Access to this full-text is provided by IMR Press.
Content available from Journal of Integrative Neuroscience
This content is subject to copyright.
Journal of Integrative Neuroscience
J. Integr. Neurosci. 2022 vol. 21(1), 1-8
©2022 The Author(s). Published by IMR Press.
Review
OnabotulinumtoxinA for the treatment of headache: an
updated review
Joseph H. Talbet1, Ayman G. Elnahry2,*
1College of Medicine, Howard University, 20059 Washington, D.C., USA
2Department of Ophthalmology,Faculty of Medicine, Cairo University, 11956 Cairo, Egypt
*Correspondence: ayman_elnahri@cu.edu.eg (Ayman G. Elnahry)
DOI:10.31083/j.jin2101037
This is an open access article under the CC BY 4.0 license (https://creativecommons.org/licenses/by/4.0/).
Submitted: 24 June 2021 Revised: 6 August 2021 Accepted: 25 August 2021 Published: 28 January 2022
Botulinum toxin (BT) is a neurotoxin produced by Clostridium bo-
tulinum, a gram-positive anaerobic bacterium. Systemic human in-
toxication from BT following oral ingestion results in acute and life-
threatening muscle paralysis called botulism. BT has a wide scope
of therapeutic uses, including conditions associated with increased
muscle tone, smooth muscle hyperactivity, salivation, sweating, and
allergies, as well as for cosmetic purposes. Several commercial forms
of BT are available for medical use, including Botox (onabotulinum-
toxinA). Multiple studies have found evidence of an analgesic efect
of onabotulinumtoxinA and demonstrated the benefits of its use for
the treatment of various chronic pain disorders. In this review, we
provide an update on the use of onabotulinumtoxinA for the treat-
ment of headache disorders.
Keywords
Botulinum toxin; Chronic headache; Chronic migraine; Cluster headache; On-
abotulinumtoxinA; Neurotoxin
1. Introduction
Botulinum toxin (BT) is one of the most powerful tox-
ins encountered in nature. It is a neurotoxin protein pro-
duced by Clostridium botulinum, a gram-positive anaero-
bic bacterium [1]. Chemically, BT is comprised of two
polypeptide chains joined by a disulfide bond. Seven anti-
genically distinct serotypes (A to G) have been identified
so far, with types A and B able to cause disease in humans
[1,2]. Oral ingestion of BT leads to systemic human intoxi-
cation and produces acute and life-threatening muscle paral-
ysis known as botulism [3]. BT causes dose-dependent, re-
versible muscle relaxation by blocking the release of acetyl-
choline from nerve endings at the neuromuscular junction
[4]. Consequently, BT has been observed to have a wide
range of therapeutic uses, including disorders associated with
increased muscle tone, smooth muscle hyperactivity, sweat-
ing, salivation, allergies and pain, and for cosmetic purposes
[5]. Several commercial forms of BT are offered for medi-
cal applications, including Botox (onabotulinumtoxinA, Al-
lergan Inc., Irvine, CA, USA), Dysport/Azzalure (abobotuli-
mumtoxinA, Ipsen, Slough, UK/Galderma, Paris, France),
Xeomin/Bocouture (incobotulinumtoxinA, Merz Pharma-
ceuticals GmbH, Frankfurt, Germany), and Jeuveau (prabo-
tulinumtoxinA, Evolus Inc., Newport beach, CA, USA) [1–
6]. Here, we review the use of onabotulinumtoxinA for the
treatment of various types of headaches.
2. Literature search
PubMed and OVID MEDLINE were searched on 24
April 2021, using the following terms: botulinum toxin,
botox, onabotulinumtoxinA, headache, migraine, tension
type headache, cluster headache, cervicogenic headache,
post-traumatic headache, and low-tension headache. There
were no date restrictions applied and all study types were in-
cluded. References contained within the included publica-
tions were also searched to identify additional relevant stud-
ies.
3. OnabotulinumtoxinA and headaches
Clinical studies have suggested an analgesic effect of BT
and various benefits for the treatment of chronic pain, in-
cluding headache disorders [6]. Headache is the most com-
mon nervous system disorder. It has a variety of causes and
negatively affects the quality of life in people of all ages [7].
Headaches are classified as primary or secondary types. The
former are those that arise without any signs of an under-
lying organic disease. Primary headaches are further sub-
classified into tension-type headaches, migraine, trigeminal
autonomic cephalalgia, and other less common forms such
as new daily persistent headache and nummular headache
[8]. The International Headache Society diagnostic criteria
for headache disorders (Third International Classification of
Headache Disorders) defines primary headache disorders as
those in which the headache itself is the disease. Headache
disorders can be further classified into episodic or chronic ac-
cording to their frequency of occurrence [9].
The Food and Drug Administration (FDA) approved
BT under the product name Oculinum (onabotulinumtox-
inA, Allergan Inc., Irvine, CA, USA) for treatment of ble-
pharospasm in 1989 [10]. BT injections were first proposed
as an effective treatment for headaches when it was found
incidentally that individuals who suffered from chronic
headaches experienced an improvement following cosmetic
BT injections [11,12]. During the 1990s, interest grew
for the treatment of tension-type headache with BT due to
its muscle-paralyzing actions. Oculinum was later renamed
Botox, and a long-term clinical trial program was launched
to test BT type A for the treatment of headaches. Subsequent
studies reported benefits from the use of onabotulinumtox-
inA to treat migraine. In 2002, several headache experts in-
dicated that onabotulinumtoxinA was safe and effective for
prophylactic and acute treatment of migraine [13]. In 2010,
the United States FDA approved Botox® for the treatment of
chronic migraine. In 2016, the American Academy of Neu-
rology recommended onabotulinumtoxinA as a treatment
option for chronic migraine patients [14]. Currently, onabo-
tulinumtoxinA for the treatment of headache is only regu-
lated and approved for patients with chronic migraine. Its
use for other subtypes of headache is considered to be off-
label treatment.
Chronic daily headache is a heterogeneous group of
headache symptoms with a frequency of more than 15
days per month, and which persists for longer than three
months [15]. The four common subtypes are chronic mi-
graine, chronic tension-type headache, new daily persistent
headache, and hemicrania continua [16]. The estimated
prevalence in the general population of this disabling neuro-
logical condition is about 4% to 5% and it is known to have a
significant negative impact on daily living and on the quality
of life [16,17].
