Botulinum toxin type-A in the prophylactic treatment of medication-overuse headache: a multicenter, double-blind, randomized, placebo-controlled, parallel group study.

Abstract

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.

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ORIGINAL
Botulinum toxin type-A in the prophylactic treatment
of medication-overuse headache: a multicenter, double-blind,
randomized, placebo-controlled, parallel group study
Giorgio Sandrini•Armando Perrotta•
Cristina Tassorelli•Paola Torelli•Filippo Brighina•
Grazia Sances•Giuseppe Nappi
Received: 1 February 2011/Accepted: 26 March 2011/Published online: 16 April 2011
? The Author(s) 2011. This article is published with open access at Springerlink.com
Abstract
sents a severely disabling condition, with a low response to
prophylactic treatments. Recently, consistent evidences
have emerged in favor of botulinum toxin type-A (onabo-
tulinum toxin A) as prophylactic treatment in chronic
migraine. In a 12-week double-blind, parallel group, pla-
cebo-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 onabotuli-
num 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
ofheadachedaysforthe28-dayperiodendingwithweek12.
Medication-overuse headache (MOH) repre-
No significant differences between onabotulinum toxin A
and placebo treatment were detected in the primary (head-
ache 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.
Keywords
headache ? Prophylactic treatment ? Migraine ? Pericranial
muscle tenderness
Botulinum toxin type-A ? Medication-overuse
Introduction
The 2nd edition of the International Headache Society’s
International Classification of Headache Disorders (ICHD-
II, IHS 2004) [1] introduced the term medication-overuse
headache (MOH: code 8.2, ICHD-II) to indicate a chronic
daily headache condition in which an excessive intake of
symptomatic drugs has played a role in the chronification,
Electronic supplementary material
article (doi:10.1007/s10194-011-0339-z) contains supplementary
material, which is available to authorized users.
The online version of this
A. Perrotta (&) ? G. Sances ? G. Nappi
Headache Science Center, IRCCS ‘‘C. Mondino Institute
of Neurology’’ Foundation, Via Mondino 2, 27100 Pavia, Italy
e-mail: armando.perrotta@uniroma1.it
A. Perrotta
Headache Clinic, IRCCS Mediterranean Neurological Institute
‘‘Neuromed’’, Pozzilli, Isernia, Italy
G. Sandrini ? C. Tassorelli
Headache Science Center, IRCCS ‘‘C. Mondino Institute
of Neurology’’ Foundation, University of Pavia,
Via Mondino 2, 27100 Pavia, Italy
P. Torelli
Headache Centre, Department of Neuroscience,
University of Parma, Parma, Italy
F. Brighina
Department of Clinical Neurosciences,
University of Palermo, Palermo, Italy
123
J Headache Pain (2011) 12:427–433
DOI 10.1007/s10194-011-0339-z

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and in which a clear relationship between increased drug
intake and worsening of the headache is detectable [2]. The
prevalence of MOH ranges from 1 to 5% in the general
population [3, 4], rising to 10% in headache clinic patients
[5] and to 80% among patients with chronic migraine in a
tertiary headache center population [6]. MOH represents a
severely disabling condition affecting social life and work
ability, with a low response to prophylactic treatments in the
absence of a concomitant drug withdrawal treatment (see
[7] for review), but also with a very high incidence of
relapse (between 30 and 50% of patients) within the first
year after withdrawal treatment [8].
Intramuscular injections of botulinum toxin type-A
(onabotulinum toxin A) has been employed to treat head-
ache pain including episodic migraine [9, 10] and chronic
tension-type headache [11–13] without univocal results as
prophylactic treatment and chronic daily headaches not
responding to previous prophylactic treatments with
encouraging results [14]. On the contrary, growing con-
sistent evidences are emerging in favor of onabotulinum
toxin A as prophylactic treatment in chronic migraine
(1.5.1, ICHD-II) [15–17] and, in particular, in subgroups of
patients with cutaneous allodynia, pericranial muscular
tenderness [18] or specific types of headache pain such as
the so defined ‘‘imploding’’ and ‘‘ocular’’ pain [19, 20].
