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Abstract

The aim of this review is to evaluate the studies available from reference systems and published congress contributions on the prophylactic treatment of idiopathic and cervicogenic headache with botulinum toxin A, and to classify these studies according to evidence-based medicine (EBM) criteria. The studies were analysed with respect to the study design, the number of patients enrolled, the efficacy parameters, and the significance of results. We used the following classification of EBM. I: randomized, controlled study with sufficient number of patients; II: well-designed, controlled study (or randomized, controlled study with insufficient number of patients, no exact diagnosis, missing data of botulinum toxin A dose); III: well-designed, descriptive study; IV: case reports, opinions of experts. For tension-type headache, two studies were found with negative evidence of I with respect to the primary endpoint. There are about as many positive as negative studies with evidence of II or III. For the therapy of migraine, one study with both negative and positive evidence of I, one in part positive study of II, and three positive studies classified as III are available. Two studies on cervicogenic headache with evidence of II and III are contradictory. In addition, we found several positive case reports. For patients with cluster headache, there are positive and negative case reports. We found one positive case report for the treatment of chronic paroxysmal hemicrania. As a result of this analysis, we consider no sufficient positive evidence for a general treatment of idiopathic and cervicogenic headaches with botulinum toxin A to date. Further studies are needed for a definite evaluation of subgroups with benefit from such treatment.

Keywords

Botulinum toxin A idiopathic headache tension-type headache migraine evidence-based-medicine

Introduction

For many years, botulinum toxin A has been used in the treatment of dystonic movement disorders and in diseases with pathologically increased muscle tonus. In particular, the focal dystonias and infantile cerebral palsy show a high benefit from treatment with botulinum toxin A. Therapy of idiopathic headaches or pain disorders (e.g. back pain) with botulinum toxin A is relatively new. Most experience exists for the treatment of tension-type headache, but the prophylactic effect on migraine has also been studied.

For a systematic evaluation of the efficacy of botulinum toxin A in headache disorders, well-defined treatment procedures and an exact diagnosis, for headache according to the criteria of the International Headache Society (IHS) (1), is mandatory. In this review, all available studies on the prophylactic treatment of idiopathic headache and cervicogenic headache with botulinum toxin A (published as full paper or abstracts) are analysed and ranked according to evidence-based medicine (EBM) criteria (2). The definitions for the different EBM classes are given in Table 1. In order to present the current overview, the studies themselves are ranked. In general, EBM criteria classify the study data of one disease or related groups of disorders rather than a single study. Because of this method, it is not possible to give definite treatment recommendations in this review. We consider evidence as sufficient if at least two positive level I studies without contradictory studies are available. A synopsis of all studies available is given in Table 2. This review has been published in part before (3).

Table 1

Classification of published studies according to their scientific validity in evidence levels (according to the criteria of the Agency for Health Care Policy and Research; Perfetto and Morris 1996)

IA	Evidence based on meta-analysis of randomized and controlled studies
IB	Evidence based on at least one randomized and controlled study (our premises: number of patients in each subgroup more than 20; exact diagnosis; defined and standardized doses and injection sites of botulinum toxin A)
II	Evidence based on at least one well-designed controlled study without randomization (our premises: number of patients in each subgroup between 10 and 20; ranking of randomized studies in this level, if number of patients was too low for IB, or if there were missing data concerning diagnosis criteria, botulinum toxin A dose or injection site)
III	Evidence based on well-designed, non-experimental, descriptive studies; for example comparison study, correlation study, or case-control study
IV	Evidence based on experiences of expert committees or experts; case reports

Table 2

Studies on botulinum toxin A in the treatment of idiopathic or cervicogenic headache

