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Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Pain. Author manuscript; available in PMC 2007 December 5.
Published in final edited form as:
PMCID: PMC1831831
NIHMSID: NIHMS14309

Exploding vs. imploding headache in migraine prophylaxis with Botulinum Toxin A

Moshe Jakubowski, Ph.D.,1 Peter J. McAllister, M.D.,3 Zahid H. Bajwa, M.D.,1 Thomas N. Ward, M.D.,4 Patty Smith, R.N.,1 and Rami Burstein, Ph.D.1,2

Abstract

Migraine headache is routinely managed using medications that abort attacks as they occur. An alternative approach to migraine management is based on prophylactic medications that reduce attack frequency. One approach has been based on local intramuscular injections of Botulinum Toxin Type A (BTX-A). Here, we explored for neurological markers that might distinguish migraine patients who benefit from BTX-A treatment (100 units divided into 21 injections sites across pericranial and neck muscles). Responders and non-responders to BTX-A treatment were compared prospectively (n=27) and retrospectively (n=36) for a host of neurological symptoms associated with their migraine. Data pooled from all 63 patients are summarized below. The number of migraine days per month dropped from 16.0±1.7 before BTX-A to 0.8±0.3 after BTX-A (down 95.3±1.0%) in 39 responders, and remained unchanged (11.3±1.9 vs. 11.7±1.8) in 24 non-responders. The prevalence of aura, photophobia, phonophobia, osmophobia, nausea, and throbbing were similar between responders and non-responders. However, the two groups offered different accounts of their pain. Among non-responders, 92% described a buildup of pressure inside their head (exploding headache). Among responders, 74% perceived their head to be crushed, clamped or stubbed by external forces (imploding headache), and 13% attested to an eye-popping pain (ocular headache). The finding that exploding headache was impervious to extracranial BTX-A injections is consistent with the prevailing view that migraine pain is mediated by intracranial innervation. The amenability of imploding and ocular headaches to BTX-A treatment suggests that these types of migraine pain involve extracranial innervation as well.

Introduction

Migraine is a throbbing headache routinely managed using medications that abort attacks as they occur. An alternative approach to migraine management is based on prophylactic medications that reduce attack frequency. One approach has been based on local intramuscular injections of Botulinum Toxin Type A (BTX-A), a neurotoxin that causes transient muscle paralysis (Black and Dolly 1986a; Black and Dolly 1986b; Dolly 2003; Foran et al. 2003; Lawrence and Dolly 2002a; Lawrence and Dolly 2002b; Simpson 1981). Clinical studies on the efficacy of BTX-A treatment for migraine prophylaxis have generally failed to demonstrate its superiority over placebo using analysis of pooled data from all participants (Binder et al. 2000; Dodick et al. 2005; Evers et al. 2004; Ondo et al. 2004; Silberstein et al. 2000; Tepper et al. 2004). However, many clinicians are well aware that in some patients BTX-A treatment dramatically reduces attack frequency, whereas in others it produces no benefit. The goal of the present study was to prospectively search for a neurological marker that would differentiate between migraine patients who respond to BTX-A treatment and those individuals who do not benefit from such treatment.

BTX-A therapy has been used in a variety of disorders associated with painful muscles spasm (Berweck and Heinen 2004; Chen and Swope 2003; Comella et al. 2000; Defazio and Livrea 2004; Jankovic 2004; Marjama-Lyons and Koller 2000; Tilton 2004) as well as migraine (Binder et al. 2000; Blumenfeld 2003; Dodick et al. 2005; Evers et al. 2004; Tepper et al. 2004; Troost 2004). Because migraine attacks are frequently associated with muscle tenderness (Jensen et al. 1988; Tfelt-Hansen et al. 1981), it is generally believed that intramuscular BTX-A may prevent abnormal sensory signals in the affected muscle from arriving to the central nervous system. If abnormal muscle physiology can trigger migraine, one would predict that BTX-A treatment should work prophylactically only in patients whose migraine attacks develop at the heels of episodic or chronic muscle tenderness. According to another view, BTX-A may block sensitization of nociceptive neurons in the dorsal horn (Aoki 2005; Cui et al. 2004; Oshinsky et al. 2004). Considering that central sensitization during migraine is manifested as cutaneous allodynia (Burstein et al. 2000a; Burstein et al. 1998; Burstein et al. 2000b), one would expect BTX-A to block the development of allodynia during migraine in BTX-A responders who were allodynic before treatment.