To explain the prophylactic effect of onabotulinum toxin
A, it has been hypothesized that this neurotoxin could
prevent or reduce the abnormal peripheral sensory signals
from the pericranial muscles to the central nervous system
and/or inhibit the sensitization of nociceptive neurons in the
dorsal horn [21]. As in chronic daily headache, including
MOH patients with migraine as primary headache, both
pericranial muscle tenderness [22] and sensitization of the
pain pathways at the trigeminal [23] and spinal levels [24]
has been demonstrated, one would predict that in these
patients onabotulinum toxin A would further improve the
benefit of the withdrawal treatment and so facilitate the
reversion to an episodic form of headache.
Ourstudywasaimed toevaluate inamulticenter,double-
blind placebo-controlled study the efficacy and safety of
onabotulinum toxin A as prophylactic treatment for patients
with MOH with migraine as primary headache, as well as to
address if specific features such as cephalic allodynia, peri-
cranial muscle tenderness, type of headache pain or of drug
overusemayinfluencetheresponsetoonabotulinumtoxinA.
Materials and methods
Study design
The enrollment phase was conducted from January 2006 to
July 2008 at: The Headache Science Center, IRCCS C.
Mondino Institute of Neurology Foundation, Pavia, Italy;
Headache Center, University of Parma, Parma, Italy; Head-
ache Center, University of Palermo, Palermo, Italy. The
study had a 4-week baseline screening phase (referred to as
baseline) and a 12-week double-blind, parallel group, pla-
cebo-controlled phase with one injection cycle at day ‘‘0’’ of
the double-blind phase, followed by a 12-week, open-label
phase (details will be described separately) (Fig. 1). All the
potential participants were selected from among patients on
the waiting list for a consultation in outpatient headache
clinics of the participating center. All the patients enrolled in
the study filled in a daily headache diary (mailed) to record
their headache symptoms and acute treatments every day for
at least 2 months before the start of the baseline period
(4 weeks) and for the entire period of the study. The study
was conducted in accordance with the Declaration of Hel-
sinki Ethical Principles and Good Clinical Practices and was
approved at each site by an independent local ethics com-
mittee. Written informed consent was obtained from each
participant prior to any study-related procedures.
Study population
Eligible patients were men or women aged 18–65 years
with a history of headache, fulfilling the diagnostic criteria
for migraine without aura (coded as 1.1) [1] as primary
headache plus medication-overuse headache (coded as 8.2)
[1, 2] with C15 headache days every 4 weeks in the past
3 months and with each headache day consisting of C4 h
of continuous headache prevalent with migraine features.
Exclusion criteria were definite or suspected diagnosis of
pathologies affecting neuromuscular function including,
myasthenia gravis, Eaton–Lambert syndrome and amyotro-
phic lateral sclerosis, and presence of cervical pathologies or
otherfactorsliabletogiverisetopericranialmuscledisorders.
Further exclusion criteria included: other primary or
secondary headaches, including a history of complicated
Fig. 1 Study design
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migraine (i.e., migrainous infarction, hemiplegic migraine,
basilar migraine or ophthalmoplegic migraine); any serious
systemic or neurological diseases or psychiatric disorders,
including depression (Beck’s Depression Inventory score
[17 at day 1 of baseline); temporo-mandibular disorder,
fibromyalgia, complex regional pain syndrome or neuro-
pathic pain [25–27]; use of prophylactic medications for
headaches, use of opiates, antidepressants, benzodiaze-
pines, hormones, muscle relaxants and agents that may
interfere with neuromuscular function within 4 weeks of
day 1 of the baseline; previous exposure to any botulinum
toxin serotype for other pathological conditions or for other
purposes. Women of childbearing potential were required
to have negative urine pregnancy test. Females who were
pregnant, nursing or planning a pregnancy during the study,
or who were unable or unwilling to use a reliable form of
contraception during the study were excluded.
Randomization, stratification and study treatment
At the end of the baseline period, patients meeting the
inclusion/exclusion criteria were admitted as inpatients
(ordinary hospitalization or day hospital) and treated
with standard withdrawal therapy for detoxification for
8 ± 2 days [28].