Primary headache	Reference	Indication to treatment	Number of patients, sex, age (years)	Methods	Results
Tension-type headache	Schmitt et al. (2001)	Prophylactic treatment of chronic tension-type headache	59 patients (36 female, 23 male), mean age 49.5±15.4 years	Randomized, double-blind, placebo-controlled; 20 U Botox®; 1 month baseline, 2 months control; 4 injection sites (frontal and temporal)	No significant differences between botulinum toxin A and placebo in all headache parameters
Tension-type headache	Rollnik et al. (2000)	Prophylactic treatment of chronic tension-type headache	21 patients, mean age 37.4±14.3 years	Randomized, double-blind, placebo-controlled; 200 U botulinum toxin A; control after 4, 8, and 12 weeks	No significant difference between botulinum toxin A and placebo
Tension-type headache	Rollnik et al. (2001)	Prophylactic treatment of chronic tension-type headache	8 patients (3 female, 5 male), mean age 54.4±7.6 years	Randomized, placebo-controlled; 500 U botulinum toxin A (Dysport®); control after 6 and 12 weeks	No significant difference between botulinum toxin A and placebo in headache (‘area under curve’)
Tension-type headache	Burch et al. (2001)	Prophylactic treatment of chronic and episodic tension-type headache	41 patients (32 female, 9 male), mean age 46 years, range 19–80	Randomized, double-blind, placebo-controlled; 50 U Botox® or placebo in frontotemporal muscles, 1 month baseline, 6 months of control	No significant difference in headache frequency (P>0.72), for group with botulinum toxin A, significant reduction in pain intensity (P<0.0001) compared with baseline data
Tension-type headache	Smuts et al. (1999)	Prophylactic treatment of chronic tension-type headache	41 patients (30 female, 11 male); 28 patients <40 years, 13 patients 40–55 years	Randomized, double-blind, placebo-controlled; 37 patients in follow-up period (22 in botulinum toxin A group, 15 in placebo group); 100 U botulinum toxin A or placebo temporal and cervical; 1 month baseline, 3 months of control	Significant reduction of headache intensity in month 3 compared with baseline data (P<0.002), significant more pain-free days in group with botulinum toxin A in all 3 months of control (P<0.001)
Tension-type headache	Relja (2000)	Prophylactic treatment of tension-type headache	25 patients	Open, not randomized, not controlled; 24 patients, in follow-up period, 15 months of control; injection of 40–90 U Botox® in pericranial muscles every 3 months	Significant increase of pain-free days over 15 months (P<0.001), significant reduction of pain intensity (P<0.001) in months 9, 12 and 15 compared with months 3 and 6
Tension-type headache	Relja and Klepac (2001)	Above study continued	27 patients	Patients of above study; randomized, double- blind, placebo-controlled; follow-up 10 months	Significant reduction of headache days and intensity compared with the control group (P>0.001), no difference of ‘total tenderness score’ between Botox® and control
Tension-type headache	Göbel et al. (1999)	Prophylactic treatment of chronic tension type headache	10 patients	Randomized, double-blind, placebo-controlled; injection of 80 U Botox® or placebo in pericranial muscles, 1 month baseline, 6 weeks of control after injection	No significant reduction of pain intensity, headache hours or use of analgesics
Tension-type headache	Porta (2000)	Prophylactic treatment of chronic (n=7) and episodic (n=13) tension-type headache	20 patients (12 female, 8 male), mean age 37.7 years, range 18–70	Randomized, single-blind, not controlled; comparison of Botox®+lidocaine against methylprednisolone+lidocaine; 10 patients Botox® 5–15 U each side (mean 8.9 U), 10 patients methylprednisolone (no information on dose)	No significant difference between groups after 30 days, significant headache reduction after 60 days in Botox® group (P<0.0003)
Tension-type headache	Mauskop (1999)	Prophylactic treatment of chronic tension-type headache	12 patients (7 female, 5 male), age range 38–63	Open, not randomized, not controlled; 6–11 injection points, 50–100 U Botox® in pericranial muscles (frontal, temporal, glabellar, neck)	One patient with pain reduction