3.1 OnabotulinumtoxinA and chronic migraine
Chronic migraine is defined as the occurrence of 15 or
more headache days per month for longer than a three-
month period, with at least 8 days per month showing fea-
tures of migraine [18]. Approximately one-third of chronic
headaches are classified as chronic migraine [19]. However,
chronic migraine varies amongst patients in terms of the in-
tensity of pain, the frequency of days with headache, allo-
dynia, and the overall migraine-related disability [20]. Al-
though various pharmacological treatment options are used
as prophylaxis for chronic migraine, a significant proportion
of patients still suffer from recurrent attacks. This has led
some experts to favor surgical intervention for the treatment
of chronic headaches [21]. Numerous studies have therefore
been carried out to find a more efficient way to control pain
in chronic headache conditions, with BT having shown good
results in this context.
The FDA has approved intramuscular injection of on-
abotulinumtoxinA as a preventive treatment for chronic mi-
graine headaches. Although some experts believe that extra
muscular injections are just as effective as intramuscular in-
jections, there are no peer-reviewed studies to support this
contention [22]. OnabotulinumtoxinA is therefore admin-
istered to the scalp, since migraine pain is believed to come
from the meninges, as well as to the forehead, bridge of the
nose, the temples, the back of the head, and neck (Figs. 1,2)
[21,23]. Some studies have suggested that the optimal in-
jection points for onabotulinumtoxinA in the treatment of
chronic migraine are in the temporal region and that it should
be administered >45 mm above the zygomatic arch to avoid
injection into the tendon [24,25]. The greater occipital nerve
is derived primarily from the C2 dorsal root and is the major
sensory nerve in the occipital area. The blocking of this nerve
is a common method used to treat various headaches, espe-
cially occipital headaches [26]. Several studies on ultrasound-
guided greater occipital nerve block using onabotulinumtox-
inA have shown effectiveness in lowering both short- and
long-term pain in patients with chronic headache in the oc-
cipital area.
Fig. 1. Botulinum toxin injection to the forehead for the treatment of
chronic migraine.
Fig. 2. Botulinum toxin injection to the bridge of the nose in the cor-
rugator supercilli muscle for the treatment of chronic migraine. The
injection is performed between the medial and lateral branches of the STN,
about 18 mm lateral to the facial midline at the level of the supraorbital
margin. F, frontalis muscle; OOC, orbicularis oculi muscle; CS, corrugator
supercilii; ML, facial midline; STN-L, lateral branch of the supratrochlear
nerve; STN-M, medial branch of the supratrochlear nerve.
2 Volume 21, Number 1, 2022
The Phase III Research Evaluating Migraine Prophylaxis
Therapy (PREEMPT) program consisted of two phase III
randomized controlled multicenter trials (PREEMPT 1 and
2) that evaluated the effectiveness of onabotulinumtoxinA in
patients with chronic migraine [27–29]. All patients in these
trials received intramuscular injections of onabotulinumtox-
inA at 31 injection sites in 7 head and neck muscles with a
fixed-site and fixed-dose injection paradigm (5 U in 0.1 mL
per injection). In addition, up to 40 units of onabotulinum-
toxinA could be administered at 8 other injection sites as
needed across three head and neck muscles with a “follow-
the-pain” approach. This standardized treatment program
is known as the PREEMPT injection paradigm [27]. The
PREEMPT studies found marked improvement in several
headache symptoms and showed that treatment was associ-
ated with improved patient functioning, vitality and overall
quality of life, as well as reduced psychological distress.
How onabotulinumtoxinA reduces the frequency and in-
tensity of migraine headaches remains to be determined [8].
The clinical impact of onabotulinumtoxinA on migraine is
observed within the first day of injection and is much faster
than the 5 or more days needed to observe clinical effects
of onabotulinumtoxinA at the neuromuscular junction [30].
After the injection of onabotulinumtoxinA into the extracel-
lular space, the heavy chain of this neurotoxin binds to re-
ceptors on the nerve terminals of C-fibers. It is then endocy-
tosed and enters the nerve terminals inside enclosed vesicles.
The light chain of the neurotoxin then dissociates from the
heavy chain and enters the cell cytoplasm where it cleaves a
critical protein (the synaptosomal-associated protein) neces-
sary for fusion of neuropeptide-bearing vesicles with nerve
terminal membranes, thus preventing neuropeptide release.
Upon activation by stimuli, the sensory nerve endings of C-
fibers in the meninges release neuropeptides. The role of on-
abotulinumtoxinA in blocking the release of these neuropep-
tides from peripheral C-fiber nerve endings is most likely the
key mechanism that underlies its therapeutic action against
chronic migraine [13].
Recent clinical studies have consistently shown onabo-
tulinumtoxinA to be effective in preventing chronic migraine
by reducing the frequency of headaches and their duration
or intensity, and hence their functional and severity im-
pact, including when administered in a targeted fashion [31–
34]. Many studies have confirmed the higher tolerability
and cost-effectiveness of onabotulinumtoxinA treatment for
chronic migraine [24,31,34,35]. Furthermore, the RE-
POSE study on onabotulinumtoxinA treatment for chronic
migraine found lower use of healthcare resources and related
costs using the PREEMPT injection paradigm [36]. Targeted
therapy may result in even better, more cost effective, and
longer-term results [32,34]. Botox was also recently found
to be cost-effective for the treatment of chronic migraine in
Norway and Sweden [37]. OnabotulinumtoxinA was also
found to improve migraine-related disability by reducing the
intensity and frequency of headache pain in patients with
chronic migraine [38]. In another recent multicenter study
of chronic migraine, early treatment with onabotulinumtox-
inA was more likely to be associated with a sustained clinical
response [39]. In the COMPEL study, treatment with on-
abotulinumtoxinA also led to improvements in disability and
quality of life measures in daily headache, but a longer pe-
riod of treatment was needed [40]. OnabotulinutoxinA was
also shown to be effective and safe in patients with allody-
nia [41]. Additional benefits of treatment with this agent
may include an improved response to acute treatment and
reduced drug intake [42–44]. Well-controlled clinical trials
have shown that patients with overuse of headache medi-
cation can be treated successfully with onabotulinumtoxinA
and topiramate [45]. Comparative studies have shown that
onabotulinumtoxinA is an effective and safe alternative for
the treatment of chronic migraine in patients who discon-
tinue topiramate treatment and can be started during the ta-
pering of topiramate [46,47]. It should be noted however
that combining classic migraine therapy with onabotulinum-
toxinA injection should be avoided in order to allow a better
understanding of the efficacy of each treatment in the indi-
vidual patient.
