Botulinum toxin for the preventive treatment of migraine

Abstract

The present invention relates to the use of botulinum toxin for the preventive treatment of migraine by intramuscular injection following specific dosing and injection schemes involving injection of botulinum toxin into the frontal, temporal, occipital and cervical areas of the head and, optionally, the shoulder area. The schemes are easy to inject and provide a new treatment approach in the preventive treatment of both episodic migraine (EM) and chronic migraine (CM).

Description

BOTULINUM TOXIN FOR THE PREVENTIVE TREATMENT OF MIGRAINEFIELD OF THE INVENTION

[0001] The present invention relates to the use of botulinum toxin for the preventive treatment of migraine by intramuscular injection following specific dosing and injection schemes involving injection of botulinum toxin into the frontal, temporal, occipital and cervical areas of the head and, optionally the shoulder area. The schemes are easy to inject and provide a new treatment approach in the preventive treatment of both episodic migraine (EM) and chronic migraine (CM).BACKGROUND OF THE INVENTION

[0002] Migraine is a primary headache disorder that afflicts about 1 in 10 people worldwide with comparable prevalence in North America (9.7%) and Europe (11.4%) (Woldeamanuel, Y. W and Cowan R. P., Neurol. Sci. 2017, 372:307-315). It can be highly disabling, presenting with recurrent pain attacks with and without aura and is associated with multiple clinical symptoms, typically lasting from 1 to 3 days. While migraine can develop at any age, gender and ethnicity, it most commonly impacts the female population between the ages of 20 to 50 (Victor et al., Cephalalgia 2010, 30(9): 1065-1072). The pathophysiology of migraine is complex and not fully clarified. Cortical spreading depolarization (CSD) and abnormal brain stem activity have been shown to be involved in the pathophysiology of migraine with aura. The pain in migraine most likely originates in the nociceptive sensory fibers transmitting signals from intracranial and extracranial blood vessels and other cranial structures such as dura mater, skin, muscles, and periosteum. Peripheral and central sensitization of trigem inovascular nociceptive pathways may develop during migraine attacks (Ashina et al., Pain Then 2021 , 10(1 ):211 -223).

[0003] Standardized criteria for diagnosis and classification of migraine are provided by the Headache Classification Committee of the International Headache Society (IHS) in the 3rd edition of the International Classification of Headache Disorders (ICHD-3)(see Cephalalgia 2018, 38(1 ): 1 -211 ), defining three main categories of migraine, i.e., migraine without aura, migraine with aura, and chronic migraine (CM). The currently discussed update (ICHD-4 alpha) will consider episodic migraine (EM) as a further main category (Goadsby, P.J. and Evers, S., International Classification of Headache Disorders - ICHD-4 alpha, Cephalalgia 2020, 40(9):887-888). CM patients (with and without aura) are defined as such when suffering from > 15 headache days I month including > 8 migraine days. Contrary to that, patients with EM (with and without aura) experience < 14 headache days.

[0004] Migraine treatments generally include pain-relieving medications (acute or abortive medications), which are taken during migraine attacks to stop symptoms, and preventive medications, which are taken regularly to reduce the frequency and severity of migraine attacks. Typical pain-relieving medications include analgesics such as ibuprofen and paracetamol, triptans such as sumatriptan, and other drugs such as dihydroergotamine, anti-nausea drugs, opioids etc. Commonly used preventive medications include blood pressure-lowering drugs (e.g., beta blockers such as propranolol, and calcium channel blockers such as verapamil), anticonvulsant drugs (e.g., sodium valproate), and antidepressants (e.g., amitriptyline). More recently, the development and FDA approval of calcitonin gene-related peptide (CGRP) smallmolecule antagonists known as gepants (e.g., ubrogepant, atogepant, and rimegepant) and monoclonal antibodies targeting the CGRP receptor (e.g., erenumab) or the CGRP molecule (e.g., eptinezumab) represented important advances in the acute and preventive migraine treatment.

[0005] However, some of the known medications are of limited efficacy, while others are poorly tolerated by some patients. Furthermore, a recent consensus statement of the American Headache Society concludes "because the severity, frequency, and characteristics of migraine vary among persons and, often, with-in individuals over time, and symptom profiles or biomarkers that predict efficacy and side effects at the individual level have not yet been identified, optimizing treatment for particular patients remains challenging. As a result, although the majority of patients with migraine respond to prescribed treatment(s), a process of trial and error is often necessary before a therapeutic plan can be individualized" (Ailani et al., Headache 2021 ,61 (7): 1021 -1039). The need for improvement is also shown by the fact that opioids, although not approved for the treatment of migraines and not recommended in guidelines, are used or kept for treatment of headache by approximately more than one third of US migraineurs; with all the associated negative consequences (Lipton et al., Neurology 2020, 95(5):e457-e468).

[0006] Botulinum toxin (BoNT), a potent neurotoxin produced by the bacterium Clostridium botulinum, inhibits acetylcholine release at neuromuscular junctions. If injected, it produces neuromuscular blockage with muscle relaxation and this has been used successfully in the treatment of numerous diseases such as muscle hyperactivity disorders (e.g., various forms of dystonia, spasticity, infantile cerebral palsy, hemifacial spasm, tics, tremor and motility disorders of the bladder and the gastrointestinal tract). Botulinum toxin has also been used to treat hyperactive exocrine gland tissues involved in hyperhidrosis and sialorrhea and disorders of hyperactive nerves including chronic pain, neuropathic pain and some allergy symptoms, and is frequently used in aesthetic treatments such as the reduction of wrinkles.

[0007] The use of botulinum toxin to treat chronic migraine (CM) is a more recently approved indication. So far, onabotulinumtoxinA (Botox®) is the only botulinum toxin approved by the US FDA and other health authorities for the treatment of migraine, more specifically for the prevention of headaches in patients with chronic migraine (CM). Although the exact mechanisms underlying the antimigraine effect of BoNT have not been fully elucidated, more recent research suggests effects on the trigem inocervical complex by a decreased exocytosis of pro-inflammatory and excitatory neurotransmitters and neuropeptides such as CGRP, substance P, and glutamate from primary afferent fibers that transmit nociceptive pain and participate in the development of peripheral and central sensitization. Also, BoNT has been found to decrease the insertion of pain-sensitive ion channels such as Transient Receptor Potential Cation Channel Subfamily V member 1 (TRPV1 ) into the membranes of nociceptive neurons.

[0008] The safety and efficacy of onabotulinumtoxinA (Botox®) for prophylaxis of headache in adults with chronic migraine (CM) has been demonstrated in the Phase 3REsearch Evaluating Migraine Prophylaxis Therapy (PREEMPT) clinical studies using an injection paradigm that was established based on data from earlier clinical trial experience (PREEMPT 1 clinical study: Aurora et al., Cephalalgia 2010, 30:793-803; and PREEMPT 2: Diener et al., Cephalalgia 2010, 30:804-814). The standardized fixed-site, fixed-dose PREEMPT injection paradigm specifies the usage of a total dose of 155 units of onabotulinumtoxinA administered intramuscularly as 0.1 ml (5 U) injections to 31 injection sites across 7 specific head / neck muscle groups as follows: frontalis (20 U in 4 sites), corrugator (10 U in 2 sites), procerus (5 U in 1 site), temporalis (40 U in 8 sites), occipitalis (30 U in 6 sites), cervical paraspinal (20 U in 4 sites), and trapezius (30 U in 6 sites).

[0009] Injections of up to additional 40 U were allowed in the PREEMPT clinical studies at the investigator’s discretion in up to three muscle groups using a follow-the- pain (FTP) approach, i.e. up to 40 U in the occipitalis, up to 50 U in the temporalis, and up to 50 U in the trapezius, resulting in a maximum dose of 195 units of onabotulinumtoxinA injected across 39 sites. All muscles should be injected bilaterally, with the exception of the procerus, which should be injected at one site only (midline). The 7 specific muscle groups of the PREEMPT paradigm align with the peripheral nerve distribution of the trigeminal, occipital, and cervical sensory nerves.

[0010] In the US, the only FDA approved injection pattern for the treatment of chronic migraine is the standardized 155 units (31 injections) PREEMPT protocol. In the EU, a total dose of up to 195 Units (39 injections) is approved allowing for additional injections into the temporalis, occipitalis and / or trapezius muscles using a follow-the- pain method. The recommended treatment schedule is every 12 weeks, and the recommended treatment cycles are at least two.

[0011] The PREEMPT injection paradigm is subject of WO 2011 / 123456 A1 , which describes a method for prophylactically treating a headache in a patient with chronic migraine headaches, the method essentially consisting of local administration of a botulinum neurotoxin to the frontalis, corrugator, procerus, occipitalis, temporalis, trapezius and cervical paraspinal muscles of the patient that suffers from the migraine headache, wherein the botulinum neurotoxin is administered as follows: to the frontalisat about 20 units divided among 4 sites of injection, to the corrugator at about 10 units divided among 2 sites of injection, to the procerus at about 5 units to 1 site of injection, to the occipitalis at about 30 units divided among 6 sites of injection to about 40 units divided among 8 sites of injection, to the temporalis at about 40 units divided among 8 sites of injection up to 50 units divided among 10 sites of injection, to the trapezius at about 30 units divided among 6 sites of injection up to about 50 units divided among 10 sites of injection and to the cervical paraspinal muscles at about 20 units divided among 4 sites of injection, wherein the botulinum neurotoxin is injected at 31 to 39 injection sites.