Tension-type headache	Zwart et al. (1994)	Prophylactic treatment of chronic tension-type headache	6 patients (4 female, 2 male), mean age 48.6 years, range 38–56	Open, not randomized, not controlled; 30–40 U Botox® in M. temporalis; baseline, day 10 injection of saline (one side), day 10–20 control data, day 20 injection of Botox® (one side), day 20–30 control data, day 30 injection of Botox® (one side), day 30–55 control data, day 55 injection of Botox® in contralateral side	No significant reduction of pain intensity and ‘pressure pain threshold’ (algometer)
Tension-type headache	Relja (1997)	Prophylactic treatment of chronic tension-type headache	10 patients (6 female, 4 male), mean age 43±13.5 years	Open, not randomized, not controlled; 15–35 U Botox® in pericranial muscles	After 2 weeks: 3 patients pain-free and 7 patients with reduction of pain intensity and duration, after 8 weeks: 2 patients pain-free and 6 patients with reduction of pain intensity from severe to mild, after 12 weeks: no effects any more
Tension-type headache	Schulte-Mattler et al. (1999)	Prophylactic treatment of chronic and episodic tension-type headache	9 patients (6 female, 3 male), age range 30–74 years	Open, not randomized, not controlled; follow-up of 8 patients, 200 U Dysport® in pericranial muscles, 1 month baseline	No significant reduction of headache days, but significant reduction of ‘area under curve’ (product of duration and intensity of headache, P<0.039)
Migraine	Silberstein et al. (2000)	Prophylactic treatment of migraine	123 patients (105 female, 18 male), age range 18–65 years	Randomized, double-blind, placebo-controlled; 3 groups: 1: placebo; 2: 25 U Botox®; 3: 75 U Botox®; 1 month baseline, injection in pericranial muscles (frontal, glabellar, temporal), of 3 months control	Significant reduction of migraine frequency (month 3, P<0.014) and intensity (month 2, P<0.008 and month 3, P<0.042) in group with 25 U compared with the control group, no significant results in 75 U group
Migraine	Brin et al. (2000)	Prophylactic treatment of migraine	56 patients	Randomized, double-blind, placebo-controlled; 4 groups: 1: frontal/temporal botulinum toxin A; 2: frontal botulinum toxin A/temporal placebo; 3: frontal placebo/temporal botulinum toxin A; 4: frontal/temporal placebo); 16 weeks of control	Significant reduction of pain intensity in group 1 compared with 4 in week 12 (P<0.04), trend to reduction of migraine frequency and duration
Migraine	Binder et al. (2000)	Prophylactic and acute treatment of migraine	106 patients (95 female, 11 male), age range 21–74 years	Open, not randomized; not controlled; prophylactic treatment: 69 patients with migraine, 15 with probable migraine, 9 without migraine; acute treatment: 2 patients with migraine, 2 with probable migraine; prophylactic and acute treatment: 8 patients with migraine, 1 with probable migraine; mean dose of botulinum toxin A 31.0 U (range 5–110 U)	Prophylactic treatment: 51% no attacks for 4.1 months (P<0.05), 38% improvement ≥50% for 2.7 months acute treatment: 7 of 10 patients pain-free after 1–2 h (P<0.05), improvement in all cases within 1–2 h
Migraine	Mauskop and Basdeo (2000)	Prophylactic treatment of migraine	27 patients (25 female, 2 male), mean age 41 years, range 26–61	Retrospective study; 12–23 injection points with 25–100 U botulinum toxin A in pericranial muscles (frontal, glabellar, temporal, neck)	23 patients with improvement for 2–6 months (complete remission or reduction of pain intensity of 50% (no reduction of frequency), 4 patients without improvement
Cervicogenic headache	Schnider et al. (2001)	Prophylactic treatment of cervicogenic headache	33 patients	Randomized, double-blind, placebo-controlled; 16 patients 90 U Botox® in 6 trigger points, 17 patients saline; in addition physical therapies such as heat and massage; 1 month baseline, control after 4, 10 and 12 weeks	No significant results