It is well known that psychiatric comorbidities including
depression and anxiety are more common in patients with
chronic migraine [48]. A study of patients suffering chronic
daily headaches with comorbid anxiety and depression found
that onabotulinumtoxinA treatment may be an effective and
safe intervention in such cases [16]. OnabotulinumtoxinA
was well tolerated in chronic migraine patients with comor-
bid depression and reduced the frequency, impact and as-
sociated disability of headaches, leading to significant im-
provement in the symptoms of anxiety and depression [49].
Furthermore, a study on chronic migraine patients with im-
pulse use disorders and medication overuse found that on-
abotulinumtoxinA injections improved anxiety symptoma-
tology and impulse control disorders [50].
BT in doses used for upper-face cosmetic purposes may
also be helpful for the treatment of certain subtypes of mi-
graine. In a study that evaluated the effect of Botox injec-
tions for cosmetic purposes on migraine subtypes, more im-
provement in headache frequency was observed in patients
with imploding and ocular migraine in comparison to pa-
tients with exploding migraine [51]. This suggests that Botox
doses used for cosmetic applications may be sufficient for the
prevention of some types of migraine attacks.
A small study in adolescents on onabotulinumtoxinA
treatment for chronic daily headaches found that all patients
experienced a decrease in headache frequency and in pain in-
tensity immediately following injection. Some cases quickly
returned to regular school attendance, thus highlighting the
ability of this treatment in allowing patients to resume their
regular daily activities [15]. A study conducted in a large pe-
diatric headache center reported on a possible reversal of the
underlying pathology when onabotulinumtoxinA was given
as an adjunct to other preventive therapies, even when the
Volume 21, Number 1, 2022 3
disease was at its peak [52]. OnabotulinumtoxinA injections
were also found to be safe during pregnancy, with no re-
ported adverse effects on pregnancy outcomes [53].
Many patients with chronic migraine have a high intake
of pharmacological agents for relief from headaches as well as
prophylaxis. It has been estimated that more than half of cases
with chronic migraine who consult in headache clinics suffer
from excessive use of analgesics [54]. This overuse of medi-
cation can lead to the development of headaches (medication
overuse headache). A study on the use of onabotulinumtox-
inA in patients with medication overuse headache showed
positive results with different dose regimes [55]. Another re-
cent study on prophylactic treatment with onabotulinumtox-
inA for medication overuse headache showed that 12 weeks
of therapy can significantly reduce the consumption of acute
analgesics and the overall number of days with headache.
The use of analgesics without serious side effects is vitally
important to reduce chronic disability associated with mi-
graine, to increase patient quality of life, and to reduce spend-
ing on health resources [56]. Another study on prophylactic
treatment with onabotulinumtoxinA for medication overuse
headache found that its efficacy and safety lasted for up to 3
years. This raises the possibility of long-term treatment with
onabotulinumtoxinA to prevent chronic migraine [57].
In conclusion, recent clinical trials have repeatedly shown
excellent benefit from onabotulinumtoxinA treatment for
chronic migraine in various age groups. Therefore, the log-
ical next question is to ask whether onabotulinumtoxinA is
also beneficial for the treatment of other types of headaches.
3.2 OnabotulinumtoxinA and episodic migraine
Episodic migraine is defined as 0–14 headache days per
month, in contrast to chronic migraine which is character-
ized by 15 or more headache days per month [58]. A study
of patients with episodic migraine (mostly <8 headache days
per month) treated with onabotulinumtoxinA found that
those with a low baseline frequency were more likely to ex-
perience complete responsiveness [59]. Another study that
investigated onabotulinumtoxinA treatment for episodic mi-
graine (approximately 5 headache days per month and 1.5
days mean duration of headache) found that treated subjects
experienced fewer migraines of any severity [60]. These au-
thors also reported fewer days with migraine needing treat-
ments, less severe attacks and reduced frequency of vomiting,
together with satisfactory safety profile and good tolerability.
A randomized, double-blind trial of onabotulinumtoxinA for
episodic migraine found more improvement in headache fre-
quency in the Botox group compared to the placebo group at
day 180 [61]. Multiple treatments with Botox proved safe and
well tolerated. However, several recent studies and a meta-
analysis of clinical trials for episodic migraine found no asso-
ciation between onabotulinumtoxinA treatment and clinical
outcome [62–67].
3.3 OnabotulinumtoxinA and tension-type headache
Tension-type headache is the most frequent chronic re-
curring head pain. It occurs more frequently in women than
men and has a lifetime prevalence of 30% to 78% in the global
population [68]. Recent research has shown that onabo-
tulinumtoxinA is effective in reducing tension-type headache
intensity and is safe and well-tolerated [69]. A randomized,
double-blind trial of onabotulinumtoxinA injection into spe-
cific myofascial trigger points found improvement in pain
from chronic tension-type headache [70]. Therapy for facial
spasms might contribute to the observed improvement for
tension-type headache by reducing the stress from the muscle
spasms, rather than from the reduced muscle stiffness [71].
Stress factors are also related to muscle exhaustion and to the
release of acetylcholine from presynaptic nerve terminals in
the peripheral pain mechanism. Because onabotulinumtox-
inA needs to be given every 12 weeks, this is more convenient
for most patients compared to taking daily analgesic drugs
[69]. However, treatment results depend on the dose given,
the site of injection, the number of cycles and the interval pe-
riods [68].
3.4 OnabotulinumtoxinA and new daily persistent headache
New daily persistent headache is a subtype of chronic daily
headache that is challenging to treat. The 3rd edition of the
International Classification of Headache Disorders classifies
it as a persistent primary daily headache with a distinct and
memorable onset. The pain becomes continuous and unre-
lenting within 24 hours and is present for >3 months. In
a case of new daily persistent headache reported in a 67-
year-old male, complete response was observed following re-
peated injections with BT type A [72]. A retrospective study
on new daily persistent headache and onabotulinumtoxinA
therapy showed a 50.0% decrease in headache frequency at
6 months, a 63.6% decrease at 12 months, a 50.0% improve-
ment in headache severity at 6 months, and a 77.8% improve-
ment at 12 months [73].