Patients were stratified based on the type and frequency
of acute drug overused during baseline, in order to balance
their distribution within the two study groups. The project
statistician created a randomized treatment allocation
schedule using a computer random number generator.
Both the patient and principal investigator, as well as the
co-investigators who administered the treatment and
assessed the safety and outcomes and the sponsor of the
study, were blinded as to the identity of the randomized
study medication. Blinding was maintained by having a
designated pharmacist (the only person to have access to
the randomization list), who provided the principal
investigator or study co-ordinator with a vial containing
the study medication labeled with the patient’s sequential
identification number from the randomized allocation
schedule. All patients remained double blinded until the
last patient had completed the study. The blind code could
be broken by the principal investigator only for safety
concern.
During the second day of hospitalization, all patients
were randomized (1:1) in a double-blind fashion to onab-
otulinum toxin A (BOTOX, Allergan Inc., Irvine, CA,
USA) or placebo treatment and received 16 (8 on the right
and 8 on the left) intramuscular injections in the following
muscles: frontalis(2 injection
(1 injection point), temporalis (1 injection point), cervical
paraspinal (2 injection points) and trapezius (2 injection
points) for a total of 100 U for patients. Intramuscular
points),corrugators
injections were administered using a sterile 30-gauge, 0.5
inch needle and 0.2 ml (saline dilution) of onabotulinum
toxin A (5 U) or placebo at each site, except for the tra-
pezius where we administered 0.4 ml of onabotulinum
toxin A (10 U). Patients were discharged and reassessed
after 4, 8 and 12 weeks as outpatients. At the end of the
study, all the onabotulinum toxin A responder patients
were offered entry into a 12-week open-label follow-up
phase to receive a second injection cycle (Fig. 1). All
patients, including those who were not willing to partici-
pate in the long-term study, were re-assessed in a follow-up
visit at 12 months.
During the withdrawal treatment, to mitigate possible
rebound effects, the patients received twice a day, intra-
venous infusion of a saline solution plus a vitamin complex
(B12, folic acid, PP, C), glutatione 600 mg, alizapride
0.25 mg and clordemetildiazepam (0.25 mg for the first
3 days, then gradually reduced until withdrawal in 4 days).
Breakthrough migraine attacks were treated with keto-
profene, 100 mg i.m., as a rescue medication.
Safety was assessed by reports of adverse events,
physical and neurological examination and laboratory tests.
After treatment at day 0, adverse events were recorded and
documented with information regarding the date of onset,
severity, duration, resolution date, relationship with study
treatment, treatment required and outcome.
Outcome measures
The primary efficacy end point was mean change from
baseline in frequency of headache days for the 28-day
period ending with week 12. A headache day was defined
as a calendar day (00:00 to 23:59) when the patient
reported not \4 h of headache. Secondary efficacy end
points were mean change from baseline in acute headache
pain medication intakes and in days with acute headache
medication consumption at 4, 8 and 12 weeks after onab-
otulinum toxin A administration. The intensity of the
headache pain was evaluated by a 0–10 numerical rating
scale (NRS) score. The analysis included two assessments
of disability measured by Headache Impact Test (HIT)-6
score and Migraine Disability Assessment Scale (MIDAS)
administered at 4 and 12 week after onabotulinum toxin A
administration. Patients were subdivided into subgroups
based on the presence/absence of cephalic cutaneous allo-
dynia measured by a prospective clinical questionnaire
[29], pericranial muscle tenderness, assessed by palpation
and type of migraine pain (exploding, imploding, ocular)
[19] at baseline. Other efficacy analysis included the inci-
dence of subjects with no less than 50% decrease from
baseline in the frequency of headache days for the 28-day
period ending with week 12 (primary end point) and during
the whole observed period from 4 to 12 weeks.
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Statistical analysis
Dataanalysiswasperformedusingnon-parametricstatistics.
Ordinal measurements, including age, headache days, acute
headache medication intake, days with drug consumption,
pain intensity and disability scales (MIDAS and HIT-6),
were compared between groups using Mann–Whitney test.