Cervicogenic headache	Freund and Schwartz (2000)	Prophylactic treatment of cervicogenic headache	26 patients (15 female, 11 male), mean age 46 years, range 29–75	Randomized, double-blind, placebo-controlled; no definite distinction from tension-type headache, 14 patients 100 U Botox®, 12 placebo, control after 2 and 4 weeks	4 weeks after injection significant pain reduction and improvement of ‘range of motion’ (P<0.01)
Cervicogenic headache	Hobson et al. (1997)	Prophylactic treatment of cervicogenic headache	1 female, 28	Case report, injection of 50 U Botox® in left M. trapezius	Within 3 months >50% reduction of attacks; recurrence after 3–4 months, reinjections led to repeated pain reduction
Cluster headache	Robbins (2001)	Prophylactic treatment of chronic and episodic cluster headache	6 male (4 chronic, 2 episodic), age range 43–63 years	Case reports, injection of 24 U Botox® in pericranial muscles, 12 injection points	Case 1: no effect; case 2: moderate effect with reduction to 1 attack daily, effect duration 4 months; case 3: no effect; case 4: immediately pain-free for 3 months; case 5: immediately pain-free; case 6: immediately pain-free after first injection, after recurrence and reinjection only moderate effect
Cluster headache	Freund and Schwartz (2000)	Prophylactic treatment of chronic cluster headache	2 male, age 38 and 46 years	Case reports, 50 U Botox® in M. temporalis (affected side) in first week of episode	Case 1: abrupt pain-free after 6 days; case 2: abrupt pain-free after 9 days; pain-free period for 10–12 weeks, after reinjection pain-free for 18–21 weeks
Chronic paroxysmal hemicrania	Göbel et al. (2001)	Prophylactic treatment of chronic paroxysmal hemicrania	1 male, 52	Case report, injection of 30 U Botox® in left M. temporalis, 3 injection points, reinjection after 14 weeks	Pain-free after 6 days, duration 14 weeks, after reinjection again pain-free
Mixed studies (or undetermined diagnosis)	Klapper et al. (2000)	Prophylactic treatment of chronic headache (>15 days of headache per month, <10 times migraine per month)	56 patients	Randomized, double-blind, placebo-controlled; group 1: 19 patients placebo frontal and suboccipital; group 2: Botox® frontal (27.5 U) and suboccipital (72.5 U); group 3: Botox® frontal (27.5 U), placebo suboccipital; group 4: placebo frontal, Botox® (72.5 U) suboccipital; 4 months of control	2nd month: significant reduction of headache intensity and duration in group 2 compared with placebo, no significant results for groups 3 and 4
Mixed studies (or undetermined diagnosis)	Smuts and Barnard (2000)	Prophylactic treatment of tension-type headache, migraine, cluster headache and cervicogenic headache	79 patients (55 chronic tension-type headache, 19 migraine, 4 cluster headache, 1 cervicogenic headache)	Open, not randomized, not controlled; 100 U Botox® in patients with tension-type headache, variable doses and injection sites in patients with migraine, injection of Botox® (no specification of dose and injection sites) for patients with cluster headache and cervicogenic headache, baseline, 3 months of control	‘Positive’ results for 30 of 50 patients with tension-type headache, for 13 of 19 patients with migraine, for 2 of 4 patients with cluster headache, for 1 with cervicogenic headache
Mixed studies (or undetermined diagnosis)	Robbins (2001)	Prophylactic treatment of chronic daily headache	79 patients	Open, not randomized, not controlled; injection of 24 U botulinum toxin A, 6 points on each side (2 temporal, 4 frontal), 1 month baseline, 3 months of control	Summary: 30% patients with moderate or good effect, 70% with mild or no effect
Mixed studies (or undetermined diagnosis)	Wheeler (1998)	Prophylactic treatment of chronic headache (mainly tension-type headache)	4 patients (2 female, 2 male), age range 37–54 years	Case reports, 10–100 U Botox®, variable injection sites	Case 1: reduction of pain intensity (4 points on the visual analogue scale); case 2: reduction of pain, in addition with capsaicin and physical therapy pain-free; case 3: remission of tension-type headache for 8 months; case 4: pain-free for 3 months

