CDH was associated with baseline headache frequency and obesity.     

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.     

Predictors of response to botulinum toxin type A (BoNTA) in chronic daily headache

OBJECTIVE: To evaluate predictors of response to botulinum toxin type A (BoNTA; BOTOX, Allergan Inc., Irvine, CA, USA) in patients with chronic daily headache (CDH). BACKGROUND: Chronic migraine (CM) and chronic tension-type headache (CTTH) form the majority of CDH disorders. Controlled trials indicate that BoNTAis effective in reducing the frequency of headache and number of headache days in patients with CDH disorders. A recent migraine study found that patients with imploding or ocular types of headaches were responders to BoNTA, whereas those with exploding headaches were not. To date, there are no data on factors that might predict response to BoNTA in patients with CDH. METHODS: A total of 71 patients with CM and 11 patients with CTTH were treated with 100 units BoNTA. Every patient received at least 2 sets of injections at intervals of 12-15 weeks; fixed sites, fixed dose, and "follow-the-pain" approaches were used for the injections. A detailed medical history was taken for each patient in addition to recording Migraine Disability Assessment Scale (MIDAS) scores at baseline and every 3 months after each set of injections. Headache frequency was assessed throughout the study from baseline to weeks 24-27. Patients recorded the frequency, severity, and duration of headaches in Headache Diaries. Patients were divided into responders (> or = 50% reduction in both headache frequency and MIDAS scores compared with baseline) and nonresponders (< 50% reduction in either of the above variables). Variables analyzed for predictors of response include headache that is predominantly unilateral or bilateral in location, presence of cutaneous allodynia (scalp allodynia), and presence of pericranial muscle tenderness (also referred to as muscle allodynia). Chi-square analysis was used for parallel-group comparisons (proportion of CM responders vs proportion of CM nonresponders and proportion of CTTH responders vs proportion of CTTH nonresponders). RESULTS: In the CM group, 76.1% (54 /71) of patients were responders to BoNTA, of which 68.5% (37/54) had headache that was predominantly unilateral in location and the remaining 31.5% (17/54) had headache that was predominantly bilateral in location (both P < .01 vs CM nonresponders). Of the 23.9% (17/71) CM nonresponders, 76.5% (13/17) reported predominantly bilateral headache and in the remaining 23.5% (4/17) the headache was unilateral. In the CM responders group, 81.5% (44/54) had clinically detectable scalp allodynia, while pericranial muscle tenderness was present in 61.1% (33/54) (both P < .01 vs CM nonresponders). The presence of scalp allodynia and pericranial muscle tenderness in the CM nonresponders was 11.8% (2/17) and 17.6% (3/17), respectively. In the CTTH group where all patients (100%, 11/11) had bilateral headache, 36.4% (4/11) of patients were responders to BoNTA. All of those CTTH responders (100%, 4/4) had pericranial muscle tenderness (P < .05 vs CTTH nonresponders). None of the CTTH nonresponders had pericranial muscle tenderness. No clinically significant serious adverse events (AEs) were reported. Mild AEs, eg, injection-site pain that persisted for 1-9 days, were reported in 11 patients. One patient had transient brow ptosis. CONCLUSIONS: A greater percentage of patients with CM responded to BoNTA than patients with CTTH. Headaches that were predominantly unilateral in location, presence of scalp allodynia, and pericranial muscle tenderness appear to be predictors of response to BoNTA in CM, whereas in CTTH, pericranial muscle tenderness may be a predictor of response.     

Oral magnesium oxide prophylaxis of frequent migrainous headache in children: a randomized,double-blind,placebo-controlled trial

OBJECTIVE: To assess whether, in children, oral magnesium oxide reduces migrainous headache frequency, severity, and associated features compared to placebo. BACKGROUND: There is no single, safe, widely well-tolerated, and effective prophylactic treatment for all children and adolescents with frequent migrainous headache. DESIGN: Randomized, double-blind, placebo-controlled, parallel-group trial. METHODS: This study was conducted between June 1997 and January 2000 using 7 selected Northern California Kaiser Permanente sites. We recruited children of ages 3 to 17 years who reported a 4-week history of at least weekly, moderate-to-severe headache with a throbbing or pulsatile quality, associated anorexia/nausea, vomiting, photophobia, sonophobia, or relief with sleep, but no fever or evidence of infection. Subjects were randomly assigned to receive either magnesium oxide (9 mg/kg per day by mouth divided 3 times a day with food) (n = 58) or matching placebo (n = 60) for 16 weeks. The number of headache days (days with at least one headache) during each of eight 2-week intervals was chosen to be the primary outcome variable. RESULTS: Of those enrolled, 86 (73%) completed the study (42 received magnesium oxide and 44 placebo); 74 of 192 eligible subjects declined to participate. Baseline information on demographic factors, health status, and headache history was similar comparing the 2 groups. By intention-to-treat analysis, we found a statistically significant decrease over time in headache frequency in the magnesium oxide group (P =.0037) but not in the placebo group (P =.086), although the slopes of these 2 lines were not statistically significantly different from each other (P =.88). The group treated with magnesium oxide had significantly lower headache severity (P =.0029) relative to the placebo group. CONCLUSIONS: This study does not unequivocally determine whether oral magnesium oxide is or is not superior to placebo in preventing frequent migrainous headache in children, but treatment with the active agent did lead to a significant reduction in headache days. Larger trials involving this safe, appealing complementary therapy are needed.     

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.     

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