Ordinal measurements before and after treatment were
compared using ANOVA for repeated measures. For post
hoc analysis of group mean differences, we used Student’s
t test with Bonferroni correction. Nominal data were ana-
lyzed using v2test. The level of significance was set at 0.05.
All statistics were calculated using the SPSS (16.0) program
for Windows (SPSS, Chicago, IL, USA).
Results
Demographic and baseline characteristics
Of the 145 patients screened, 68 were randomized to
onabotulinumtoxinA(n = 33)
Twelve (17.7%) subjects discontinued prior to week 12, six
(8.8%) randomized to onabotulinum toxin A and six (8.8%)
to placebo, and 56 (82.3%) completed the study, 27
(48.2%) randomized to onabotulinum toxin A and 29
(51.7%) to placebo. As a consequence, the number of
participants was small and represented a limitation of the
present work. In subjects who dropped-out, discontinuation
was due to being lost to follow-up (1 onabotulinum toxin
A; 2 placebo); adverse events (2 onabotulinum toxin A; 0
placebo) or personal reasons (3 onabotulinum toxin A; 4
placebo). Demographic and clinical characteristics of the
study population at baseline are reported in Table 1.
Headache pain intensity and assessment of disability
(MIDAS and HIT-6) at baseline were reported as Online
Resource 1. The prevalence of cutaneous allodynia, peri-
cranial muscle tenderness, type of migraine pain and drug
overuse is summarized in Table 2. There were no between-
group significant differences at baseline for demographic
and clinical characteristics (Table 1), as well as for head-
ache pain intensity and disability measurements (MIDAS
and HIT-6) (Online Resource 1).
orplacebo(n = 35).
Outcome measures
Overall subjects
When the whole group of randomized subjects (onabotul-
inum toxin A and placebo) was considered, despite a clear
tendency of onabotulinum toxin A-treated subjects to show
better results than placebo-treated subjects, no significant
differences were detected in primary (headache days) and
secondary (acute pain drug consumption, days with acute
pain drug consumption) end points, pain intensity and
headache impact on functioning (HIT-6 and MIDAS),
except for a significant reduction in mean acute pain drug
consumption at 12 weeks in the onabotulinum toxin
A-treated compared to placebo-treated patients (Table 1).
Subjects with pericranial muscle tenderness and cephalic
allodynia
Significant differences in onabotulinum toxin A-treated
versus placebo-treated patients were observed for primary
Table 1 Demographic and clinical characteristics of the study pop-
ulation at baseline and at 4, 8 and 12 weeks
BoNTA (n = 27) Placebo (n = 29)
p values
Mean age
(years)
48.5 ± 9.2 (28–65)49.0 ± 10.1 (28–64) 0.806
Female2124
Duration
(years)
19.720.3
Mean headache days/28 days
Baseline24.2 ± 5.0 (14–30)25.5 ± 5.6 (15–30)0.209
4 16.6 ± 8.2 (0–30)19.0 ± 9.6 (0–30)0.234
814.7 ± 9.1 (1–30)18.0 ± 9.5 (0–30)0.212
1212.0 ± 9.0 (4–30)15.9 ± 9.5 (0–30)0.081
Mean acute pain drug consumption/28 days
Baseline 31.0 ± 12.7 (12–60) 34.7 ± 18.5 (12–90) 0.675
4 14.6 ± 12.8 (0–56) 19.6 ± 15.3 (0–60)0.192
8 16.2 ± 14.3 (2–60) 19.0 ± 15.5 (0–60) 0.478
1212.1 ± 14.6 (0–58)18.0 ± 14.4 (0–90)0.030
Mean days with acute pain drug consumption/28 days
Baseline22.7 ± 6.4 (12–30) 23.6 ± 6.6 (12–30)0.587
4 12.0 ± 9.0 (0–30)15.3 ± 10.1 (0–30)0.240
812.1 ± 9.5 (1–30)15.1 ± 10.2 (0–30)0.256
1210.7 ± 10.1 (2–30)14.3 ± 9.1 (0–30)0.085
Table 2 Headache characteristics of the study population at baseline
BoNTA (n = 27) Placebo (n = 29)
Headache characteristics
Cutaneous allodynia21 (77.8%) 25 (86.2%)
Pericranial muscle tenderness 14 (51.9%) 15 (51.7%)
Exploding pain 12 (44.4%)10 (34.5%)
Imploding pain 13 (48.1%)14 (48.3%)
Ocular pain2 (7.4%)5 (17.2%)
Drug overused
Combination5 (18.5%)6 (20.7%)
Ergot1 (3.7%) 1 (3.4%)
FANS10 (37.0%) 13 (44.8%)
Triptans 11 (40.7%)9 (31.0%)
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and secondary end points at 12 weeks in those with peri-
cranial muscle tenderness. In patients with pericranial
muscle tenderness, onabotulinum toxin A-treatment was
found to show, when compared with placebo treatment, a
significant reduction in frequency of headache days (pri-
mary end point) (Fig. 2), as well as in both headache pain
medication intake (Fig. 3) and days with acute headache
medication consumption (Fig. 4) for the 28-day period at
12 weeks.