3.5 OnabotulinumtoxinA and cluster headache
Cluster headache, also known as suicidal headache, is a
well-defined primary headache disorder that can present in
both episodic and chronic forms. It is a primary headache
syndrome that often does not respond satisfactorily to drug
therapies. Several studies on the efficacy of onabotulinum-
toxinA for cluster headache have shown significant improve-
ment in headache frequency within a week of treatment and
lasting for up to 6 months [74]. A recent study showed
that onabotulinumtoxinA was highly effective when used
as add-on therapy in patients with refractory chronic clus-
ter headache [75]. A prospective study on treatment of in-
tractable chronic cluster headache with a single injection of
onabotulinumtoxinA to the sphenopalatine ganglion found a
significant reduction in cluster attack frequency at 24 weeks
of follow up [76]. An open label, single-center study of
onabotulinumtoxinA as an add-on therapy for prophylactic
treatment of cluster headache found improvement in some
4 Volume21, Number 1, 2022
but not all patients with chronic cluster headache, but no
benefit in those with episodic cluster headache [77]. Clus-
ter headache may be associated with blepharospasm, which
could also benefit from treatment with BT injections [78].
3.6 OnabotulinumtoxinA and cervicogenic headache
Cervicogenic headache can arise from several factors as-
sociated with the back of the head and neck. Typically, cer-
vicogenic headache starts at the rear of the head, neck and
ear, and subsequently spreads to the zygomatic region. Cer-
vicogenic headache is associated with throbbing pain and is
always triggered by mechanical causes [79]. Several studies
have reported benefits for onabotulinumtoxinA treatment in
headaches related to the neck [23]. In a case report of a pa-
tient with a 5-year history of cervicogenic headache follow-
ing whiplash injury, a dramatic response was observed af-
ter a single BT injection despite being medically refractory
to usual therapies [80]. The patient required repeat injec-
tions to maintain the improvement thereafter. A recent study
reported significant improvement in the range of neck mo-
tion and in pain reduction at 4 weeks [79]. Compared to
pre-treatment levels, BT injection significantly lowered the
frequency and severity of pain at 6- and 12-week follow-
ing treatment. However, a double-blind, placebo-controlled,
clinical trial of onabotulinumtoxinA for the treatment of
chronic whiplash syndrome found that BT was not effec-
tive against chronic neck pain [81]. Nevertheless, another
double-blind, placebo-controlled, clinical trial of BT type
A (Dysport) for whiplash-associated disorder did find some
benefit from this form of treatment [82].
3.7 OnabotulinumtoxinA and post-traumatic headache
Traumatic brain injury and post-traumatic headache as-
sociated with this injury negatively impact the lives of pa-
tients and their families [83]. As originally defined in the
third edition of the International Classification of Headache
Disorders, post-traumatic headache begins within 7 days of
a mild, moderate, or severe traumatic brain injury and con-
tinues for longer than 3 months [83]. In a study of mili-
tary veterans, onabotulinumtoxinA was shown to improve
the frequency and intensity of post-traumatic headache when
compared to placebo [83]. In another study of active-duty
military patients, onabotulinumtoxinA was beneficial for the
treatment of headaches related to concussion [84]. More-
over, a case study of onabotulinumtoxinA for the treatment
of post-traumatic headache showed complete absence of pain,
even after 5 years with this condition [85]. Bruxism is a
rhythmic grinding of teeth that can sometimes occur follow-
ing traumatic brain injury and lead to headache. This con-
dition was also successfully treated with BT type A injection
[86].
3.8 OnabotulinumtoxinA and chronic post-craniotomy headache
Chronic post-craniotomy headache is localized pain over
the surgical site experienced by the majority of patients with
craniotomy. Some patients describe it as a mild to moder-
ate sensation of pressure involving the entire head and being
more severe at the surgical site, and/or a throbbing sensa-
tion that can be accompanied by nausea and vomiting [87].
A study on peri-incisional onabotulinumtoxinA for chronic
post-craniotomy headache following traumatic brain injury
concluded that onabotulinumtoxinA injections may be use-
ful for the treatment of chronic peri-incisional head pain after
remote craniotomy and without any serious adverse effects.
Furthermore, onabotulinumtoxinA appears to have several
important benefits over current oral analgesics for the treat-
ment of chronic post-craniotomy headaches. Based on a re-
cent case series, patients can enjoy an extended period of pain
relief following a single administration and without experi-
encing any side effects such as cognitive problems or som-
nolence [87]. Another case series of late-onset headache in
post-temporal craniotomy patients who developed temporo-
facial pain due to total or partial temporal muscle hypertro-
phy found that onabotulinumtoxinA treatment significantly
reduced pain without any adverse effects [88].
3.9 OnabotulinumtoxinA and low-tension headache
Diagnosis of orthostatic low cerebrospinal fluid (CSF)
pressure headaches due to reduced CSF volume is based on
clinical presentation with at least one abnormal magnetic res-
onance imaging (MRI) finding, cisternography findings, or
an opening pressure less than the normal value of 65 mm
H2O. A case report described significantly improved outcome
following onabotulinumtoxinA injections in a patient suffer-
ing from refractory low-pressure headache. The patient con-
tinued to experience daily headaches but these were of lower
intensity, suggesting that onabotulinumtoxinA may be effec-
tive for low CSF pressure headaches [89].
3.10 OnabotulinumtoxinA and nummular headache
Nummular headache is a primary headache character-
ized by superficial, coin-shaped pain. A recent study of
this disorder found that the number of headache days per
month, including intense headache, decreased following on-
abotulinumtoxinA injection and without any serious adverse
events [90].
4. Conclusions
BT treatment using onabotulinumtoxinA is associated
with clinically significant benefits in terms of reducing
headache frequency, severity, and headache-related impacts,
thus improving the quality of life for many patients who suf-
fer from various types of headache disorders [91]. Patients
who take daily oral medication for headache relief will benefit
from the less frequent treatment with onabotulinumtoxinA,
which also shows better efficacy and safety compared to the
currently used pharmacological drugs.