Tension-type headache

In five randomized, double-blind, and placebo-controlled studies on patients suffering from tension-type headache, contradictory results for the efficacy of botulinum toxin A were found. Schmitt et al. (4) enrolled 59 patients and could not find any significant difference between 20 U Botox^® and placebo. Because of the high number of patients, an evidence level of IB is reached. The results of Burch et al. (5) could also not reveal a significant difference in headache frequency between treatment with Botox® (50 U) and placebo injected in pericranial muscles (41 patients). However, there was a significant decrease of pain intensity in the treatment group with Botox® compared with the control group. The study is ranked as IB. Rollnik et al. (6) studied the efficacy of 200 U botulinum toxin A (presumably Dysport®) against placebo. After 4, 8, and 12 weeks, the 21 patients showed no significant difference. Smuts et al. (7) showed a significant decrease of headache days in the 3 following months and, in month 3, a significant reduction of pain intensity in patients treated with 100 U Botox® compared with placebo (37 patients in follow-up period). In 27 patients randomized to placebo or the injection of 40–95 U Botox® every 3 months over a period of 10 months, the verum group experienced a significant reduction of headache frequency and intensity compared with the placebo group (8). These three studies reach an evidence level of II.

The design of the above studies mainly followed the recommendations of the IHS for studies on tension-type headache (9). In particular, the primary endpoint was the reduction of headache frequency. However, except for Schmitt et al. (4) and Burch et al. (5), the number of patients in the single subgroups is too small for evidence I. Furthermore, the dose of botulinum toxin A and the injection sites were not always standardized. The study design of Göbel et al. (10) was very similar to those above. No difference was found between botulinum toxin A and placebo in this study, but the number of patients was only 10. All additional studies of the prophylactic effect of botulinum toxin A on tension-type headache are either open, not controlled, have no exact diagnosis, have a too low number of patients, or do not define the reduction of headache frequency as the primary endpoint. The comparison between an injection of Botox® plus lidocaine and methylprednisone plus lidocaine (number of patients was 20) showed no significant difference after 30 days (11). After 60 days, the treatment group with Botox® suffered significantly less headache compared with the patients treated with methylprednisone plus lidocaine. Klapper et al. (12) enrolled 56 patients in their study. However, they separated into four subgroups, and no exact headache diagnosis (‘chronic headache’) was given. Treatment with botulinum toxin A in both frontal and suboccipital sites caused a significant reduction of headache compared with the other three subgroups. The open study of Robbins (13) with 79 patients treated with 24 U botulinum toxin A describes only chronic daily headache as diagnosis. After a control period of 3 months, 30% of the patients showed a good or moderate efficacy, 70% had no relief. Two studies of Relja (14, 15) either showed no significant results, the number of patients was under 16, or the design did not allow a statement on the evidence. Similar concerns are raised by the studies of Mauskop (16), Zwart et al. (17), Schulte-Mattler et al. (18), Smuts and Barnard (19), and Wheeler (20). Schulte-Mattler et al. (18) found a significant reduction of the ‘area under curve’. However, the defined primary endpoint, the reduction of headache days, was not influenced by botulinum toxin A. Rollnik et al. (21), in another study, examined the efficacy of 500 U botulinum toxin A (Dysport®) in chronic tension-type headache and also studied the EMG activity of different face and neck muscles. The study was placebo-controlled and parallel grouped (four patients in each group). Although EMG activity was significantly reduced by botulinum toxin A, there was no effect on the headache.