[0012] A similar method for prophylactically treating a headache in a patient suffering from chronic migraine headaches is disclosed in WO 2016 / 149092 A1 . The method is based on a combined fixed site / fixed dose scheme and an optional follow-the-pain variable dosage and injection site paradigm for optimizing clinical effectiveness of botulinum toxin administration for the prophylactic treatment of chronic migraine, wherein botulinum toxin is administered to one or more administration targets comprising the frontalis, corrugator, procerus, occipitalis, temporalis, trapezius and cervical paraspinal muscles, wherein the administering step comprises limiting the injection to a defined tissue depth and injection angle.

[0013] According to the published Botox® Injection Workbook for Chronic Migraine (2022), the PREEMPT protocol should not be modified since "departures from the approved paradigm may lead to efficacy results and adverse events different from those seen in the clinical trials". Likewise, Blumenfeld and Silberstein (Headache 2020, 60(10):2597-9) explicitly warn against changing the PREEMPT injection protocol since the injection sites were not determined arbitrarily but were based on the understanding of the underlying mechanisms of action of onabotulinumtoxinA for chronic migraine, in particular the peripheral nerve distribution of the trigeminal, occipital, and cervical sensory nerves in the 7 injected muscles.

[0014] Besides the PREEMPT protocol, various other injection schemes for botulinum toxin for the prevention of chronic migraine have been described in the scientific and patent literature. Amirlak et al. (Plast. Reconstr. Surg. Glob. Open. 2016,4(12):e1194) disclose a flexible injection scheme for the treatment of CM with up to 30 intramuscular injection sites / areas for an average of 155 units, wherein the injection sites are defined by the anatomical nerve course. Jabbari (Jabbari, B., Botulinum Toxin Treatment of Pain Disorders, 1 st ed., Springer, 2022, pp. 87-88) suggests an injection scheme with 19 fixed intramuscular injections for a total of 175 units using 3 different doses per injection site i.e., 5, 10 and 15 units, for the treatment of CM, involving special injection sites. Zandieh and Cutrer (Zandieh, A. and Cutrer F.M., BMC Neurology 2022, 22(1 ):218) describe an injection scheme with 25 fixed intramuscular injections for a total of 150 units or 33 injections for a total of 200 units using 3 different doses per injection site, i.e. 2.5, 5, 6.25, and 8.33 units, for the treatment of CM.

[0015] Furthermore, Freitag et al. (Headache 2008, 48(2):201 -209) suggest a fixed injection scheme with 22 subcutaneous, rather than intramuscular, injections for 100 units for the treatment of CM. Stovner et al. (Cephalalgia 2022, 42(7):590-7) also suggest subcutaneous injections for the treatment of CM, specifically the use of a fixed injection scheme with 18 subcutaneous injections for 90 units alongside the skull sutures. Bratbak et al. (Cephalalgia 2017, 37(4):356-64) report on a fixed injection scheme with bilateral injections of 25 units towards the sphenopalatine ganglion for the treatment of CM. Furthermore, Bono et al. (Toxins 2023, 15(5), 324) suggest a flexible injection scheme (individualized dosing by the "follow-the-pain approach") with 20 to 40 subcutaneous injection sites for 100 to 200 units in the occipital or trigeminal skin area for the treatment of CM.

[0016] WO 2021 / 041978 A1 relates to a method for reducing the severity of a symptom associated with a migraine headache, which comprises administering a Clostridial neurotoxin into at least five of the muscle regions selected from the frontalis, corrugator, procerus, masseter, nasalis, oculi, occipitalis, temporalis, and trapezius muscle regions. Various specific injection schemes are disclosed with minimum 21 to maximum 26 fixed intramuscular injections for 145 to 190 units, excluding the well- established injections to the cervical paraspinal muscular area. Further, injections to the masseter, orbicularis oculi, and nasalis muscle are suggested. Three different doses, i.e., 2.5, 5 and 10 units, are preferably used. A similar method is described in WO 2022 / 183064 A1.

[0017] As is evident from the above, the current prior art for the preventive treatment of migraine with BoNT suggests a fixed-dose, fixed site PREEMPT injection protocol and variations thereof as well as other injection schemes with, for example, (a) additional flexible intramuscular injections to well established muscle areas, (b) additional fixed or flexible injections to new muscle areas (e.g., masseter / nasalis / orbicularis oculi), (c) alternative routes of administration (subcutaneous, near sutures, into sphenopalatine ganglion), and (d) use of three different doses and / or concentrations for intramuscular injections.

[0018] However, the injection schemes known in the art are not fully satisfactory. Some schemes are only partly effective and many patients therefore still suffer from migraine symptoms. Furthermore, some schemes are characterized by low patient comfort and tolerability, while others are complex, require special devices or are timeconsuming and / or burdensome for the physicians. Thus, there is an ongoing need in the art for an optimized preventive treatment of migraine using botulinum toxin that alleviates, mitigates or eliminates one or more of the above disadvantages.OBJECT OF THE INVENTION

[0019] It is an object of the present invention to provide a preventive treatment for migraine using botulinum toxin that is simple, well-tolerated and effective.SUMMARY OF THE INVENTION

[0020] The present invention relates to the use of botulinum toxin for the preventive treatment of migraine. It was found that the use of specific dosing and injection schemes for the administration of botulinum toxin is effective in the preventive treatment of migraine. The schemes can be used in a simple and convenient way both in terms of patient comfort and ease of use by the physician.

[0021] In a first aspect, present invention relates to a botulinum toxin for use in the preventive treatment of migraine, wherein the botulinum toxin is injected at least intothe frontal, temporal, occipital and cervical areas of the head, and optionally in the shoulder area, wherein(i) in the frontal area, the botulinum toxin is injected into (a) 6 injection sites at a total dose of 30 U to 40 U or (b) 7 injection sites at a total dose of 28 U to 42 U, preferably 35 U, wherein in case of (a) the botulinum toxin is injected into 2 injection sites in the corrugator supercilii muscle at a dose of 7.5 U to 10 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 3.75 U to 5 U per injection site, and wherein in case of (b) the botulinum toxin is injected into 1 injection site in the procerus muscle at a dose of 4 U to 6 U, preferably 5 U, into 2 injection sites in the corrugator supercilii muscle at a dose of 4 U to 6 U, preferably 5 U, per injection site, and into 4 injection sites in the frontalis muscle at a dose of 4 U to 6 U, preferably 5 U, per injection site,(ii) in the temporal area, the botulinum toxin is injected into 4, 6 or 8, preferably 6, injection sites in the temporalis muscle at a dose of 5 U to 10 U, preferably 5 U or 7.5 U or 10 U, per injection site, wherein the total dose injected in the temporal area is 20 U to 60 U,(iii) in the occipital area, the botulinum toxin is injected into 4 or 6 injection sites in the occipital muscle at a dose of 5 U to 10 U, preferably 5 U or 7.5 U or 10 U, per injection site, wherein the total dose injected in the occipital area is 20 U to 60 U,(iv) in the cervical area, the botulinum toxin is injected into 2 or 4 injection sites in the cervical paraspinal muscles at a dose of 5 U to 10 U, preferably 5 U or 7.5 U or 10 U, per injection site, wherein the total dose injected in the cervical area is 10 U to 20 U, and wherein the total dose administered to the frontal, temporal, occipital and cervical areas is 78 U to 182 U and the total number of injection sites in the frontal, temporal, occipital and cervical areas is 16 to 25.

[0022] The intramuscular injection scheme used in the first aspect of the present invention is preferably a fixed-site, fixed-dose injection scheme that is generallysymmetrical (except for the single injection into the procerus muscle). This includes that the injection dose per injection site in a treatment area selected from the temporal area, occipital area and cervical area, and where applicable the shoulder area, is fixed, i.e. the same, and the injection dose per injection site in the frontal area is either fixed or selected from two different doses. Most preferably, only two different doses per injection point are injected into the different treatment areas, with a fixed dose within each treatment area.

[0023] Within the present invention, the botulinum toxin may not be injected in any further areas than those mentioned above, i.e. the frontal, temporal, occipital and cervical areas. However, it is also contemplated that the botulinum toxin is additionally injected into the shoulder area, wherein(v) in the shoulder area, the botulinum toxin is injected into 2, 4 or 6, preferably 2 or 4, injection sites in the trapezius muscle at a dose of 5 U to 10 U per injection site, wherein the total dose injected in the shoulder area is 10 U to 30 U.

[0024] The migraine treated is preferably episodic migraine (EM) and / or chronic migraine (CM). Also, the migraine treated in accordance with the present invention preferably involves migraine headaches resulting from migraine associate vertigo, post-traumatic stress disorder, vestibular migraine and / or traumatic brain injury.