Author contributions
JHT and AGE designed the research study. JHT searched
the literature and wrote the manuscript draft. AGE searched
the literature and edited the manuscript. Both authors read
and approved the final manuscript.
Volume 21, Number 1, 2022 5
Ethics approval and consent to participate
This report was approved by Cairo University research
ethics committee and followed the tenets of the Declaration
of Helsinki.
Acknowledgment
The authors would like to thank The Illustrated Book of
Medicine, LLC for their assistance in creating the figures.
Funding
This research received no external funding.
Conflict of interest
The authors declare no conflict of interest.
References
[1] Ashkenazi A, Blumenfeld A. OnabotulinumtoxinA for the Treat-
ment of Headache. Headache. 2013; 53: 54–61.
[2] Silberstein SD. The Use of Botulinum Toxin in the Management
of Headache Disorders. Seminars in Neurology. 2016; 36: 92–98.
[3] Dhaked RK, Singh MK, Singh P, Gupta P. Botulinum toxin:
bioweapon & magic drug. The Indian Journal of Medical Research.
2010; 132: 489–503.
[4] Nigam PK, Nigam A. Botulinum toxin. Indian Journal of Derma-
tology. 2010; 55: 8–14.
[5] Awan KH. The therapeutic usage of botulinum toxin (Botox) in
non-cosmetic head and neck conditions—an evidence based re-
view. Saudi Pharmaceutical Journal. 2017; 25: 18–24.
[6] Sandrini G, De Icco R, Tassorelli C, Smania N, Tamburin S. Bo-
tulinum neurotoxin type a for the treatment of pain: not just in
migraine and trigeminal neuralgia. The Journal of Headache and
Pain. 2017; 18: 38.
[7] Ahmed F. Headache disorders: differentiating and managing the
common subtypes. British Journal of Pain. 2012; 6: 124–132.
[8] Saltvig I, Matzen SH. Incidental Treatment of a Subclinical
Chronic Tension-Type Headache by Cosmetic Use of Botulinum
Toxin a: a Case Report. Case Reports in Dermatology. 2017; 9:
249–253.
[9] Headache Classification Committee of the International Headache
Society (IHS). The International Classification of Headache Disor-
ders, 3rd edition (beta version). Cephalalgia.2013; 33: 629–808.
[10] Finkel AG. Botulinum Toxin and the Treatment of Headache: a
Clinical Review. Headache. 2011; 51: 1565–1572.
[11] Bendtsen L, Sacco S, Ashina M, Mitsikostas D, Ahmed F, Pozo-
Rosich P, et al. Guideline on the use of onabotulinumtoxinA
in chronic migraine: a consensus statement from the European
Headache Federation. The Journal of Headache and Pain. 2018;
19: 91.
[12] Goldman ND, Dorton LH, Marcum KK, Gilbert RM, Sandoval LF.
Evaluation of headache relief with cosmetic onabotulinumtoxinA
injections. Journal of Cosmetic Dermatology. 2014; 13: 224–231.
[13] Becker WJ. Botulinum Toxin in the Treatment of Headache. Tox-
ins. 2020; 12: 803.
[14] Escher CM, Paracka L, Dressler D, Kollewe K. Botulinum toxin
in the management of chronic migraine: clinical evidence and ex-
perience. Therapeutic Advances in Neurological Disorders. 2017;
10: 127–135.
[15] Schroeder AS, Huss K, Blaschek A, Koerte IK, Zeycan B, Roser T,
et al. Ten-year follow-up in a case series of integrative botulinum
toxin intervention in adolescents with chronic daily headache and
associated muscle pain. Neuropediatrics. 2012; 43: 339–345.
[16] Zhang H, Zhang H, Wei Y, Lian Y, Chen Y, Zheng Y. Treatment
of chronic daily headache with comorbid anxiety and depression
using botulinum toxin a: a prospective pilot study. International
Journal of Neuroscience. 2017; 127: 285–290.
[17] Hepp Z, Rosen NL, Gillard PG, Varon SF, Mathew N, Dodick
DW. Comparative effectiveness of onabotulinumtoxinA versus
oral migraine prophylactic medications on headache-related re-
source utilization in the management of chronic migraine: Retro-
spective analysis of a us-based insurance claims database. Cepha-
lalgia. 2016; 36: 862–874.
[18] Hollier-Hann G, Curry A, Onishchenko K, Akehurst R, Ahmed
F, Davies B, et al. Updated cost-effectiveness analysis of onabo-
tulinumtoxinA for the prevention of headache in adults with
chronic migraine who have previously received three or more
preventive treatments in the UK. Journal of Medical Economics.
2020; 23: 113–123.
[19] Gandolfi M, Donisi V, Marchioretto F, Battista S, Smania N, Del
Piccolo L. A Prospective Observational Cohort Study on Pharma-
cological Habitus, Headache-Related Disability and Psychological
Profile in Patients with Chronic Migraine Undergoing Onabo-
tulinumtoxinA Prophylactic Treatment. Toxins. 2019; 11: 504.
[20] MacGregor EA, Brandes J, Eikermann A, Giammarco R. Impact
of migraine on patients and their families: the Migraine and
Zolmitriptan Evaluation (MAZE) survey–Phase III. Current Med-
ical Research and Opinion. 2004; 20: 1143–1150.
[21] Filipović B, de Ru JA, Hakim S, van de Langenberg R, Borggreven
PA, Lohuis PJFM. Treatment of Frontal Secondary Headache At-
tributed to Supratrochlear and Supraorbital Nerve Entrapment
with Oral Medication or Botulinum Toxin Type a vs Endoscopic
Decompression Surgery. JAMA Facial Plastic Surgery. 2018; 20:
394–400.
[22] Wu-Fienberg Y, Ansari H, Zardouz S, Narouze S, Blaha T, Swan-
son M, et al. Anatomical Look into OnabotulinumtoxinA Injection
for Chronic Migraine Headache. Regional Anesthesia and Pain
Medicine. 2018; 43: 869–874.
[23] Becker WJ, Chitsantikul P. Cervicogenic headache and onabo-
tulinumtoxinA: where do we stand? Cephalalgia. 2011; 31: 979–
980.
[24] Choi Y, Lee W, Lee H, Lee K, Kim H, Hu K. Effective Botulinum
Toxin Injection Guide for Treatment of Temporal Headache.