In summary, only two studies on the treatment of tension-type headache with an evidence of IB are found, the studies are negative. Further studies with similar design show too small a number of patients for an evidence level of I. As for evidence level of II, the number of positive and negative studies is the same. Only the studies ranked at level III show more positive than negative results.

Migraine

Silberstein et al. (22) enrolled 123 patients with migraine (diagnosis according to IHS criteria) with two to eight attacks per month. The study was randomized, double-blind, and placebo-controlled. The patients were treated with 25 U or 75 U Botox® against placebo. The follow-up control revealed a significant reduction of migraine frequency in month 3 and of pain intensity in months 2 and 3 in the 25 U group compared with placebo. Significantly more patients in the 25 U group had a reduction of >50% in month 3 compared with the control group. However, the patients treated with 75 U showed no significant results. According to the EBM criteria of the AHCPR (see Table 1), it is possible to separate this study into both a positive (for 25 U) and a negative (for 75 U) evidence. This evidence can be ranked as IB because of the high number of patients, the exact diagnosis, and a correct primary endpoint. Brin et al. (23) were able to show a significant reduction of pain intensity but not of migraine frequency. The study was randomized, double-blind, and placebo-controlled, but the differentiation of 56 patients into four subgroups, the unknown diagnosis criteria, and the unknown dose of botulinum toxin A do not support a classification better than evidence level II. The positive results of Binder et al. (24) can only be ranked as level III. Patients with migraine and with probable migraine were analysed together, the study was open and not controlled, and different doses of botulinum toxin A were used. Furthermore, some patients received several injections as acute and prophylactic treatment which resulted in a different frequency of the injections within the study. Mauskop and Basdeo (25) realized an open, not controlled study with 25 patients treated with botulinum toxin A in different doses and injection sites. The positive prophylactic effect of the patients can be classified as a positive study with an evidence level of III. Smuts and Barnard (19) treated different idiopathic headaches with botulinum toxin A including 19 patients with migraine. Positive results were found in 13 of 19 cases. There was no statement on significance, different doses were injected in different sites, and there was no randomization or control. This study can be ranked as only level III.

For the prophylactic treatment of migraine with botulinum toxin A, one study with both positive and negative evidence of level IB can be found. One study with an evidence of II presents significant positive results for pain intensity, but not for migraine frequency. Three positive studies can be ranked in evidence level III.

Cervicogenic headache

Freund and Schwartz (26) treated 24 patients with cervicogenic headache (criteria according to Sjaastad et al. (27)) and six patients with possible cervicogenic headache (a clear distinction between cervicogenic headache and tension-type headache was not possible) with 100 U Botox® or placebo. The control examination after 4 weeks showed a significant pain reduction in the Botox® group. The study can only be ranked as an evidence of III because of partially inexact diagnoses, small number of patients, and unknown injection sites. A further randomized, double-blind, placebo-controlled trial showed only a trend to a lower analgesic use and a trend to a reduction of pain duration in weeks 5–9 after the injection of botulinum toxin A (28). The results must be classified as a negative study of evidence level II. Beside these studies, only positive case reports are available (19, 29).

Cluster headache

The application of botulinum toxin A for the treatment of cluster headache was reported only as case reports. Robbins (30) treated four patients with chronic and two patients with episodic cluster headache with 24 U Botox®. Two patients experienced abrupt pain relief, two patients felt a moderate effect with a reduction of attack frequency, and two patients reported no effect. Smuts and Barnard (19) reported four patients, of whom two had a benefit after injection. In two cases of Freund and Schwartz (31), the patients were pain-free after injection, one patient after 6 days, the other after 9 days. The effect had a duration of several weeks, a second injection after recurrence was again successful. One successful case report on the treatment of chronic paroxysmal hemicrania was published by Göbel et al. (32)

Pathophysiological considerations

For the explanation of successful treatment of idiopathic headaches with botulinum toxin A, different hypotheses with different pathophysiological concepts can be found. Various authors discuss peripheral myogenic as well as central antinociceptive mechanisms (33–35).