[0025] The botulinum toxin is preferably of type A. Further, the botulinum toxin may be in a form that is free of complexing proteins or is in the form of a complex that contains complexing proteins. Preferably, the botulinum toxin is of type A and in a form that is free of complexing proteins or, in an alternative preferred embodiment, is of type A and in the form of a complex that contains complexing proteins.

[0026] In a second aspect, the present invention relates to a method for treating a patient with migraine, for example, a method for the preventive treatment of migraine of a patient or a method of preventing or reducing the occurrence of migraine in a patient or a method of reducing the seventy of one or more symptoms associated with a migraine of a patient, the method comprising administration by injection of botulinumtoxin, for example in the form of a therapeutic composition comprising botulinum toxin as an active agent, into the frontal, temporal, occipital and cervical areas of the head, and optionally in the shoulder area, wherein(i) in the frontal area, the botulinum toxin is injected into (a) 6 injection sites at a total dose of 30 U to 40 U or (b) 7 injection sites at a total dose of 28 U to 42 U, preferably 35 U, wherein in case of (a) the botulinum toxin is injected into 2 injection sites in the corrugator supercilii muscle at a dose of 7.5 U to 10 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 3.75 U to 5 U per injection site, and wherein in case of (b) the botulinum toxin is injected into 1 injection site in the procerus muscle at a dose of 4 U to 6 U, preferably 5 U, into 2 injection sites in the corrugator supercilii muscle at a dose of 4 U to 6 U, preferably 5 U, per injection site, and into 4 injection sites in the frontalis muscle at a dose of 4 U to 6 U, preferably 5 U, per injection site,(ii) in the temporal area, the botulinum toxin is injected into 4, 6 or 8, preferably 6, injection sites in the temporalis muscle at a dose of 5 U to 10 U, preferably 5 U or 7.5 U or 10 U, per injection site, wherein the total dose injected in the temporal area is 20 U to 60 U,(iii) in the occipital area, the botulinum toxin is injected into 4 or 6 injection sites in the occipital muscle at a dose of 5 U to 10 U, preferably 5 U or 7.5 U or 10 U, per injection site, wherein the total dose injected in the occipital area is 20 U to 60 U,(iv) in the cervical area, the botulinum toxin is injected into 2 or 4 injection sites in the cervical paraspinal muscles at a dose of 5 U to 10 U, preferably 5 U or 7.5 U or 10 U, per injection site, wherein the total dose injected in the cervical area is 10 U to 20 U, and wherein the total dose administered to the frontal, temporal, occipital and cervical areas is 78 U to 182 U and the total number of injection sites in the frontal, temporal, occipital and cervical areas is 16 to 25.

[0027] The migraine is preferably episodic migraine (EM) and / or chronic migraine (CM). Further, the migraine treated in accordance with the present invention preferably involves migraine headaches resulting from migraine associate vertigo, post-traumatic stress disorder, vestibular migraine and / or traumatic brain injury.

[0028] The present methods may be carried out using any of the therapeutic compositions, including therapeutic compositions comprising botulinum toxin as an active agent, administration routes and conditions, including injections, injection sites, injection schemes, formulations and dosages, and patient populations or other selection criteria, described herein.

[0029] Preferred embodiments are set forth in the appended dependent claims and in the following detailed description taken in connection with the examples provided herein and the accompanying figures.BRIEF DESCRIPTION OF THE FIGURES

[0030] FIG. 1 shows the location of the injection sites in the frontal, temporal, occipital, cervical and shoulder areas of the injection schemes A and B of the present invention. The injection points indicated target the following muscles: A: procerus; B1 and B2: corrugator supercilii; C1 , C2, C3 and C4: frontalis; D1 , D2 and D3: temporalis; E1 , E2 and E3: occipitalis; F1 and F2: cervical paraspinal muscle; G1 : trapezius. A: Injection scheme A with 195 U BoNT and 25 injection sites. B: Injection scheme B with 155 U BoNT and 21 injection sites.

[0031] FIG. 2 shows the location of the injection sites in the frontal, temporal, occipital, cervical and shoulder areas of further injection schemes according to the present invention (injection schemes C, D, E, and F; the injection pattern of injection schemes C and D are identical). The injection points indicated target the following muscles: A: procerus; B1 and B2: corrugator supercilii; C1 , C2, C3 and C4: frontalis; D1 , D2, D3 and D4: temporalis; E1 , E2 and E3: occipitalis; F1 and F2: cervical paraspinal muscle; G1 and G2: trapezius. C / D: Injection schemes C and D with 22 injection sites and 200 U and 150 U, respectively. E: Injection scheme E with 145 UBoNT and 29 injection sites. F: Injection scheme F with 95 U BoNT and 19 injection sites.DETAILED DESCRIPTION OF THE INVENTION

[0032] The present invention provides specific injection schemes for the treatment of episodic and chronic migraine, more specifically to the preventive treatment of episodic and chronic migraine, which are efficient in reducing migraine symptoms, safe and well-tolerated. These schemes are based on the same well-established muscle areas as those of the PREEMPT injection protocol but use a lower number of injection sites compared to the PREEMPT injection protocol in combination with a higher dose and volume in areas requiring larger BoNT distribution. The approach to increase the dose and volume in areas requiring a larger BoNT distribution, offers the advantage of reaching more sensory nerve branches in the injected area, while still being able to reduce the number of injection sites in some areas.

[0033] The new fixed schemes are easy to inject and require only two different doses per injection site, which can be easily achieved by adjusting the injection volume and / or the concentration of the injected botulinum toxin formulation. Thus, the injection schemes of the present invention provide an easy and convenient "one fits all" dosing approach.

[0034] The reduction in the number of injection sites results in a less painful procedure for the patients and is of special advantage when keeping in mind that the treatment needs to be repeated, for example every 12 weeks for both chronic and episodic migraine. Furthermore, the procedures with less injection sites (e.g., injection schemes A, B, C, and D; see examples) can be carried out more quickly than a 31 injection sites procedure, resulting in time savings for the treating physicians.

[0035] According to the PREEMPT paradigm, needles must be changed frequently to reduce patient discomfort, with using 1 needle per area (i.e., 5 needles overall) or changing the needle every 4 to 6 sites (i.e., 5 to 8 needles overall). For the injection schemes of the present invention, especially for injection schemes having no morethan 25 injection points (e.g., injection schemes A, B, C, D, and F; see examples), 4 needles are considered sufficient for the treatment of most patients. Accordingly, these injection schemes are associated with lower material costs, less wastage, and are more sustainable as compared to a 31 + injection sites procedure.

[0036] In summary, the unique combination of various treatment aspects utilized in the injection schemes of the present invention result in a beneficial BoNT treatment effect with favorable safety and tolerability, both in the treatment of episodic and chronic migraine.

[0037] The term "treatment", as used herein, means to partially or entirely prevent, reduce, alleviate or resolve a symptom, disorder, disease, or condition, such as a migraine, migraine headache and / or migraine condition. Preferably, treatment includes preventive treatment (as opposed to acute treatment), unless otherwise stated. The term "preventive treatment", as used herein, is synonymous with "prophylactic treatment" and can refer to partially or entirely prevent, reduce, alleviate or resolve a symptom, disorder, disease, or condition, such as a migraine, migraine headache and / or migraine condition. A preventive treatment is the application of a treatment measure to prevent a disease, condition, disorder or symptom thereof, such as a migraine. In an embodiment, "a method for treating a patient with migraine headaches" refers to treatment resulting in at least partial prevention or reduction of the occurrence of a migraine headache in a patient, such as a reduction as compared to a prior period of migraine headaches (e.g., 6-12 months) for a patient, for example, a reduction by at least a 30% reduction, at least a 50% reduction or at least a 75% reduction. In an embodiment, "a method for treating a patient with migraine headaches" refers to treatment resulting in at least partial improvement of a patient in the reported degree of impairment or disability caused by migraine, such as a reduction as compared to a prior period of migraine headaches (e.g., 6-12 months) for a patient, for example, a reduction by at least 5 points in the Headache Impact Test (HIT-6) score (American Headache Society, The American headache society position statement on integrating new migraine treatments into clinical practice, Headache 2019; 59: 1 -18). The term "treatment" in accordance with the present invention does not mean acute treatment of an ongoing migraine attack.

[0038] In an embodiment, "a method for treating a patient with migraine headaches" refers to a treatment resulting in a reduction in the severity of a migraine or a symptom or condition associated with a migraine headache, such as a reduction of headache pain, reduction of the duration of a migraine headache, and / or a reduction frequency of a migraine headaches. In some embodiments, a prevention, reduction or alleviation of a migraine or a symptom or condition associated with a migraine headache may occur over a period of time after treating a patient by the present methods, such as a period of 7 days to 14 days after treatment. The diagnosis, occurrence, frequency and severity of symptoms of migraine or a symptom or condition associated with a migraine headache in a patient may be determined using methods known in the art, including a headache diary (see, e.g., Nappi et al., Diaries and calendars for migraine, A review, Cephalalgia 2006, 26(8):905-16).