Toxins. 2016; 8: 265.
[25] Kim YG, Bae JH, Kim H, Wang SJ, Kim ST. A Proposal for Bo-
tulinum Toxin Type A Injection Into the Temporal Region in
Chronic Migraine Headache. Toxins. 2020; 12: 214.
[26] Janis JE, Hatef DA, Ducic I, Reece EM, Hamawy AH, Becker S, et
al. The Anatomy of the Greater Occipital Nerve: Part II. Compres-
sion Point Topography. Plastic and Reconstructive Surgery. 2010;
126: 1563–1572.
[27] Blumenfeld A, Silberstein SD, Dodick DW, Aurora SK, Turkel
CC, Binder WJ. Method of injection of onabotulinumtoxinA for
chronic migraine: a safe, well-tolerated, and effective treatment
paradigm based on the PREEMPT clinical program. Headache.
2010; 50: 1406–1418.
[28] Aurora S, Dodick D, Turkel C, DeGryse R, Silberstein S, Lipton
R, et al. OnabotulinumtoxinA for treatment of chronic migraine:
Results from the double-blind, randomized, placebo-controlled
phase of the PREEMPT 1 trial. Cephalalgia. 2010; 30: 793–803.
[29] Diener HC, Dodick DW, Aurora SK, Turkel CC, DeGryse RE,
Lipton RB, et al. OnabotulinumtoxinA for treatment of chronic
migraine: results from the double-blind, randomized, placebo-
controlled phase of the PREEMPT 2 trial. Cephalalgia. 2010; 30:
804–814.
[30] Gerwin R. Treatment of chronic migraine headache with onabo-
tulinumtoxinA. Current Pain and Headache Reports. 2011; 15:
336–338.
[31] Russo M, Manzoni GC, Taga A, Genovese A, Veronesi L,
Pasquarella C, et al. The use of onabotulinum toxin a (Botox®) in
the treatment of chronic migraine at the Parma Headache Centre:
a prospective observational study. Neurological Sciences. 2016; 37:
1127–1131.
[32] Janis JE, Barker JC, Palettas M. Targeted Peripheral Nerve-
directed Onabotulinumtoxin A Injection for Effective Long-
6 Volume21, Number 1, 2022
term Therapy for Migraine Headache. Plastic and Reconstructive
Surgery. Global Open. 2017; 5: e1270.
[33] Janis JE, Dhanik A, Howard JH. Validation of the peripheral trig-
ger point theory of migraine headaches: single-surgeon experi-
ence using botulinum toxin and surgical decompression. Plastic
and Reconstructive Surgery. 2011; 128: 123–131.
[34] Schoenbrunner AR, Khansa I, Janis JE. Cost-Effectiveness of
Long-Term, Targeted OnabotulinumtoxinA versus Peripheral
Trigger Site Deactivation Surgery for the Treatment of Refrac-
tory Migraine Headaches. Plastic & Reconstructive Surgery. 2020;
145: 401e–406e.
[35] Batty AJ, Hansen RN, Bloudek LM, Varon SF, Hayward EJ, Pen-
nington BW, et al. The cost-effectiveness of onabotulinumtoxinA
for the prophylaxis of headache in adults with chronic migraine in
the UK. Journal of Medical Economics. 2013; 16: 877–887.
[36] Kollewe K, Gaul C, Gendolla A, Sommer K. Real-life use of on-
abotulinumtoxinA reduces healthcare resource utilization in indi-
viduals with chronic migraine: the REPOSE study. The Journal of
Headache and Pain. 2021; 22: 50.
[37] Hansson-Hedblom A, Axelsson I, Jacobson L, Tedroff J,
Borgström F. Economic consequences of migraine in Sweden and
implications for the cost-effectiveness of onabotulinumtoxinA
(Botox) for chronic migraine in Sweden and Norway. The Journal
of Headache and Pain. 2020; 21: 99.
[38] Torres-Ferrus M, Gallardo VJ, Alpuente A, Pozo-Rosich P. In-
fluence of headache pain intensity and frequency on migraine-
related disability in chronic migraine patients treated with Onabo-
tulinumtoxinA. The Journal of Headache and Pain. 2020; 21: 88.
[39] Ornello R, Guerzoni S, Baraldi C, Evangelista L, Frattale I, Marini
C, et al. Sustained response to onabotulinumtoxin a in patients
with chronic migraine: real-life data. The Journal of Headache and
Pain. 2020; 21: 40.
[40] Young WB, Ivan Lopez J, Rothrock JF, Orejudos A, Man-
ack Adams A, Lipton RB, et al. Effects of onabotulinumtoxinA
treatment in chronic migraine patients with and without daily
headache at baseline: results from the COMPEL Study. The Jour-
nal of Headache and Pain. 2019; 20: 12.
[41] Young WB, Ivan Lopez J, Rothrock JF, Orejudos A, Manack
Adams A, Lipton RB, et al. Effects of onabotulinumtoxinA treat-
ment in patients with and without allodynia: results of the COM-
PEL study. The Journal of Headache and Pain. 2019; 20: 10.
[42] Silberstein SD, Diener H, Dodick DW, Manack Adams A, De-
Gryse RE, Lipton RB. The Impact of OnabotulinumtoxinA vs.
Placebo on Efficacy Outcomes in Headache Day Responder and
Nonresponder Patients with Chronic Migraine. Pain and Ther-
apy. 2020; 9: 695–707.
[43] Diener H, Dodick DW, Lipton RB, Manack Adams A, DeGryse
RE, Silberstein SD. Benefits beyond Headache Days with Onabo-
tulinumtoxinA Treatment: a Pooled PREEMPT Analysis. Pain
and Therapy. 2020; 9: 683–694.
[44] Schulman E, McGeeney BE. Current concepts in refractory mi-
graine. Current Treatment Options in Neurology. 2013; 15: 40–
55.
[45] Silberstein SD, Blumenfeld AM, Cady RK, Turner IM, Lipton RB,
Diener H, et al. OnabotulinumtoxinA for treatment of chronic mi-
graine: PREEMPT 24-week pooled subgroup analysis of patients
who had acute headache medication overuse at baseline. Journal
of the Neurological Sciences. 2013; 331: 48–56.