Furthermore, a statistical significant reduction in scores
for pain intensity as well as for disability measures,
MIDAS and HIT-6, were detected at both 4 and 12 weeks
in onabotulinum toxin A-treated when compared with
placebo-treated patients (Online Resource 2 Figs. 1–3).
No differences were detected at any time point between
the onabotulinum toxin A- and placebo-treated subjects in
primary and secondary end points, as well as in pain
intensity and headache impact on functioning scores in
subgroups of patients with cephalic allodynia (all p[0.05).
Subjects with exploding versus imploding/ocular headache
In the subgroups of randomized subjects based on the type
of headache pain (exploding and imploding/ocular), no
significant differences were found between onabotulinum
toxin A- and placebo-treated patients, except for a signif-
icantly better mean MIDAS score at 4 (p = 0.012) and 12
(p = 0.008) weeks in the exploding pain subgroup that had
onabotulinum toxin A treatment when compared with
placebo treatment.
Responders versus non-responders
A significantly greater percentage of onabotulinum toxin
A-treated than placebo-treated patients had at least a 50%
decrease from baseline in the frequency of headache days
when both headache days at 12 weeks (Z = -2.915;
p = 0.004) and that across all time points (Z = 2.121;
p = 0.034) were considered (Fig. 5).
Fig. 2 Primary end point: mean change (±SE) from baseline in
frequency of headache days for the 28-day period in MOH patients
with pericranial muscle tenderness
Fig. 3 Secondary end point: mean change (±SE) from baseline in
acute headache pain medication intake for the 28-day period in MOH
patients with pericranial muscle tenderness
Fig. 4 Secondary end point: mean change (±SE) from baseline in
days with acute headache medication consumption in MOH patients
with pericranial muscle tenderness
Fig. 5 Percentage of patients with at least a 50% decrease from
baseline in the frequency of headache days across all time points and
at 12 weeks in BoNTA and placebo treated
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Safety
A total of 16 (28.5%) subjects in the randomized popula-
tion experienced adverse events. Treatment-related adverse
events were reported in 25.9% of the onabotulinum toxin
A-treated (7 patients) and in 17.2% of the placebo-treated
(5 patients) patients. Two patients randomized to onabo-
tulinum toxin A (7.4%) discontinued due to adverse events
(neck pain). No clinically significant serious adverse events
were reported in any of the 56 subjects. Most common
adverse events ([5%) were pain at the site of injection and
muscular weakness, all of which resolved without sequelae.
Discussion
The study evaluated the efficacy and safety of onabotuli-
num toxin A as prophylactic treatment in MOH patients
with migraine as primary headache, reporting on clinical
features that could play as predictors of response to
onabotulinum toxin A.
Results showed that when the whole group of random-
ized subjects was considered, a significant reduction in
mean acute pain drug consumption at 12 weeks, as well as
a clear but not significant trend toward better clinical
results across all time points in primary and other sec-
ondary end points in favor of onabotulinum toxin A-treated
whencomparedwith placebo-treated
observed. It is worth noting that a significantly greater
percentage of onabotulinum toxin A-treated with respect to
placebo-treated patients showed 50% or more improve-
ment in the primary end point (mean headache days), both
when the 12-week time point and the entire post-treatment
period, from 4 to 12 weeks, were considered.