[0039] The expression "administration by injection" refers to administration of a therapeutic composition, such as a composition comprising botulinum toxin as an active agent, via one or more injections provided to a patient undergoing treatment, for example, via intramuscular injection, intradermal injection, subcutaneous injection or any combination thereof. In some embodiments, administration by injection refers to carrying out an injection scheme comprising a plurality of injections provided at selected doses and selected injection sites of a patient, such as a fixed-site, fixed-dose injection scheme. In some embodiments, administration by injection refers to injection at one or more anatomical features (e.g., shoulder area / region and / or frontal, temporal, occipital and cervical areas of the head) and / or into one or more muscles of the patient (e.g., corrugator supercilii muscle, frontalis muscle, procerus muscle, temporalis muscle, occipital muscle, cervical paraspinal muscles, and trapezius muscle) as presented in Tables 1 to 8 and Figures 1 and 2. Administration by injection may be achieved in the present methods using techniques and administration parameters (e.g., injection depth, injection volume, injection angle, etc.) known in the art.

[0040] The term "migraine", as used herein, has generally the same meaning as commonly understood by a skilled person in the art of migraine treatment. As known in the art, migraine is a primary headache characterized by episodes of moderate-to-severe headaches. As used herein, the term "migraine" preferably refers to a headache disorder as defined by current diagnostic criteria set out in the 3rd edition of the International Classification of Headache Disorders (ICHD-3) (available at the website https: / / ichd-3.org; see also Cephalalgia 2018, 38(1 ): 18-34; each of which are incorporated by reference herein in its entirety for descriptions of diagnosis of migraine). Migraine can be subdivided depending on whether there is an aura or not (migraine without aura and migraine with aura) and classified into an episodic form (episodic migraine or EM) or a chronic form (chronic migraine or CM) based on the frequency of the headaches. Within the present invention the term "migraine" is intended to include episodic migraine and chronic migraine.

[0041] The term "migraine without aura" (also referred to as common migraine; hemicrania simplex), as used herein, generally refers to a recurrent headache disorder manifesting in attacks lasting 4 to 72 hours. Typical characteristics of the headache are unilateral location, pulsating quality, moderate or severe intensity, aggravation by routine, physical activity and association with nausea and / or photophobia and phonophobia. Preferably, the term "migraine without aura", as used herein, is a headache disorder that meets the diagnostic criteria defined for migraine without aura in the 3rd edition of the International Classification of Headache Disorders (ICHD-3) (see Cephalalgia 2018, 38(1 ):18-34).

[0042] The term "migraine with aura", as used herein, generally refers to a headache disorder characterized by recurrent attacks, lasting minutes, of unilateral fully reversible visual, sensory or other central nervous system symptoms that usually develop gradually and are usually followed by headache and associated migraine symptoms. Preferably, the term "migraine with aura", as used herein, is a headache disorder that meets the diagnostic criteria defined for migraine with aura in the 3rd edition of the International Classification of Headache Disorders (ICHD-3) (see Cephalalgia 2018, 38(1 ): 18-34).

[0043] The term "chronic migraine" or "CM", as used herein, refers to very frequent migraine attacks generally defined as headache occurring on 15 or more days / month for more than three months, which, on at least eight days / month, fulfil the criteria formigraine (migraine with or without aura). Preferably, the term "chronic migraine", as used herein, is a headache disorder that meets the diagnostic criteria defined for chronic migraine in the 3rd edition of the International Classification of Headache Disorders (ICHD-3) (see Cephalalgia 2018, 38(1 ): 18-34). The International Classification of Headache Disorders (3rd edition, 2013) (Cephalalgia 2018, 38(1 ): 18- 34; or available at the website https: / / ichd-3.org) is incorporated by reference herein in its entirety for descriptions of diagnosis of chronic migraine.

[0044] The term "episodic migraine" or "EM", as used herein, is defined as a headache occurring on less than 15 days a month (i.e. 1 to 14 days) over the last 3 months, which on some days fulfil the criteria for migraine (migraine with or without aura), as put forward in the currently discussed update of the International Classification of Headache Disorders (ICHD-4 alpha) (Goadsby, P.J. and Evers, S., International Classification of Headache Disorders - ICHD-4 alpha, Cephalalgia 2020, 40(9):887-888). In this definition of episodic migraine, the criteria for migraine that occurs on some days ("migraine days") are the same as those set out in the definition of chronic migraine in the 3rd edition of the International Classification of Headache Disorders (ICHD-3) (see Cephalalgia 2018, 38(1 ): 18-34).

[0045] Using current diagnostic criteria, episodic and chronic migraine are clinically and diagnostically distinct from secondary headaches, such as headaches caused by traumatic brain injury (TBI) or headaches attributable to post-traumatic stress disorder (PTSD). By these current diagnostic criteria, episodic and chronic migraine are also clinically and diagnostically distinct from vestibular migraine. Vestibular migraine has also sometimes been referred to as migrainous vertigo, migraine-related dizziness, migraine with prominent vertigo, or migraine-related vestibulopathy. Herein, the term vestibular migraine is used exclusively for this condition.

[0046] Traumatic brain injury (TBI) can result from a wide variety of impacts to the head / brain or body, particularly the neck, including penetration of the head / brain with a foreign object and whiplash injury and ranges from mild, moderate or severe brain injury. TBI has an array of symptoms including headache. By current diagnostic criteria, headache caused by TBI is described as a newly occurring secondaryheadache or a significant worsening in intensity or frequency of a preexisting primary headache that occurs in close temporal relation to the traumatic event (e.g. within 7 days after the event) and can show features of migraine or other primary headaches such as tension-type headaches or cluster headaches (see, The International Classification of Headache Disorders (3rd Edition, 2013), supra). Headache caused by TBI that persist for more than three months are designated as chronic. The International Classification of Headache Disorders (3rd Edition, 2013) (available at the website https: / / ichd-3.org) is incorporated by reference herein in its entirety for descriptions of diagnosis of headache caused by TBI.

[0047] Post-Traumatic stress disorder (PTSD) is a psychiatric disorder associated with exposure to a traumatic event which is defined by specific diagnostic criteria (see, for example, B. Grinage (2003), "Diagnosis and Management of Post-traumatic Stress Disorder", Am. Fam. Physician 63(12):2401 -2409). Current criteria for diagnosis of PTSD are detailed in Diagnostic and Statistical Manual of Mental Disorders (DSM-5- TR), American Psychiatric Association (2022) and include, among other criteria, direct or indirect exposure to death / serious injury or the threat of death or serious injury (e.g., trauma); persistent re-experience of the trauma; avoiding stimuli related to the trauma, a variety of symptoms that cause distress or impair function and where symptoms last for more than 1 month. Headache may be caused by or attributed to PTSD. By current diagnostic criteria, headache caused by or attributable to PTSD is a headache that requires at least a confirmed diagnosis of PTSD, first develops after exposure to the trauma stressor and occurs exclusively in the context of other symptoms of PTSD, e.g. upon exposure to reminders of the trauma (see, The International Classification of Headache Disorders (3rd Edition, 2013), supra). Such headaches can show features of migraine or other primary headaches (B. Grinage (2003) and Diagnostic and Statistical Manual of Mental Disorders (DSM-5-TR), American Psychiatric Association (2022), are each incorporated by reference herein in its entirety for the descriptions therein of diagnostic criteria for PTSD. The International Classification of Headache Disorders (3rd Edition, 2013) (available at the website https: / / ichd-3.org) is incorporated by reference herein in its entirety for descriptions of headache caused by or attributed to PTSD.

[0048] Vestibular migraine is a type of migraine where people experience episodes of vestibular symptoms of moderate to severe intensity, such as vertigo, dizziness, vestibulo-visual, or postural symptoms as defined by the Barany Society’s Classification of Vestibular Symptoms (Bisdorff A. and von Brevern M., Lempert T. and Newman-Toker D.E. (on behalf of the Committee for the Classification of Vestibular Disorders of the Barany Society), "Classification of vestibular symptoms: Towards an international classification of vestibular disorders", J. Vest. Res. (2009), 19:1 -13.) Vestibular symptoms, e.g., various forms of dizziness, are described as lasting from minutes to days in combination with migraine features. Vestibular symptoms are described as also occurring without headaches. If headaches are experienced, they are often one-sided, pulsating and aggravated by physical activity, and of moderate to serve intensity. Vestibular migraine and probable vestibular migraine are herein defined by the diagnostic criteria as detailed in The International Classification of Headache Disorders (3rd Edition, 2013) (available at the website https: / / ichd-3.org). (see also T. Lempert et al. (2022), "Vestibular migraine: Diagnostic criteria (Update)", J. Vestib. Res. 32(1 ): 1 -6).