The results of the prospective study indicated that BTX-A responders did not differ from non-responders in terms of muscle tenderness, cutaneous allodynia or any other known feature of migraine that we examined. Much to our surprise, however, responders and non-responders were sharply divided in the way they described their migraine headache. To test the validity of this finding, we conducted a triple-blind retrospective study in which patients from two other clinics were interviewed after they had already undergone routine prophylactic BTX-A treatment.

Methods

Patient selection

The studies herein were carried out in compliance with 1983 revision of the 1975 Helsinki Declaration, and according to the ethical standards of the Beth Israel Deaconess Medical Center (BIDMC) Committee on Clinical Investigation on Human Experimentation, including an informed consent form. Included in the study were patients who met the criteria of the International Headache Classification Committee for Migraine. (Headache-classification-committee-of-the-International-Headache-Society 1988). Excluded were patients with chronic daily headache, tension-type headache, peripheral nervous system injuries, and patients using opioids for reasons other than migraine. With the exception of 2 patients in the retrospective study, no patient was taking any prophylactic drugs for a period of 3–6 months prior and 3–4 month after BTX-A injections.

Prospective study

Sixty migraine patients (25–57 year-old) were recruited for the prospective study at the BIDMC pain clinic, Boston, MA. Of those, 18 patients dropped out of the study without receiving BTX-A treatment. The remaining 42 patients were designated to visit the clinic 5 times as described below.

Visit 1

This visit took place when the patients were migraine-free for at least 2 days. They were interviewed for migraine history and accompanied symptoms, and tested for their baseline skin sensitivity in the absence of migraine.

The interview included the following items: family history; migraine history (age of onset and number of years with migraine); past and present medication usage; attack frequency/duration and headache intensity; associated neurological symptoms (aura, nausea, vomiting, photophobia, phonophobia, osmophobia). Patients were asked if they experience neck muscle tenderness during migraine, and if so, whether it starts before and after the onset of the headache. In addition, patients were asked to give a detailed account of their migraine headache, including the affected area (e.g., ocular, frontal, parietal, occipital, unilateral, bilateral) and the characteristics of the pain (e.g., pressuring, throbbing). A significant portion of the interview was devoted to a novel set of questions aimed at delineating the directionality of the pain. These questions were constructed on the basis of subjective testimonies that we have collected from migraine patients over the years. Collectively, these subjective testimonies suggested that some patients perceived a painful buildup of pressure inside the head (e.g., “my head is exploding”) whereas others perceived a painful assault on the outside of the head (e.g., “I have a crushing headache”). Initially, patients were prompted to provide a free-form description of how they felt their headache using words or metaphors of their choosing. Next, they were specifically asked whether their pain felt like a pressure inside the head pointing outward (i.e., inside to outside direction) or a crushing/piercing pain outside the skull pointing inward (i.e., outside to inside direction). Finally, they were asked to chose from the following options: (a) it feels as if my head is exploding, (b) it feels as if my head is being crushed or pierced on the outside.

After the interview, baseline skin sensitivity was measured using quantitative sensory testing (QST) according to the method of limits (Fruhstorfer et al. 1976; Yarnitsky 1997) as described before (Burstein et al. 2000b). Pain thresholds to thermal and mechanical stimuli of the skin were measured at the temple on the usual side of the headache. Patients were supine in a dimly-lit room and were unable to observe the source of the stimulation at use.

At the end of the visit patients were asked to keep records of attack frequency, attack duration and pain intensity for the duration of the study.

Visit 2

This visit took place within 3 month of visit 1. Patients arrived at the clinic during a migraine attack, 4 h after the onset of the pain. The time of onset was defined as the time at which the headache begun to throb spontaneously, or intensify in response to physical activities. Patients were asked to rate their headache intensity on a visual analog scale ranging from 0 (no pain) to 10 (worst pain). Their skin sensitivity was measured again as per visit 1, only this time it was measured during an attack. At the end of the visit, patients were offered the choice of receiving rescue medication to terminate the attack.