A direct myotonolytic effect of botulinum toxin A as the underlying mechanism of a potential pain relief seems obvious, and is based on the experience that in dystonia the substance can offer a pain-decreasing effect independently from the anti-spastic effect in adults (36, 37) and in children (38). However, this hypothesis might not suffice as an explanation, because to date there is no evidence that a pathologically increased muscle tonus is the only reason for a primary headache. On the contrary, most experimental studies are not in concordance with this hypothesis (39). The concept of a peripheral mode of action is supported by the effect of botulinum toxin A on muscle spindles in experimental animal studies (40, 41). A direct affect of intra- and extrafusal γ-fibres was demonstrated, resulting in a reduced activity of α-motor neurons and a decreased muscle tonus.

Experimental studies on the central effect of botulinum toxin A were able to show that the substance is internalized in neurons and can be transported afferently, and that uptake in cultures of hippocampal neurons and astrocytes is possible (42, 43). This uptake in nociceptive neurons leads to a decreased release of neuropeptides (e.g. substance P) in an in vitro animal model (44). An increased release of neuropeptides as well as sensitization of trigeminal nociceptors of the first branch are well known mechanisms in idiopathic headaches (45).

Our current experimental knowledge about the central antinociceptive mechanisms of botulinum toxin A is based on animal models; human studies are missing. However, the studies also show that botulinum toxin A might have an impact on nociceptive (and antinociceptive) structures located in the brain-stem which exert influence on the pathophysiology of idiopathic headache.

Discussion

In this review, we analysed the current published data on botulinum toxin A in pain therapy. For classification, we used the EBM criteria as published by Perfetto and Morris (2), and modified them by including a limit of at least 20 subjects in a single subgroup. Although arbitrary, we think it is appropriate to demand this number of patients for evidence level I.

The analysis of the available studies and experience with botulinum toxin A in the treatment of idiopathic headache shows that a general efficacy of this therapy cannot be postulated to date. However, with respect to the often insufficient design of the trials, an inverse statement of a general inefficacy in idiopathic headache is not possible, either.

For tension-type headache, only two studies with an evidence level of I are available, with a negative result. Within the evidence levels of II and III, the number of positive and negative studies is about the same. It is necessary to take into consideration that the probability of publishing negative results or case reports is poorer.

Concerning the prophylactic treatment of migraine, one both positive and negative study (dependent on the dose) with an evidence level of I can be found. Beside this study, one level II and three level III studies found an efficacy of botulinum toxin A. This small number of studies does not allow a final evaluation.

For cervicogenic headache, no definite classification is possible to date, either. One negative study (level II) and one positive study (level III) show contradictory results. Several positive case reports can be added.

For patients with cluster headache, only case reports have been published to date. Approximately half of the patients experienced relief. Notably, the phenomenon that some patients were pain-free directly after the injection cannot easily be explained by the known pharmacological characteristics of botulinum toxin A. The treatment of cluster headache with botulinum toxin A must still be considered as purely experimental.

In conclusion, a study design according to the IHS recommendations would be helpful for a reliable classification of the studies. Botulinum toxin A might be a sufficient therapy for defined subgroups of patients with idiopathic headache, but well-designed and controlled studies with a high number of patients are needed for a valid evaluation. Furthermore, the known standard therapies in headache treatment need to be compared with botulinum toxin A. This can be performed in blinded double-dummy studies, which are, however, very difficult to design. It is nevertheless important for the development of treatment recommendations to discuss the advantages and disadvantages of this particular prophylactic procedure in comparison with oral medication (e.g. considering the therapeutic gain or the number needed to treat).

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Treatment of Headache with Botulinum Toxin A—a Review According To Evidence-Based Medicine Criteria

Abstract

Keywords

Introduction

Tension-type headache

Migraine

Cervicogenic headache

Cluster headache

Pathophysiological considerations

Discussion

References