[0049] By these current diagnostic criteria, vestibular migraine is characterized by (A) at least 5 episodes with moderate or severe intensity vestibular symptoms lasting 5 min to 72 hours; (B) a current or previous history of migraine with or without aura; (C) one or more migraine features with at least 50% of the episodes; and (D) not better accounted for by another vestibular or headache diagnosis. Migraine features are described in these criteria as (1 ) headache with at least two of the following characteristics: one sided location, pulsating quality, moderate or severe pain intensity, or aggravation by routine physical activity; (2) photophobia or phonophobia; and (3) visual aura. Probable vestibular migraine is similarly characterized by these diagnostic criteria but requires only one of B or C above. Vestibular migraine or the possible synonymous or similar conditions of migrainous vertigo, migraine-related dizziness, migraine with prominent vertigo, migraine-related vestibulopathy or migraine- associated vertigo may be or may have been variously defined by others in the art or in the prior art. The conditions designated vestibular migraine and probable vestibular migraine as used herein are defined by the diagnostic criteria outlined above. Episodes of dizziness may be a symptom associated with episodic or chronic migraine. Suchsymptoms accompanying migraine do not alone support a diagnosis of vestibular migraine. The diagnostic criteria outlined above are required for such diagnosis. The International Classification of Headache Disorders (3rd Edition, 2013) (available at the website https: / / ichd-3.org) is incorporated by reference herein in its entirety for diagnostic criteria for vestibular migraine.

[0050] The use of botulinum toxin and method of use, respectively, according to the present invention is generally focused on treating chronic and episodic migraine, however it can also be used for the treatment of other headaches, including those caused by traumatic brain injury (TBI) or attributed to post-traumatic stress disorder (PTSD).

[0051] The use of the botulinum toxin and method of use, respectively, according to the present invention is generally focused on treating chronic and episodic migraine, however it can also be used for the treatment of vestibular migraine and probable vestibular migraine. The method of the present invention can also be used to treat migraine where the patient exhibits vestibular symptoms that do not fit the current diagnostic criteria of vestibular migraine. In a particular embodiment the use of the botulinum toxin and the method of use, respectively, according to the present invention encompasses the treatment of perimenstrual migraine, where perimenstrual migraine comprises "menstrually-related migraine" with migraine symptoms occurring before and during the menstruation period (e.g., 2 days before and 3 days after start of menstruation), and additionally at other times of the cycle, as well as "pure menstrual migraine" with migraine symptoms occurring before and during the menstruation period (e.g., 2 days before and 3 days after start of menstruation) and at no other times of the cycle in menstruating women.

[0052] The term "cervical", as used herein, refers to the cervical region or area, more specifically the posterior cervical region or area, in particular the upper posterior cervical region or area. As used herein, the term "cervical" is synonymous with "cervical paraspinal". The cervical area includes various muscles, which are referred to herein as cervical paraspinal muscles. Within the present invention, botulinum toxin is generally injected into the upper cervical paraspinal muscles.

[0053] The term "shoulder", as used herein, refers to the trapezius, and "trapezius" or "trapezius muscle" is synonymous with "shoulder". Further, the term "shoulder area" or "shoulder region" means the area or region of the trapezius.

[0054] The term "patient", as used herein, is not particularly limited and generally refers to a human, who is in the need of migraine treatment. Preferably, a "patient" in the context of the present invention is a human suffering from chronic migraine (CM) and / or episodic migraine (EM), as defined hereinabove.

[0055] The term "comprising", like the terms "including" and containing", and any variations thereof such as "comprises", "includes" and "contains", are intended to refer to a non-exclusive inclusion, such that a process, method, product-by-process, composition or formulation that comprises, includes, or contains an element or list of elements does not include only those elements but can include other elements not expressly listed for such process, method, product-by-process, composition or formulation. In addition, within the framework of the present invention, it is intended that each of the terms "comprises," "comprising", "includes", "including", "contains", "containing", and any variations thereof, can be replaced by the term "consists" or "consisting", or any variation thereof, which will be understood to refer to an exclusive inclusion of the elements indicated. Furthermore, the terms "a" and "an" and "the" and similar reference used in the context of the present invention are to be construed to cover both the singular and the plural and, thus, may also relate to "at least one" or "more than one", unless otherwise indicated herein or clearly contradicted by the context.

[0056] In the context of the present invention, numerical values without decimal places shall be understood to include all numerical values with one or more decimal places that, applying common rules of rounding, give the numerical value without decimal places. For example, the numerical value 5 includes 4.5 or 4.50 (which are rounded up to 5) and 5.4 or 5.49 (which are rounded off to 5), and all numerical values in between. Likewise, numerical values with one decimal place shall be understood to include all numerical values with two or more decimal places that, applying commonrules of rounding, give the numerical value with one decimal place (e.g., 3.95 and 4.04 are rounded up / off to 4.0). Also, numerical values with two decimal places shall be understood to include all numerical values with three or more decimal places that, applying common rules of rounding, give the numerical value with two decimal places (e.g., 3.745 and 3.754 are rounded up / off to 3.75). As regards endpoints of ranges, the same applies.

[0057] In a first aspect, the present invention relates to a botulinum toxin for use in the preventive treatment of migraine, wherein the botulinum toxin is injected at least into the frontal, temporal, occipital and cervical areas of the head, wherein(i) in the frontal area, the botulinum toxin is injected into (a) 6 injection sites at a total dose of 30 U to 40 U or (b) 7 injection sites at a total dose of 28 U to 42 U, preferably 35 U, wherein in case of (a) the botulinum toxin is injected into 2 injection sites in the corrugator supercilii muscle at a dose of 7.5 U to 10 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 3.75 U to 5 U per injection site, and wherein in case of (b) the botulinum toxin is injected into 1 injection site in the procerus muscle at a dose of 4 U to 6 U, preferably 5 U, into 2 injection sites in the corrugator supercilii muscle at a dose of 4 U to 6 U, preferably 5 U, per injection site, and into 4 injection sites in the frontalis muscle at a dose of 4 U to 6 U, preferably 5 U, per injection site,(ii) in the temporal area, the botulinum toxin is injected into 4, 6 or 8, preferably 6, injection sites in the temporalis muscle at a dose of 5 U to 10 U, preferably 5 U or 7.5 U or 10 U, per injection site, wherein the total dose injected in the temporal area is 20 U to 60 U,(iii) in the occipital area, the botulinum toxin is injected into 4 or 6 injection sites in the occipital muscle at a dose of 5 U to 10 U, preferably 5 U or 7.5 U or 10 U, per injection site, wherein the total dose injected in the occipital area is 20 U to 60 U,(iv) in the cervical area, the botulinum toxin is injected into 2 or 4 injection sites in the cervical paraspinal muscles at a dose of 5 U to 10 U, preferably 5 Uor 7.5 U or 10 U, per injection site, wherein the total dose injected in the cervical area is 10 U to 20 U, and wherein the total dose administered to the frontal, temporal, occipital and cervical areas is 78 U to 182 U and the total number of injection sites in the frontal, temporal, occipital and cervical areas is 16 to 25.

[0058] Preferably, for an injection scheme of the present invention, the injection dose per injection site in a treatment area selected from the temporal area, occipital area and cervical area, and where applicable the shoulder area, is fixed, i.e. the same, and the injection dose per injection site in the frontal area is either fixed or selected from two different doses. Most preferably, only two different doses per injection point are injected into the different treatment areas, with a fixed dose within each treatment area.

[0059] The injection sites preferably cover well-established muscle areas with the associated trigeminal, occipital and cervical sensory nerve endings. Regarding the location of the injection sites, the location is preferably as follows:(i) in the frontal area, the procerus muscle is injected in the single injection site designated "A" in FIG. 2E, the corrugator supercilii muscle is injected in "B1" and "B2" shown in FIG. 2E, and the frontalis muscle is injected in "C1 ", "C2", "C3" and "C4" shown in FIG. 2E,(ii) in the temporal area, the temporalis muscle is injected in "D1" and "D2" shown in FIG. 2E (in case of 2 injections on each side, i.e. 4 injections in total), in "D1", "D2" and "D3" shown in FIG. 2E (in case of 3 injections on each side, i.e. 6 injections in total), and in "D1", "D2", "D3" and "D4" shown in FIG. 2E (in case of 4 injections on each side, i.e. 8 injections in total),(iii) in the occipital area, the occipital muscle is injected in "E1" and "E2" shown in FIG. 2E (in case of 2 injections on each of left and right side, i.e. 4 injections in total), and in "E1", "E2" and "E3" shown in FIG. 2E (in case of 3 injections on each of left and right side, i.e. 6 injections in total)(iv) in the cervical area, the cervical paraspinal muscles are injected in "F1" shown in FIG. 2E (in case of 1 injection on each of left and right side, i.e. 2 injections in total), and in "F1" and "F2" shown in FIG. 2E (in case of 2injections on each of left and right side, i.e. 4 injections in total).