Visit 3

This visit took place within 7 days of visit 2 (typically in the absence of migraine) in order to administer BTX-A. A total of 100 units of BTX-A (Allergan) dissolved in 4 ml saline were divide into 21 intramuscular injections using a 30-gauge, 0.5-inch-long needle. The following muscles were injected: frontal/glabellar (7 sites, 5 units each); occipital (1 injection/side, 10 units each); temporalis (2 injections/side, 3.25 units each); trapezius (2 injections/side, 5 units each); semispinalis (1 injection/side, 2.5 units each); splenius capitis (1 injection/side, 2.5 units each). No placebo group was employed as we were only interested in finding a marker that would distinguish responders from non-responders, rather than evaluating the efficacy of BTX-A.

Visit 4

This visit took place between week 4 and week 12 after visit 3. As per visit 2, patients arrived at the clinic 4 h after the onset of migraine headache, and their skin sensitivity and headache intensity were recorded again. Patients who became migraine-free between weeks 4 and 12 after treatment were asked to wait until they underwent another attack, once the effect of BTX-A wore off.

Visit 5

This visit took place 12 weeks after visit 3. Patients provided information summarizing their experience during weeks 4–12 post-treatment regarding attack frequency, attack duration and pain intensity during an attack.

Allodynia

Whether or not a patient was allodynic during a migraine attack was determined based on the pain thresholds at visits 2 and 4 (migraine), with reference to the corresponding values from visit 1 (baseline). In healthy subjects, pain thresholds for heat, cold and mechanical skin stimuli were shown to range between 42–47 °C (Lindblom 1994), 5–18 °C (Harrison and Davis 1999; Lindblom 1994), and 75–281 g (Strigo et al. 2000), respectively. Using somewhat more stringent criteria, we considered a patient to be allodynic if the pain threshold was below 40 °C for heat, above 20 °C for cold, and below 30 g for skin indentation. Meeting the criterion for any one modality was sufficient to determine that the patient was allodynic at the time of testing.

Retrospective study

Thirty six migraine patients (25–70 year-old) were interviewed retrospectively at their doctor’s office in two headache clinics unaffiliated with BIDMC: 26 patients were from the Associate Neurologists of Southern Connecticut, Fairfield, CT; 10 patients were from the Dartmouth-Hitchcock Medical Center, Hanover, NH. These patients received BTX-A injections for the purpose of migraine prophylaxis before (and independent of) the prospective study at BIDMC.

The interview was conducted by the same investigator and in the same way described in the prospective study. To minimize any bias, the interview was carried out in a triple-blind fashion: the interviewer remained uninformed about the outcome of the treatment until the very end of the process, while the tending physician and the patient were both oblivious to the findings of the prospective study as well as which item might be associated with the treatment outcome. Our goal was to recruit as many non-responders as responders, but we found that fewer non-responders were motivated to participate in the study.

Statistical analysis

Data analysis included only patients who were clear-cut responders or non-responders. In responders, the number of migraine days per month (attack frequency × attack duration) had to drop 80% or more below the pre-BTX-A level. In non-responders, the number of migraine days per month either remained unchanged or dropped by no more than 33%. A third subset of 15 patients who were unsure whether they benefited from BTX-A treatment were excluded from data analysis, albeit the type of headache (see Results).