[46] Blumenfeld AM, Patel AT, Turner IM, Mullin KB, Manack Adams
A, Rothrock JF. Patient-Reported Outcomes from a 1-Year, Real-
World, Head-to-Head Comparison of OnabotulinumtoxinA and
Topiramate for Headache Prevention in Adults with Chronic Mi-
graine. Journal of Primary Care & Community Health. 2020; 11:
2150132720959936.
[47] Rothrock JF, Adams AM, Lipton RB, Silberstein SD, Jo E, Zhao
X, et al. FORWARD Study: Evaluating the Comparative Effec-
tiveness of OnabotulinumtoxinA and Topiramate for Headache
Prevention in Adults with Chronic Migraine. Headache. 2019; 59:
1700–1713.
[48] Blumenfeld AM, Aurora SK, Laranjo K, Papapetropoulos S. Un-
met clinical needs in chronic migraine: Rationale for study and
design of COMPEL, an open-label, multicenter study of the long-
term efficacy, safety, and tolerability of onabotulinumtoxinA for
headache prophylaxis in adults with chronic migraine. BMC Neu-
rology. 2015; 15: 100.
[49] Boudreau GP, Grosberg BM, McAllister PJ, Lipton RB, Buse DC.
Prophylactic onabotulinumtoxinA in patients with chronic mi-
graine and comorbid depression: an open-label, multicenter, pi-
lot study of efficacy, safety and effect on headache-related dis-
ability, depression, and anxiety. International Journal of General
Medicine. 2015; 8: 79–86.
[50] d’Onofrio F, de Falco A, Costanzo A, Spitaleri D, Casucci G, Raimo
S. Impulse control disorders in chronic migraine with medica-
tion overuse after onabotulinumtoxinA: a single-center prospec-
tive cohort study. Journal of Clinical Neuroscience. 2020; 80: 152–
155.
[51] Kim CC, Bogart MM, Wee SA, Burstein R, Arndt KA, Dover JS.
Predicting migraine responsiveness to botulinum toxin type a in-
jections. Archives of Dermatology. 2010; 146: 159–163.
[52] Kabbouche M, O’Brien H, Hershey AD. OnabotulinumtoxinA in
Pediatric Chronic Daily Headache. Current Neurology and Neu-
roscience Reports. 2012; 12: 114–117.
[53] Wong H, Khalil M, Ahmed F. OnabotulinumtoxinA for chronic
migraine during pregnancy: a real world experience on 45 pa-
tients. The Journal of Headache and Pain. 2020; 21: 129.
[54] Negro A, Curto M, Lionetto L, Martelletti P. A two years open-
label prospective study of OnabotulinumtoxinA 195 U in medi-
cation overuse headache: a real-world experience. The Journal of
Headache and Pain. 2015; 17: 1.
[55] Negro A, Curto M, Lionetto L, Crialesi D, Martelletti P. Onabo-
tulinumtoxinA 155 U in medication overuse headache: a two years
prospective study. SpringerPlus. 2015; 4: 826.
[56] Sandrini G, Perrotta A, Tassorelli C, Torelli P, Brighina F, Sances
G, et al. Botulinum toxin type-a in the prophylactic treatment of
medication-overuse headache: a multicenter, double-blind, ran-
domized, placebo-controlled, parallel group study. The Journal of
Headache and Pain. 2011; 12: 427–433.
[57] Guerzoni S, Pellesi L, Baraldi C, Cainazzo MM, Negro A, Martel-
letti P, et al. Long-term Treatment Benefits and Prolonged Efficacy
of OnabotulinumtoxinA in Patients Affected by Chronic Migraine
and Medication Overuse Headache over 3 Years of Therapy. Fron-
tiers in Neurology. 2017; 8: 586.
[58] Matharu M, Halker R, Pozo-Rosich P, DeGryse R, Manack Adams
A, Aurora SK. The impact of onabotulinumtoxinA on severe
headache days: PREEMPT 56-week pooled analysis. The Journal
of Headache and Pain. 2017; 18: 78.
[59] Binder WJ, Brin MF, Blitzer A, Schoenrock LD, Pogoda JM.
Botulinum toxin type a (BOTOX) for treatment of migraine
headaches: an open-label study. Otolaryngology—Head and Neck
Surgery. 2000; 123: 669–676.
[60] Silberstein S, Mathew N, Saper J, Jenkins S. Botulinum Toxin
Type a as a Migraine Preventive Treatment. Headache. 2000; 40:
445–450.
[61] Aurora SK, Gawel M, Brandes JL, Pokta S, Vandenburgh AM.
Botulinum toxin type a prophylactic treatment of episodic mi-
graine: a randomized, double-blind, placebo-controlled ex-
ploratory study. Headache. 2007; 47: 486–499.
[62] Finkel AG. Botulinum toxin and the treatment of headache: a clin-
ical review. Toxicon. 2015; 107: 114–119.
[63] Shuhendler AJ, Lee S, Siu M, Ondovcik S, Lam K, Alabdullatif
A, et al. Efficacy of Botulinum Toxin Type a for the Prophylaxis
of Episodic Migraine Headaches: a Meta-analysis of Random-
ized, Double-Blind, Placebo-Controlled Trials. Pharmacotherapy.
2009; 29: 784–791.
[64] Luvisetto S, Gazerani P, Cianchetti C, Pavone F. Botulinum Toxin
Type a as a Therapeutic Agent against Headache and Related Dis-
orders. Toxins. 2015; 7: 3818–3844.
[65] Simpson DM, Hallett M, Ashman EJ, Comella CL, Green MW,
Volume 21, Number 1, 2022 7
Gronseth GS, et al. Practice guideline update summary: Botulinum
neurotoxin for the treatment of blepharospasm, cervical dystonia,
adult spasticity, and headache. Neurology. 2016; 86: 1818–1826.
[66] Elkind AH, O’Carroll P, Blumenfeld A, DeGryse R, Dimitrova R.
A series of three sequential, randomized, controlled studies of re-
peated treatments with botulinum toxin type a for migraine pro-
phylaxis. The Journal of Pain. 2006; 7: 688–696.
[67] Relja M, Poole AC, Schoenen J, Pascual J, Lei X, Thompson C. A
multicentre, double-blind, randomized, placebo-controlled, par-
allel group study of multiple treatments of botulinum toxin type
a (BoNTA) for the prophylaxis of episodic migraine headaches.