[0060] In one embodiment (referred to as "A'-D1embodiment"), the botulinum toxin for use in the preventive treatment of migraine according to the first aspect of the present invention, is injected as follows:(i) in the frontal area, the botulinum toxin is injected into (a) 6 injection sites at a total dose of 30 U to 40 U or (b) 7 injection sites at a total dose of 28 U to 42 U, preferably 35 U, wherein in case of (a) the botulinum toxin is injected into 2 injection sites in the corrugator supercilii muscle at a dose of 7.5 U to 10 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 3.75 U to 5 U per injection site, and wherein in case of (b) the botulinum toxin is injected into 1 injection site in the procerus muscle at a dose of 4 U to 6 U, preferably 5 U, into 2 injection sites in the corrugator supercilii muscle at a dose of 4 U to 6 U, preferably 5 U, per injection site, and into 4 injection sites in the frontalis muscle at a dose of 4 U to 6 U, preferably 5 U, per injection site,(ii) in the temporal area, the botulinum toxin is injected into 6 or 8, preferably 6, injection sites in the temporalis muscle at a dose of 7.5 U to 10 U, preferably 10 U, per injection site, wherein the total dose injected in the temporal area is 45 U to 60 U,(iii) in the occipital area, the botulinum toxin is injected into 4 or 6 injection sites in the occipital muscle at a dose of 7.5 U to 10 U, preferably 10 U, per injection site, wherein the total dose injected in the occipital area is 40 U to 60 U,(iv) in the cervical area, the botulinum toxin is injected into 2 or 4 injection sites in the cervical paraspinal muscles at a dose of 5 U to 10 U, preferably 5 U or 7.5 U or 10 U, per injection site, wherein the total dose injected in the cervical area is 15 U to 20 U, and wherein the total dose administered to the frontal, temporal, occipital and cervical areas is 128 U to 182 U and the total number of injection sites in the frontal, temporal, occipital and cervical areas is 18 to 25.

[0061] In a preferred embodiment (referred to as "A-D"), the botulinum toxin for use in the preventive treatment of migraine according to the first aspect of the present invention, is injected as follows:(i) in the frontal area, the botulinum toxin is injected into (a) 6 injection sites at a total dose of 30 U to 40 U or (b) 7 injection sites at a total dose of 35 U, wherein in case of (a) the botulinum toxin is injected into 2 injection sites in the corrugator supercilii muscle at a dose of 7.5 U to 10 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 3.75 U to 5 U per injection site, and wherein in case of (b) the botulinum toxin is injected into 1 injection site in the procerus muscle at a dose of 5 U, into 2 injection sites in the corrugator supercilii muscle at a dose of 5 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 5 U per injection site,(ii) in the temporal area, the botulinum toxin is injected into 6 injection sites in the temporalis muscle at a dose of 7.5 U to 10 U, preferably 10 U, per injection site, wherein the total dose injected in the temporal area is 45 U to 60 U,(iii) in the occipital area, the botulinum toxin is injected into 4 or 6 injection sites in the occipital muscle at a dose of 7.5 U to 10 U, preferably 10 U, per injection site, wherein the total dose injected in the occipital area is 40 U to 60 U,(iv) in the cervical area, the botulinum toxin is injected into 2 or 4 injection sites in the cervical paraspinal muscles at a dose of 5 U to 10 U, preferably 5 U or 7.5 U or 10 U, per injection site, wherein the total dose injected in the cervical area is 15 U to 20 U, and wherein the total dose administered to the frontal, temporal, occipital and cervical areas is 130 U to 180 U and the total number of injection sites in the frontal, temporal, occipital and cervical areas is 18 to 23.

[0062] In a further preferred embodiment (referred to as "A-B"), the botulinum toxin for use in the preventive treatment of migraine according to the first aspect of the present invention, is injected as follows:(i) in the frontal area, the botulinum toxin is injected into 7 injection sites at a total dose of 35 U, wherein the botulinum toxin is injected into 1 injection site in the procerus muscle at a dose of 5 U, into 2 injection sites in the corrugator supercilii muscle at a dose of 5 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 5 U per injection site,(ii) in the temporal area, the botulinum toxin is injected into 6 injection sites in the temporalis muscle at a dose of 10 U per injection site, wherein the total dose injected in the temporal area is 60 U,(iii) in the occipital area, the botulinum toxin is injected into 4 or 6 injection sites in the occipital muscle at a dose of 10 U per injection site, wherein the total dose injected in the occipital area is 40 U to 60 U,(iv) in the cervical area, the botulinum toxin is injected into 4 injection sites in the cervical paraspinal muscles at a dose of 5 U per injection site, wherein the total dose injected in the cervical area is 20 U, and wherein the total dose administered to the frontal, temporal, occipital and cervical areas is 155 U to 175 U and the total number of injection sites in the frontal, temporal, occipital and cervical areas is 21 to 23.

[0063] In another further preferred embodiment (referred to as "C-D"), the botulinum toxin for use in the preventive treatment of migraine according to the first aspect of the present invention, is injected as follows:(i) in the frontal area, the botulinum toxin is injected into 6 injection sites at a total dose of 30 U to 40 U, wherein the botulinum toxin is injected into 2 injection sites in the corrugator supercilii muscle at a dose of 7.5 U to 10 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 3.75 U to 5 U per injection site,(ii) in the temporal area, the botulinum toxin is injected into 6 injection sites in the temporalis muscle at a dose of 7.5 U to 10 U per injection site, whereinthe total dose injected in the temporal area is 45 U to 60 U,(iii) in the occipital area, the botulinum toxin is injected into 6 injection sites in the occipital muscle at a dose of 7.5 U to 10 U per injection site, wherein the total dose injected in the occipital area is 45 U to 60 U,(iv) in the cervical area, the botulinum toxin is injected into 2 injection sites in the cervical paraspinal muscles at a dose of 7.5 U to 10 U per injection site, wherein the total dose injected in the cervical area is 15 U to 20 U, and wherein the total dose administered to the frontal, temporal, occipital and cervical areas is 135 U to 180 U and the total number of injection sites in the frontal, temporal, occipital and cervical areas is 20.

[0064] In another embodiment (referred to as "E-F"), the botulinum toxin for use in the preventive treatment of migraine according to the first aspect of the present invention, is injected as follows:(i) in the frontal area, the botulinum toxin is injected into 7 injection sites at a total dose of 35 U, wherein the botulinum toxin is injected into 1 injection site in the procerus muscle at a dose of 5 U, into 2 injection sites in the corrugator supercilii muscle at a dose of 5 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 5 U per injection site,(ii) in the temporal area, the botulinum toxin is injected into 4, 6 or 8 injection sites in the temporalis muscle at a dose of 5 U per injection site, wherein the total dose injected in the temporal area is 20 U to 40 U,(iii) in the occipital area, the botulinum toxin is injected into 4 or 6 injection sites in the occipital muscle at a dose of 5 U per injection site, wherein the total dose injected in the occipital area is 20 U to 30 U,(iv) in the cervical area, the botulinum toxin is injected into 2 or 4 injection sites in the cervical paraspinal muscles at a dose of 5 U per injection site, wherein the total dose injected in the cervical area is 10 U to 20 U, and wherein the total dose administered to the frontal, temporal, occipital and cervical areas is 85 U to 125 U and the total number of injection sites in the frontal, temporal, occipital and cervical areas is 17 to 25.

[0065] In accordance with the present invention, the botulinum toxin for use according to the first aspect, including the embodiments thereof described herein, may or may not be additionally injected in the shoulder areas, more specifically into the trapezius muscle on both sides of the neck. In other words, it is contemplated herein that the botulinum toxin is not injected into any other area than into the frontal, temporal occipital and cervical areas, in particular, is not injected into any other injection points as those in the frontal, temporal occipital and cervical areas as described herein. On the other hand, it is also contemplated herein that the botulinum toxin is additionally injected into the shoulder area, wherein(v) in the shoulder area, the botulinum toxin is injected into 2, 4 or 6, preferably 2 or 4, injection sites in the trapezius muscle at a dose of 5 U to 10 U per injection site, wherein the total dose injected in the shoulder area is 10 U to 30 U.

[0066] Preferably, the botulinum toxin is injected into 2 injection sites in the trapezius muscle at a dose of 5 U to 10 U, preferably 7.5 U or 10 U, per injection site, wherein the total dose injected in the shoulder area is 10 U to 20 U. Within the present invention, the botulinum toxin may also suitably be injected into 4 injection sites in the trapezius muscle at a dose of 5 U to 10 U, preferably 5 U or 7.5 U, per injection site, wherein the total dose injected in the shoulder area is 20 U to 30 U.

[0067] In a particularly preferred embodiment (referred to as "A"), the botulinum toxin for use in the preventive treatment of migraine according to the first aspect of the present invention, is injected into 25 injection sites in the frontal, temporal, occipital, cervical and shoulder areas at a total dose of 195 U, wherein(i) in the frontal area, the botulinum toxin is injected into 7 injection sites at a total dose of 35 U, wherein the botulinum toxin is injected into 1 injection site in the procerus muscle at a dose of 5 U, into 2 injection sites in the corrugator supercilii muscle at a dose of 5 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 5 U per injection site,(ii) in the temporal area, the botulinum toxin is injected into 6 injection sites inthe temporalis muscle at a dose of 10 U per injection site, resulting in a total dose injected in the temporal area of 60 U,(iii) in the occipital area, the botulinum toxin is injected into 6 injection sites in the occipital muscle at a dose of 10 U per injection site, resulting in a total dose injected in the occipital area of 60 U,(iv) in the cervical area, the botulinum toxin is injected into 4 injection sites in the cervical paraspinal muscles at a dose of 5 U per injection site, resulting in a total dose injected in the cervical area of 20 U, and(v) in the shoulder area, the botulinum toxin is injected into 2 injection sites in the trapezius muscle at a dose of 10 U per injection site, resulting in a total dose injected in the shoulder area of 20 U, and, preferably, wherein the location of the injection sites is as shown in Figure 1A.