Data analysis was performed using non-parametric statistics (Siegel 1956). Ordinal measurements (e.g., age, attack frequency, attack duration, pain intensity) were compared between responders and non-responders using Mann-Whitney U test. Repeated ordinal measurements (i.e., before and after treatment) were compared within each group using Wilcoxon matched-pairs signed-rank test. Nominal data were analyzed using either simple χ test or Fisher exact probability test, depending on sample size and expected frequencies (Siegel 1956). The level of significance was set at 0.05

Results

Prospective study

During the period between weeks 4 and 12 after BTX-A treatment, 27 of the 42 patients who participated in the study were clear responders or non-responders (Fig. 1): non-responders (n=13) experienced no improvement, and responders (n=14) reported significant drops in attack frequency (down 88.4±3.1%, p<0.002), attack duration (down 82.0±7.6%, p<0.002), and headache intensity (down 53.4±11.9%, p<0.005). These 27 patients (25 women, 2 man) were 41.9±1.7 years of age (mean±SEM) with a history of 24.3±2.1 years of migraine (onset at 17.7±1.7 years of age). According to their migraine history documented prior to BTX-A treatment (visits 1–3), they experienced 9.0±1.3 attacks/month, each lasting 2.0±0.3 days, with headache intensity rated at 8.3±0.3 on a 0–10 VAS.

Fig. 1
Prospective study: effects of BTX-A on mean±SEM attack frequency, attack duration and pain intensity in responders and non-responders. Gray and black bars depict values before and after treatment, respectively.

At the end of the study, information collected in visits 1, 2 and 4 was analyzed in search for any difference between responders and non-responders. The number of years with migraine (mean±SEM) was similar between the two groups (23.6±3.2 vs. 24.9±2.9, p>0.9). Analysis of the following migraine symptoms indicated they were as prevalent in responders as in non-responders (p>0.6): aura (50 vs. 38%, respectively); photophobia (100 vs. 92%); phonophobia (93 vs. 92%); osmophobia (86 vs. 69%); nausea (86 vs. 77%); vomiting (57 vs. 46%); throbbing (93 vs. 92%); or unilateral headache (57 vs. 69%). Analysis of the incidence of neck-muscles tenderness showed no significant difference between responders and non-responders (79 vs. 54%; p>0.4). Analysis of medication overuse, as defined by Silberstein et al (Silberstein et al. 2005), yielded no difference between the two groups of patients (36 vs. 38%). Analysis of the incidence of cutaneous allodynia during migraine (Table 1) showed no significant difference between responders and non-responders before BTX-A treatment (86 vs. 62%, p>0.3). Moreover, between weeks 4 and 12 post-treatment, all allodynic patients but one (a non-responder) continued to exhibit allodynia during migraine.

TABLE 1
Prospective study: classification by QST of skin sensitivity to heat, cold and mechanical stimulation in individual migraine patients before and after BTX-A treatment. ○ normal sensitivity; ● hypersensitivity. A, allodynic; NA, non-allodynic. ...

Our last set of data analysis dealt with the way patients described their headache and its directionality. Patients were specifically asked to make a distinction between the universal perception of throbbing, which was typically pointed and always emanating outward, and their perception of pain in the larger area affected by the headache as described in Methods. Based on the testimonies, we came to recognize 2 classes of migraine pain, which we denoted ‘exploding headache’ and ‘imploding headache’. Patients with exploding headache perceived a buildup of pressure inside their head as if the skull was about to split open (Fig. 2A). Patients with imploding headache perceived their skull to be assaulted by external forces typically referred as crushing, clamping or stubbing (Fig. 2B, 2C). We also encountered a third subgroup of patients whose testimonies did not fit the description of either exploding or imploding headache. These patients attested to an eye-popping pain which we denoted ‘ocular headache’ (Fig. 2D). Typical quotes for each of the 3 categories are summarized in Fig. 2.

Fig. 2
Illustrations of migraine pain and its directionality based on patients’ testimonies. A. exploding headache, B. Imploding (crushing and stabbing) headache, C. Ocular headache.

Much to our astonishment, responders and non-responders offered very different accounts of their pain: Of 14 responders, 79% had imploding headache and 14% ocular headache; conversely, all 13 non-responders had exploding headache.

Of the 42 patients who participated in the study, 15 were unsure as to whether they benefited from BTX-A treatment. Of those, 4 had exploding headache, 4 had imploding headache, and 7 testified to having both types of headache.