The most relevant result of the study emerged when the
subgroup of patients with muscular tenderness was con-
sidered. In this case, a significant improvement in both
primary (mean headache days) and secondary end points
(mean drugs consumption and mean days with consump-
tion) at 12 weeks, as well as in pain intensity and headache
impact on functioning (HIT-6 and MIDAS) across all time
points (4 and 12 weeks) was found.
The analysis of the results should take into account some
questions. The sample size was not sufficient to reach an
adequate statistical power and we could only speculate on
the results. In this sense, the lack of significance in the pri-
mary end point in the whole population could be a conse-
quenceofasmallsamplesize.However,acleartrendtoward
a better performance of the onabotulinum toxin A-treated
patients across all time points and for all considered
parameters, including pain perception and disability mea-
sures, was detected. There were no significant differences
favoring placebo for any efficacy variable at any time point
patients was
in the study. Furthermore, the proportion of responders was
clearlyinfavorofonabotulinumtoxinA-treated.Inaddition,
as the patients underwent withdrawal treatment due to a
medication-overuse, the role of this treatment in the clinical
improvement should be taken into account. Withdrawal
treatment represents a pivotal strategy to treat patients with
MOH [28] and this is also confirmed from the clear clinical
improvement observed in MOH patients treated with pla-
cebo. However, as the intake of acute pain medication and
the withdrawal treatment were similar between the groups
(placebo and onabotulinum toxin A), but the proportion of
responders was clearly in favor of the onabotulinum toxin A
treated, we hypothesized that the injection of onabotulinum
toxin A could be responsible for this further significant
clinical improvement detectable in MOH patients treated
with onabotulinum toxin A.
Another relevant result is the statistically significant
improvement in patients-reported quality of life measures,
such as HIT-6 and MIDAS scores, observed in onabotuli-
num toxin A-treated patients with pericranial muscle ten-
derness and muscular allodynia when compared with the
placebo treated.
Treatment-related adverse events were reported in
25.9% of the onabotulinum toxin A-treated (7 patients),
and 7.4% of the onabotulinum toxin A-treated patients (2
patients) discontinued due to treatment-related adverse
events. No clinically significant serious adverse events
were reported in any of the 56 subjects. These data confirm
the favorable safety profile of onabotulinum toxin A
injected into the head and neck muscles.
Our data confirm and support previous clinical trial
findings obtained in patients with chronic migraine in
which only two-thirds overused acute pain medication
during the baseline period [15–17]. As the presence of
medication overuse represents a risk factor for the devel-
opment of chronification [3, 6] as well as a factor that
reduces the efficacy of the prophylactic treatment [8], the
success rate of preventing migraine attacks using onabo-
tulinum toxin A in our MOH samples could be considered
a further confirmation of the efficacy of this treatment in
chronic migraine prophylaxis and, in particular, in patients
with peculiar clinical characteristics such as pericranial
muscle tenderness.
From a pathophysiological point of view, as in a pre-
vious study, we demonstrate that the withdrawal treatment
reduces both the clinical severity as well as the sensitiza-
tion in pain processing that take place in patients with
MOH [24]. We hypothesize that, in view of these results,
onabotulinum toxin A could influence, through the inhi-
bition of peripheral sensitization [21], the central mecha-
nisms responsible for the facilitation in pain processing,
which contribute to the development and maintenance of
chronification in these patients.
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In conclusion, our data permit the identification as pre-
dictor of clinical response to onabotulinum toxin A in
patients with complicated form of migraine such as MOH,
the presence of pericranial muscle tenderness and so to
support it as prophylactic treatment in patients with these
features.
Acknowledgments
Irvine, CA, USA.
The study was sponsored by Allergan, Inc.,
Conflict of interest
None.
Open Access
Creative Commons Attribution License which permits any use, dis-
tribution and reproduction in any medium, provided the original
author(s) and source are credited.
This article is distributed under the terms of the
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