[0068] In another particularly preferred embodiment (referred to as "B"), the botulinum toxin for use in the preventive treatment of migraine according to the first aspect of the present invention is injected into 21 injection sites in the frontal, temporal, occipital, and cervical and areas, and not in the shoulder areas, at a total dose of 155 U, wherein(i) in the frontal area, the botulinum toxin is injected into 7 injection sites at a total dose of 35 U, wherein the botulinum toxin is injected into 1 injection site in the procerus muscle at a dose of 5 U, into 2 injection sites in the corrugator supercilii muscle at a dose of 5 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 5 U per injection site,(ii) in the temporal area, the botulinum toxin is injected into 6 injection sites in the temporalis muscle at a dose of 10 U per injection site, resulting in a total dose injected in the temporal area of 60 U,(iii) in the occipital area, the botulinum toxin is injected into 4 injection sites in the occipital muscle at a dose of 10 U per injection site, resulting in a total dose injected in the occipital area of 40 U,(iv) in the cervical area, the botulinum toxin is injected into 4 injection sites in the cervical paraspinal muscles at a dose of 5 U per injection site, resultingin a total dose injected in the cervical area of 20 U, and, preferably, wherein the location of the injection sites is as shown in Figure 1 B.

[0069] In a further particularly preferred embodiment (referred to as "C"), the botulinum toxin for use in the preventive treatment of migraine according to the first aspect of the present invention is injected into 22 injection sites in the frontal, temporal, occipital, cervical and shoulder areas at a total dose of 200 U, wherein(i) in the frontal area, the botulinum toxin is injected into 6 injection sites at a total dose of 40 U, wherein the botulinum toxin is injected into 2 injection sites in the corrugator supercilii muscle at a dose of 10 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 5 U per injection site,(ii) in the temporal area, the botulinum toxin is injected into 6 injection sites in the temporalis muscle at a dose of 10 U per injection site, resulting in a total dose injected in the temporal area of 60 U,(iii) in the occipital area, the botulinum toxin is injected into 6 injection sites in the occipital muscle at a dose of 10 U per injection site, resulting in a total dose injected in the occipital area of 60 U,(iv) in the cervical area, the botulinum toxin is injected into 2 injection sites in the cervical paraspinal muscles at a dose of 10 U per injection site, resulting in a total dose injected in the cervical area of 20 U, and(v) in the shoulder area, the botulinum toxin is injected into 2 injection sites in the trapezius muscle at a dose of 10 U per injection site, resulting in a total dose injected in the shoulder area of 20 U, and, preferably, wherein the location of the injection sites is as shown in Figure 1 C.

[0070] In a still further particularly preferred embodiment (referred to as "D"), the botulinum toxin for use in the preventive treatment of migraine according to the first aspect of the present invention is injected into 22 injection sites in the frontal, temporal, occipital, cervical and shoulder areas at a total dose of 150 U, wherein(i) in the frontal area, the botulinum toxin is injected into 6 injection sites at atotal dose of 30 U, wherein the botulinum toxin is injected into 2 injection sites in the corrugator supercilii muscle at a dose of 7.5 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 3.75 U per injection site,(ii) in the temporal area, the botulinum toxin is injected into 6 injection sites in the temporalis muscle at a dose of 7.5 U per injection site, resulting in a total dose injected in the temporal area of 45 U,(iii) in the occipital area, the botulinum toxin is injected into 6 injection sites in the occipital muscle at a dose of 7.5 U per injection site, resulting in a total dose injected in the occipital area of 45 U,(iv) in the cervical area, the botulinum toxin is injected into 2 injection sites in the cervical paraspinal muscles at a dose of 7.5 U per injection site, resulting in a total dose injected in the cervical area of 15 U, and(v) in the shoulder area, the botulinum toxin is injected into 2 injection sites in the trapezius muscle at a dose of 7.5 U per injection site, resulting in a total dose injected in the shoulder area of 15 U, and, preferably, wherein the location of the injection sites is as shown in Figure 1 D.

[0071] In yet another particularly preferred embodiment (referred to as "E"), the botulinum toxin for use in the preventive treatment of migraine according to the first aspect of the present invention is injected into 29 injection sites in the frontal, temporal, occipital, cervical and shoulder areas at a total dose of 145 U, wherein(i) in the frontal area, the botulinum toxin is injected into 7 injection sites at a total dose of 35 U, wherein the botulinum toxin is injected into 1 injection site in the procerus muscle at a dose of 5 U, into 2 injection sites in the corrugator supercilii muscle at a dose of 5 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 5 U per injection site,(ii) in the temporal area, the botulinum toxin is injected into 8 injection sites in the temporalis muscle at a dose of 5 U per injection site, resulting in a total dose injected in the temporal area of 40 U,(iii) in the occipital area, the botulinum toxin is injected into 6 injection sites inthe occipital muscle at a dose of 5 U per injection site, resulting in a total dose injected in the occipital area of 30 U,(iv) in the cervical area, the botulinum toxin is injected into 4 injection sites in the cervical paraspinal muscles at a dose of 5 U per injection site, resulting in a total dose injected in the cervical area of 20 U, and(v) in the shoulder area, the botulinum toxin is injected into 4 injection sites in the trapezius muscle at a dose of 5 U per injection site, resulting in a total dose injected in the shoulder area of 20 U, and, preferably, wherein the location of the injection sites is as shown in Figure 1 E.

[0072] In still another particularly preferred embodiment (referred to as "F"), the botulinum toxin for use in the preventive treatment of migraine according to the first aspect of the present invention is injected into 19 injection sites in the frontal, temporal, occipital, cervical and shoulder areas at a total dose of 95 U, wherein(i) in the frontal area, the botulinum toxin is injected into 7 injection sites at a total dose of 35 U, wherein the botulinum toxin is injected into 1 injection site in the procerus muscle at a dose of 5 U, into 2 injection sites in the corrugator supercilii muscle at a dose of 5 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 5 U per injection site,(ii) in the temporal area, the botulinum toxin is injected into 4 injection sites in the temporalis muscle at a dose of 5 U per injection site, resulting in a total dose injected in the temporal area of 20 U,(iii) in the occipital area, the botulinum toxin is injected into 4 injection sites in the occipital muscle at a dose of 5 U per injection site, resulting in a total dose injected in the occipital area of 20 U,(iv) in the cervical area, the botulinum toxin is injected into 2 injection sites in the cervical paraspinal muscles at a dose of 5 U per injection site, resulting in a total dose injected in the cervical area of 10 U, and(v) in the shoulder area, the botulinum toxin is injected into 2 injection sites in the trapezius muscle at a dose of 5 U per injection site, resulting in a total dose injected in the shoulder area of 10 U, and, preferably,wherein the location of the injection sites is as shown in Figure 1 F.

[0073] In accordance with the present invention, the botulinum toxin is injected with a volume per injection point of between 0.05 mL and 0.2 ml, in particular with a volume per injection point of between 0.10 ml and 0.20 ml. A suitable botulinum concentration for injection is in the range of from 25 ll / rnl to 100 ll / rnl and is preferably 50 ll / rnl.

[0074] The botulinum toxin used within the present invention is not particularly limited and includes botulinum toxin of any serotype (BoNT / A-H) in a form that is free of complexing proteins or in the form of a complex that contains complexing proteins. Preferably, the botulinum toxin is of serotype A or B (BoNT / A, BoNT / B), with serotype A (BoNTA) being particularly preferred. More preferably, the botulinum toxin is of serotype A, still more preferably of serotype A1 (BoNT / A1 ), and most preferably BoNT / A1 produced by Clostridium botulinum Hall strain. Preferably, the botulinum toxin is of type A and in a form that is free of complexing proteins or is in the form of a complex that contains complexing proteins and, more preferably, is botulinum toxin of type A in a form that is free of complexing proteins.

[0075] As used herein, the term "botulinum toxin" ("BT") is synonymously used with the term "botulinum neurotoxin" ("BoNT"). These terms are intended to refer to a toxin form that is free of complexing proteins, i.e. , the (active) neurotoxic polypeptide that ultimately inhibits acetylcholine release (also referred to herein as the "pure botulinum neurotoxin", "neurotoxic component", "150 kDa neurotoxin" or "Clostridium botulinum neurotoxin (150 kD)") and a toxin form that is a complex containing complexing proteins (i.e., a complex of the neurotoxic component and complexing proteins). The botulinum toxin complex is a high-molecular complex of the neurotoxic component and a set of complexing proteins (NAPs), including the 900 kDa, 500 kDa, and 300 kDa C. botulinum type A toxin complexes. The complexing proteins are nontoxic nonhaemagglutinin (NTNHA) and, in strains of serotype A-D, different haemagglutinins (HAs). For example, the 900 kDa complex is included in onabotulinumtoxin A (Botox®A / istabel®, Allergan, Inc., Irvine, CA, USA), and also abobotulinumtoxin A (Dysport®, Azzalure®, Ipsen, Paris, France), Alluzience® (Ipsen / Galderma) and Innotox® (Medytox) contain a toxin complex as active agent. Preferably, the botulinumtoxin is the pure botulinum neurotoxin that is contained in Xeomin® or is Xeomin®, or is the toxin complex contained in Botox® or Dysport® or is Botox® or Dysport®.