Retrospective study

Patients included in this study (35 women, 1 man) were 48.3±1.7 years of age (mean±SEM) with a history of 27.3±2.3 years of migraine (onset at 20.9±2.3 years of age). They testified that their migraine history prior to BTX-A treatment consisted of 13.3±1.7 attacks/month, each lasting 1.3±0.1 days, with headache intensity rated at 8.9±0.2 on a 0–10 VAS. After BTX-A treatment, the patients fell into two categories (Fig. 3): non-responders (n=11), who experienced no improvement, and responders (n=25), who reported significant drops in attack frequency (down 86.2±3.2%, p<0.001), attack duration (down 65.6±8.3%, p<0.001), and headache intensity (down 59.4±7.7%, p<0.001).

Fig. 3
Retrospective study: effects of BTX-A on mean±SEM attack frequency, attack duration and pain intensity in responders and non-responders. Gray and black bars depict values before and after treatment, respectively.

In agreement with the prospective study, there was no significant difference in the number of years with migraine (mean±SEM) between responders and non-responders (29.3±3.0 vs. 22.8±3.0, p>0.1). Likewise, every migraine symptom analyzed was as prevalent in responders as in non-responders (p>0.4): aura (36 vs. 55%, respectively); photophobia (96 vs. 100%); phonophobia (96 vs. 73%); osmophobia (76 vs. 82%); nausea (92 vs. 100%); vomiting (68 vs. 64%); throbbing (88 vs. 91%), and unilateral headache (56 vs. 73%). Nor was there a significant difference between the two groups in the incidence of neck-muscles tenderness (76 vs. 91%; p>0.9), or medication overuse (36 vs. 18%; p>0.4).

As with the prospective study, the only factor that distinguished responders from non-responders was the way they described the headache and its directionality. Of the 25 responders, 72% had imploding headache and 12% had ocular headache, while only 16% had exploding headache. Conversely, of the 11 non-responders, 82% had exploding headache, and only 18% had imploding headache.

Summary of data combined from both studies

Since the findings of the prospective and retrospective studies were not significantly different from each other, we pooled the data for the following analyses.

Response to BTX-A

Dissection of the data on the basis of the type of headache (Table 2) indicated that non-responders constituted 81% of the patients with exploding headache (n=27), whereas responders constituted 94% of the patients with imploding headache (n=31) and 100% of those with ocular headache (n=5). Fig. 4 shows that the mean±SEM number of days of migraine per month (attack frequency × attack duration) dropped a whopping 90.0±0.05% in imploding headache patients (p<0.0001), 96.5±0.03% in ocular headache patients (p<0.05) but remained unchanged in exploding headache patients (p>0.9).

Fig. 4
Effects of BTX-A on mean±SEM number of days of migraine per month (attack frequency × attack duration) according to the type of headache in imploding (n=31), ocular (n=5) and exploding (n=27) headache patients pooled from the prospective ...
TABLE 2
Combined tudies: distribution of responders and non-responders according to the classification of the headache

Episodic vs. chronic migraine

Of the 63 patients, 36 had episodic migraine (1–14 days of migraine per month) and 27 had chronic migraine (15–30 days of migraine per month). Of the episodic migraine patients, 58% were responders and 42% were non-responders. Of the chronic migraine patients, 67% were responders and 33% were non-responders. The distribution of responders and non-responders between episodic and chronic migraine patients proved non-significant (χ2=0.84; p>0.5).

Neck-muscle tenderness

Contrary to our working hypothesis, the data in Table 3 demonstrate that the distribution of responders and non-responders was similar among patients who developed muscle tenderness before (n=21) or after (n=22) the onset of a migraine attack, as well as among patients who had no muscle tenderness at all (n=15).

