Cady Roger, Schreiber Curtis
Headache Care Center, Springfield, MO, USA.
Headache. 2008 Jun;48(6):900-13. doi: 10.1111/j.1526-4610.2007.00953.x. Epub 2007 Nov 28.
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.
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.
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.
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.
探讨A型肉毒毒素（BoNTA；保妥适：艾尔建公司，加利福尼亚州欧文市）对因依从性问题导致预防性治疗失败的偏头痛患者进行预防性治疗的疗效、安全性及满意度。背景：多种因素（如不良反应、耐受性、成本、给药频率、每日服药的顾虑、治疗未完成）对偏头痛预防性药物治疗的依从性产生负面影响。BoNTA因其作用持续时间长、注射给药途径及其耐受性（不良事件[AE]）特征，可能有助于提高依从性。
这是一项关于BoNTA的随机、双盲、单中心、安慰剂对照研究（第1至3个月），随后交叉至开放标签的BoNTA治疗（第4至6个月）。纳入标准包括因依从性、耐受性或坚持性问题导致预防性治疗失败的致残性头痛患者（国际头痛协会，《头痛疾病国际分类》[ICHD-I]诊断为1.1、1.2、1.7或2.2，且头痛影响测试[HIT]-6评分≥56）。基线评估后，受试者按2:1随机分为接受一组BoNTA（共139单位[U]；17个部位/6个肌肉组）或安慰剂注射。第3个月后，仅接受安慰剂治疗的受试者有资格在开放标签的延续研究中接受BoNTA治疗。通过头痛发作次数、天数和最大头痛严重程度评估治疗结果。通过HIT-6、偏头痛残疾评估（MIDAS）评分和生活质量（QoL）问卷评估头痛影响。使用偏头痛影响问卷（MIQ）评估治疗满意度，该问卷包括MIDAS和QoL。
在73名筛查的受试者中，61名（40名BoNTA；21名安慰剂）符合所有研究标准的偏头痛诊断为1.1和1.2的患者被纳入为期3个月的盲法研究，54名完成研究；21名接受安慰剂治疗的受试者中有19名参与了开放标签期（第4至6个月），18名完成研究。通过对受试者头痛日记的分析进行的组间比较，在第1至3个月时，头痛发作次数或天数（主要终点）未达到统计学显著性。在第2个月时，BoNTA治疗组的受试者头痛发作次数（-0.99±2.38；P = 0.0147，而0.42±3.23；P =无显著性差异[NS]）和头痛天数（-1.52±3.84；P = 0.0194，而0.23±4.67；P = NS）较基线有所减少，而安慰剂治疗组未出现这种情况。在开放标签研究期间，BoNTA治疗组的受试者在第5和6个月时头痛发作次数减少（分别为-1.58±2.88和-1.58±2.85；两者均P < 0.05 vs基线），头痛天数在第5和6个月时减少（分别为-2.84±4.47和-2.73±4.86；两者均P < 0.05 vs基线）。在研究的前3个月，与基线或安慰剂相比，BoNTA对最大头痛严重程度无影响。在第3个月时，BoNTA治疗组受试者的HIT-6评分下降显著大于安慰剂治疗组（-7.77对-3.58，P = 0.0466）。在盲法试验的每个月中，BoNTA治疗组受试者的HIT-6评分组内下降均显著（第1至3个月分别为-5.10±8.85、-6.63±7.49、-7.77±8.78；所有均P < 0.0001 vs基线），且在研究的整个开放标签部分（第4至6个月分别为-7.89±6.48、-10.39±10.81、-9.00±11.12；所有均P < 0.01 vs基线）。安慰剂治疗组受试者在第1和3个月时组内下降显著（分别为-3.35±6.07和-3.58±5.40；两者均P < 0.05）。在第3个月时，BoNTA在降低MIDAS总分方面显著优于安慰剂（P = 0.001）。BoNTA治疗组受试者的MIDAS总分较基线变化显著（-21.62±38.70；P < 0.0001），而安慰剂接受者则无变化（4.76±18.85；P = NS）。在第3和6个月时，BoNTA治疗组受试者在MIQ中分别有13项治疗满意度评估中的11项和7项得到改善，而安慰剂组在研究的任何测量时间间隔内均无改善。在第3个月（盲法期），两组均未报告与治疗相关的不良事件。然而，BoNTA组有18例可能/很可能与治疗相关的不良事件发生。在第6个月（开放标签期），报告了4例与治疗相关的不良事件，以及2例可能发生的事件。大多数与治疗相关的不良事件是短暂的，严重程度为轻度至中度，没有受试者因不良事件而停止研究。
在本研究中，BoNTA治疗组受试者在头痛频率测量方面较基线有所改善，在头痛影响和治疗满意度方面较基线及与安慰剂治疗相比在多个时间点有所改善。然而，在头痛频率和严重程度测量方面，BoNTA治疗组受试者与安慰剂治疗组受试者无差异。对于口服预防性治疗方案依从性差、坚持性差或不良事件特征明显的头痛患者，BoNTA可能是一种有用的治疗选择。