Cephalalgia. 2007; 27: 492–503.
[68] Wieckiewicz M, Grychowska N, Zietek M, Wieckiewicz G,
Smardz J. Evidence to Use Botulinum Toxin Injections in
Tension-Type Headache Management: a Systematic Review.
Toxins. 2017; 9: 370.
[69] Pihut M, Ferendiuk E, Szewczyk M, Kasprzyk K, Wieckiewicz M.
The efficiency of botulinum toxin type a for the treatment of mas-
seter muscle pain in patients with temporomandibular joint dys-
function and tension-type headache. The Journal of Headache and
Pain. 2016; 17: 29.
[70] Harden RN, Cottrill J, Gagnon CM, Smitherman TA, Wein-
land SR, Tann B, et al. Botulinum Toxin a in the Treatment of
Chronic Tension-Type Headache with Cervical Myofascial Trig-
ger Points: a Randomized, Double-Blind, Placebo-Controlled Pi-
lot Study. Headache. 2009; 49: 732–743.
[71] Mizuma A, Nagata E, Yasuda T, Kouchi M, Nakayama T, Honma
K, et al. Botulinum toxin a is effective to treat tension-type
headache caused by hemifacial spasm. Journal of Clinical Neuro-
science. 2017; 44: 284–288.
[72] Spears RC. Efficacy of botulinum toxin type a in new daily persis-
tent headache. The Journal of Headache and Pain. 2008; 9: 405–
406.
[73] Ali A, Kriegler J, Tepper S, Vij B. New Daily Persistent Headache
and OnabotulinumtoxinA Therapy. Clinical Neuropharmacology.
2019; 42: 1–3.
[74] Freund B, Kotchetkov I, Rao A. The Efficacy of Botulinum Toxin
in Cluster Headache: a Systematic Review. Journal of Oral & Facial
Pain and Headache. 2020; 34: 129–134.
[75] Lampl C, Rudolph M, Bräutigam E. OnabotulinumtoxinA in the
treatment of refractory chronic cluster headache. The Journal of
Headache and Pain. 2018; 19: 45.
[76] Bratbak DF, Nordgård S, Stovner LJ, Linde M, Folvik M, Bugten
V, et al. Pilot study of sphenopalatine injection of onabotulinum-
toxinA for the treatment of intractable chronic cluster headache.
Cephalalgia. 2016; 36: 503–509.
[77] Sostak P, Krause P, Förderreuther S, Reinisch V, Straube A. Bo-
tulinum toxin type-a therapy in cluster headache: an open study.
The Journal of Headache and Pain. 2007; 8: 236–241.
[78] Bagheri A, Mohammadi M, Harooni G, Khosravifard K, Feizi M,
Yazdani S. Cluster Headache Associated with Secondary Unilat-
eral Blepharospasm: a Case Report and Review of the Literature.
Journal of Ophthalmic & Vision Research. 2017; 12: 225–227.
[79] Karadaş O, Oztürk B, Ulaş UH, Kütükçü Y, Odabaşı Z. The Effi-
cacy of Botulinum Toxin in Patients with Cervicogenic Headache:
a Placebo-Controlled Clinical Trial. Balkan Medical Journal. 2012;
29: 184–187.
[80] Hobson DE, Gladish DF. Botulinum toxin injection for cervico-
genic headache. Headache. 1997; 37: 253–255.
[81] Padberg M, de Bruijn SFTM, Tavy DLJ. Neck pain in chronic
whiplash syndrome treated with botulinum toxin. a double-blind,
placebo-controlled clinical trial. Journal of Neurology. 2007; 254:
290–295.
[82] Carroll A, Barnes M, Comiskey C. A prospective randomized con-
trolled study of the role of botulinum toxin in whiplash-associated
disorder. Clinical Rehabilitation. 2008; 22: 513–519.
[83] Zirovich MD, Pangarkar SS, Manh C, Chen L, Vangala S, Elashoff
DA, et al. Botulinum Toxin Type a for the Treatment of Post-
traumatic Headache: a Randomized, Placebo-Controlled, Cross-
over Study. Military Medicine. 2021; 186: 493–499.
[84] Yerry JA, Kuehn D, Finkel AG. Onabotulinum Toxin a for the
Treatment of Headache in Service Members with a History of Mild
Traumatic Brain Injury: a Cohort Study. Headache. 2015; 55: 395–
406.
[85] Lippert-Grüner M. Botulinum toxin in the treatment of post-
traumatic headache - case study. Neurologia i Neurochirurgia Pol-
ska. 2012; 46: 591–594.
[86] Ivanhoe CB, Lai JM, Francisco GE. Bruxism after brain injury:
successful treatment with botulinum toxin-A. Archives of Phys-
ical Medicine and Rehabilitation. 1997; 78: 1272–1273.
[87] MacKenzie HM, Teasell R, Miller TA, Sequeira K. Peri-Incisional
Botulinum Toxin for Chronic Postcraniotomy Headache after
Traumatic Brain Injury: a Case Series. PM and R. 2015; 7: 785–
788.
[88] Ranoux D, Martiné G, Espagne G, Salle H, Caire F. Delayed-onset
post-craniotomy headache responsive to botulinum toxin a: a case
series. Acta Neurochirurgica. 2017; 159: 1375–1378.
[89] Mathew PG, Cutrer FM. Injecting under pressure: the pain of low
CSF pressure headache responsive to botulinum toxin injections.
Current Neurology and Neuroscience Reports. 2014; 14: 477.
[90] García-Azorín D, Trigo-López J, Sierra Á, Blanco-García L,
Martínez-Pías E, Martínez B, et al. Observational, open-label,
non-randomized study on the efficacy of onabotulinumtoxinA in
the treatment of nummular headache: the pre-numabot study.
Cephalalgia. 2019; 39: 1818–1826.
[91] Nahabet E, Janis JE, Guyuron B. Neurotoxins: Expanding Uses of
Neuromodulators in Medicine–Headache. Plastic and Reconstruc-
tive Surgery. 2015; 136: 104S–110S.
8 Volume21, Number 1, 2022
Content uploaded by Ayman Elnahry
Author content
All content in this area was uploaded by Ayman Elnahry on Jan 31, 2022
Content may be subject to copyright.