TABLE 3
Combined studies: classification of muscle tenderness among responders and non-responders

Addendum: retrospective analysis of migraine patients who received placebo injections

After finding a relationship between headache type and outcome of BTX-A treatment (initially presented at the International Headache Conference in Kyoto, Japan, October 2005), we made it a general practice in the 3 participating clinics to inquire patients about their headache type, regardless of whether they had received any BTX-A treatment. We then asked Allergan to provide us with code names of patients that had received placebo injections in our 3 clinics in an earlier phase 2, double-blind, randomized, placebo-controlled study that evaluated BTX-A injections as a preventative treatment for migraine headache. A summary of the placebo treatment in the earlier Allergan study was provided to the attending physicians and analyzed against the type of migraine headache in individual patients. Twelve placebo subjects were thus identified, and none of them was exposed to any BTX-A treatment. As shown in Fig. 5, the mean±SEM number of days of migraine per month remained unchanged in patients with imploding/ocular headache (n=6) or exploding headache (n=6). The maximal drop in number of migraine days per month after placebo injections was 21, 24, 29 and 45% in 4 patients (1 with imploding, 2 with exploding, 1 with ocular headache, respectively). Among the remaining 8 patients, the drop in migraine days/month was either minimal (<10%) or nil (4 with imploding, 4 with exploding headache).

Fig. 5
Effects of placebo injections on mean±SEM number of days of migraine per month (attack frequency × attack duration) according to the type of headache in imploding/ocular (n=6) and exploding (n=6) headache patients. Gray and black bars ...

Discussion

The success rate of preventing migraine attacks prophylactically using BTX-A was associated with the type of headache individual patients had. Patients who testified to ‘imploding’ or ‘ocular’ headache were likely to experience a drastic decline in the number of migraine days per month between weeks 4 and 12 after a single treatment session. In contrast, patients who testified to ‘exploding’ headache were unlikely to respond to BTX-A treatment. Thus, migraine perceived as exploding headache appears to be fundamentally different in pathophysiology from migraine perceived as imploding or ocular headache, suggesting that the subjective perception of pain be incorporated into migraine diagnosis.

Considering that migraine prophylaxis may be associated with a placebo effect (Binder et al. 2000; Dodick et al. 2005; Evers et al. 2004; Ondo et al. 2004), we examined whether the incidence of migraine could be selectively reduced by placebo injections in patients with imploding or ocular headache, but not in those with exploding headache. Retrospective analysis indicated that the mean number of migraine days per month remained unchanged after placebo injections in 6 patients with imploding/ocular headache, as well as in 6 patients having exploding headache. Patient-by-patient analysis indicated that 4 out of 12 patients (33%) experienced a 21–45% drop in migraine days/month. It should be noted, however, that the definition of response to BTX-A in the current study was much higher (>80% drop in migraine days/month), suggesting that the selective response to BTX-A treatment in our patients with imploding/ocular headache was unlikely to be due to a placebo effect. Using a lower threshold for response to BTX-A (e.g., >50% rather than >80% drop in migraine days/month), as in other studies, would slikely increase the size of the placebo effect.

Migraine patients typically describe their headache using familiar terms such as throbbing, pounding, pressing or tightening (Olesen et al. 2005). In recent years, we have become aware that some patients perceive their pain as pressure buildup inside their head (exploding headache) while others perceive their pain to be inflicted from the outside (imploding headache). Subjective accounts of exploding headaches often consisted of phrases such as: “My head is exploding”, or “my brain feels so swollen that there isn’t enough room inside”, or “I wish someone would drill a hole in my head to let the pressure out”. Subjective accounts of imploding headaches included phrases such as: “someone is tightening a vise around my head and it is going to crush”, or “an elephant is sitting on my head”, or “someone is stubbing a knife in my head”. We must admit that this novel delineation of the type of headache according to its directionality may not be a simple task for either the interviewing physician or the patient. So far, we have employed a three-tier approach in the interview: first, allow the patients to volunteer their own answer to the best of their recollection; second, ask the patients to choose between inward and outward headache; third, present a sample of common testimonies (Fig. 2) and ask the patients which fits best their perception of migraine pain. To minimize inter-observer variability, it will first be necessary to optimize a standardized line of questioning presented to the patient and, second, apply the standardized interview in different clinics in order to validate the consistency of the diagnosis.

Although we do not understand the pathophysiological difference between exploding and imploding headaches, we have made it a routine to ask patients to describe their headache and its directionality. We found that the proportion of migraineurs with imploding headache was 42 and 44% in the prospective and retrospective study, respectively. Exploding headache was found in 54% of the patients in the prospective study and 33% of the patients in the retrospective study. While the relative prevalence of exploding and imploding headaches remains to be determined in the general population of migraineurs, our preliminary survey of 50 patients in BIDMC headache clinic suggests that 70% have exploding and 30% imploding or ocular migraine headache.

A number of factors proved unrelated to the prophylactic action of BTX-A. Symptoms such as aura, photophobia, phonophobia, osmophobia, nausea, vomiting or throbbing, were equally prevalent among responders and non-responders. Also unrelated to the prophylactic action of BTX-A is the frequency of migraine attacks: among responders 54% of the patients were ‘episodic’ and 46% were ‘chronic”. Given that medication overuse often renders patients refractory to common migraine therapy, the finding that medication overuse was equally prevalent between responders and non-responders suggests that medication overuse does not interfere with the prophylactic action of BTX-A.

The finding that migraine prophylaxis was unrelated to concurrent muscle tenderness suggests that the effect was independent of the inhibitory action of BTX-A at the level of the neuromuscular junction. The notion that migraine prophylaxis may be achieved through direct inhibition at the level of the central nervous system did not gain support either. The responsiveness to BTX-A was not associated with any centrally-mediated migraine symptoms such as aura and cutaneous allodynia. Considering that cutaneous allodynia is driven by sensitized central trigeminovascular neurons (Burstein et al. 2000b), it is worth noting that BTX-A proved virtually ineffective in blocking allodynia during migraine in both responders and non-responders.

Rather than acting centrally, BTX-A may exert its prophylactic action on migraine through inhibition of peripheral sensory neurons (Aoki 2005). That BTX-A can inhibit sensory neurons is consistent with evidence that the toxin inhibits release of substance P from embryonic dorsal root ganglion neurons in vitro (Welch et al. 2000), or CGRP from trigeminal ganglion neurons in vitro (Durham and Cady 2004), or glutamate from peripheral nociceptors terminating in the dorsal horn in vivo (Cui et al. 2004). Using quantitative sensory testing, however, Blersch et al (2002) showed that subcutaneous injection of BTX-A did not change pain thresholds to local cold, heat and electrical stimulation, and concluded that BTX-A may block pain through chemodenervation or anti-inflammatory action, rather than by direct peripheral anti nociceptive effect.

Regardless of the exact peripheral mechanism of BTX-A action, at issue here is whether the peripheral action is exerted intracranially or extracranially. The finding that exploding headache was impervious to extracranial BTX-A injections is consistent with the general view that migraine pain is mediated by intracranial nociceptors innervating the meninges and sinuses of the dura. Such a concept may also be tested in the future using patients whose headache stems from a clear intracranial pathophysiology. On the other hand, the amenability of imploding and ocular headaches to BTX-A treatment suggests that these types of migraine pain also involve extracranial sensory fibers adjacent to the injection sites. Involvement of extracranial tissue in the pathophysiology of certain migraine patients has been proposed some five decades ago (Selby and Lance 1960; Wolff et al. 1953). If so, it is tempting to speculate that imploding headache involves activation of extracranial nociceptors that innervate scalp tissues, such as bone and periostium.

The dramatic difference between responders and non-responders in the incidence of migraine after BTX-A treatment suggests that previous studies that pooled data from all treated patients without such distinction (Binder et al. 2000; Dodick et al. 2005; Evers et al. 2004) may have missed the full magnitude of the prophylactic effect of the toxin at the level of the individual patient. Of the 42 subjects that participated in our prospective study, only 14 (33%) were clear-cut responders, while 13 (31%) were clear-cut non-responders. It remains to be determined what types of headache are present in patients whose attack frequency after BTX-A dropped between 33 and 80% (‘partial responders’).

Finally, we would like to emphasize that the present study does not intend and cannot be used to recommend the use of BTX-A as prophylactic migraine therapy. The only goal of this study was to explore for neurological markers that might single out migraine patients who respond to BTX-A treatment from those who do not.

Acknowledgments

Supported by an unrestricted grant from Allergan, and by NIH grant NS051484 to Dr. Burstein. We thank Virginia artist Lorraine Fink for the illustrations in FIG. 2. Dr. Jakubowski had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Footnotes

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