[0076] Within the present invention, the botulinum toxin may be a natural neurotoxin obtainable from the bacteria Clostridium botulinum or any other botulinum toxin such as a botulinum toxin obtainable from alternative sources, including recombinant technologies and genetic or chemical modification. Chimeric or genetically modified botulinum toxins, i.e., botulinum toxins containing mutations including substitutions, deletions and insertions, are also encompassed by the terms "botulinum toxin", "neurotoxic component" and the like. Preferably, the mutation does not compromise any of the biological activities of botulinum toxin. However, it is also envisaged to use mutations to modulate the biological activity of the botulinum toxin. Also included are botulinum toxins containing chemically modified amino acids, for example one or more amino acids which are glycosylated, acetylated or otherwise modified, which may be beneficial to the uptake or stability of the toxin. Particularly preferred is the lipidation of the neurotoxic component.

[0077] In the context of the present invention, the dose is expressed in biological units because the used botulinum toxin may contain, for example, variable percentages of inactive toxin that contribute to the overall protein load without contributing to efficacy. Within the context of the present invention, the biological potency of botulinum toxin is determined using the mouse bioassay (MBA). The MBA determines the mean lethal dose (LD50) of toxin / neurotoxin after intraperitoneal injection in mice, i.e., the dose of toxin / neurotoxin capable of killing 50% of a group of mice. On this basis, 1 unit (U) of toxin / neurotoxin, as used herein, is defined as one mouse LD50 (1.0 LD50 = 1.0 U). The LD50 mouse bioassay is the gold standard among various biological, chemical or immunological detection and activity determination methods for botulinum toxin and is known to those skilled in the art (see, e.g., Pearce, L.B.; Borodic, G.E.; First, E.R.; MacCallum, R.D. Measurement of botulinum toxin activity: Evaluation of the lethality assay. Toxicol. Appl. Pharmacol. 1994, 128, 69-77).

[0078] Another useful method for determining the biological activity (biological potency) of a botulinum neurotoxin is a cell-based potency assay as it is disclosed, for example, in W02009 / 114748, WO 2013 / 049508 or WO 2014 / 207109. The activity results obtained with such cell-based assays correspond to the activity values obtained in the mouse i.p. LD50 assay because the values are calibrated using the LD50 reference standard.

[0079] Due to differences in the LD50 tests used by manufacturers of commercial botulinum toxin formulations, the unit potencies indicated by the manufacturers for their commercial botulinum toxin formulations is proprietary and cannot easily be compared. Therefore, within the framework of the present invention, the conversion rates provided below are used to establish the comparative potencies of incobotulinumtoxinA ("INCO"; Xeomin®, Bocouture®; botulinum toxin serotype A, free of complexing proteins; Merz Pharmaceuticals GmbH), onabotulinumtoxinA ("ONA"; Botox®, Vistabel®; botulinum toxin complex of serotype A; Allergan Inc.), abobotulinumtoxinA ("ABO"; Dysport®, Azzalure®; botulinum toxin complex of serotype A; Medicis Pharmaceutical Corp., Galderma Lab.), rimabotulinumtoxinB ("RIM"; Myobloc®, NeuroBloc®; botulinum toxin serotype B; Solstice Neurosciences Inc.), and PurTox® ("TBD"; botulinum toxin serotype A; Mentor Worldwide LLC). For use herein, the conversion rate of ONA and INCO is 1 :1. The conversion rate of ONA / INCO:ABO is 1 :2.5. The conversion rate of ONA / INCO:RIM is 1 :50, and the conversion rate of ONA / INCO:TBD is 1 :1.5. Furthermore, within the context of the present invention, 1 U of INCO (Xeomin®) and 1 U of onabotulinumtoxinA ("ONA"; Botox®) shall be deemed to correspond to one mouse LD50 (1 .0 LD50), or 1 U, measured as described above.

[0080] Generally, the botulinum toxin used within the present invention, such as a therapeutic composition comprising botulinum toxin as an active agent, is in the form of a liquid composition. The liquid composition can be formulated by various techniques dependent on the desired application, as known in the art. It may be provided as a ready-to-use liquid formulation or in the form of a lyophilized powder that is to be reconstituted, typically in physiological saline, prior to use. Preferably, the botulinum toxin used within the present invention, such as a therapeutic composition comprising botulinum toxin as an active agent, is in the form of an aqueous solution,more preferably a saline solution or a physiological saline solution, and most preferably a phosphate buffered physiological saline solution. The aqueous solution may additionally comprise one or more pharmaceutically acceptable substances. Suitable pharmaceutically acceptable substances comprise those well known in the art, see, e.g., Remington’s Pharmaceutical Sciences, Mack Publishing Company, Easton, Pennsylvania.

[0081] In particular, the aqueous botulinum toxin solution or composition may include other carriers or non-toxic, non-therapeutic, non-immunogenic stabilizers and the like. Thus, the aqueous botulinum toxin composition may contain glycerol, protein stabilizers (HSA) or non-protein stabilizers such as polyvinyl pyrrolidone (PVP), hyaluronic acid or free amino acids, e.g., methionine or histidine. Suitable non- proteinaceous stabilizers are disclosed in WO 2005 / 007185 or WO 2006 / 020208. Also, it may be free of amino acids and / or free of stabilizing peptides (e.g., consisting of 5 to 50 amino acids, 10 to 40 amino acids or 15 to 30 amino acids). The botulinum toxin composition can also include non-ionic or ionic surfactant, e.g., polysorbate or poloxamer. A suitable formulation for HSA-stabilized formulation comprising a botulinum toxin according to the present invention is, for example, disclosed in US 8,398,998 B2.

[0082] Preferably, the botulinum toxin used within the present invention is in the form of an aqueous solution comprising sodium chloride (NaCI), preferably in the form of a physiological saline solution (i.e. a solution including sodium chloride in physiological concentration, e.g., about 9 g / l NaCI), which further comprises one or more of the following (i) to (ix): (i) no other excipient (except NaCI), (ii) human serum albumin (HSA) and a sugar, in particular a monosaccharide or a disaccharide, (iii) human serum albumin (HSA) and lactose, (iv) human serum albumin (HSA) and sucrose, (v) a monosaccharide and / or a disaccharide (e.g. lactose and / or sucrose), (vi) no buffer, (vii) no single amino acids, (viii) no human serum albumin (HSA), sodium chloride and lactose or no HSA, sodium chloride and sucrose, or (ix) no HSA and sodium chloride, or any combination of (i) to (ix).

[0083] Particularly preferred, the botulinum toxin is in the form of an aqueous formulation comprising botulinum toxin, sodium chloride and human serum albumin, or an aqueous formulation comprising botulinum toxin, sodium chloride, human serum albumin and lactose, or an aqueous formulation comprising botulinum toxin, sodium chloride, human serum albumin and sucrose. Another particularly preferred aqueous formulation comprises botulinum toxin, sodium chloride, human serum albumin and histidine. Such formulations are for example disclosed in WO2023 / 156389 and WO2023 / 156385. The botulinum toxin can be as defined herein above, in particular, the botulinum toxin is in a form that is free of complexing proteins or is in the form of a complex that contains complexing proteins, and preferably is botulinum toxin type A in a form that is free of complexing proteins or botulinum toxin type A in the form of a complex that contains complexing proteins.

[0084] In a second aspect, the present invention relates to a method for the preventive treatment of migraine, the method comprising injection of botulinum toxin, for example in the form of a therapeutic composition comprising botulinum toxin as an active agent, into the frontal, temporal, occipital and cervical areas of the head, wherein(i) in the frontal area, the botulinum toxin is injected into (a) 6 injection sites at a total dose of 30 U to 40 U or (b) 7 injection sites at a total dose of 28 U to 42 U, preferably 35 U, wherein in case of (a) the botulinum toxin is injected into 2 injection sites in the corrugator supercilii muscle at a dose of 7.5 U to 10 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 3.75 U to 5 U per injection site, and wherein in case of (b) the botulinum toxin is injected into 1 injection site in the procerus muscle at a dose of 4 U to 6 U, preferably 5 U, into 2 injection sites in the corrugator supercilii muscle at a dose of 4 U to 6 U, preferably 5 U, per injection site, and into 4 injection sites in the frontalis muscle at a dose of 4 U to 6 U, preferably 5 U, per injection site,(ii) in the temporal area, the botulinum toxin is injected into 4, 6 or 8, preferably 6, injection sites in the temporalis muscle at a dose of 5 U to 10 U, preferably 5 U or 7.5 U or 10 U, per injection site, wherein the total dose injected in thetemporal area is 20 U to 60 U,(iii) in the occipital area, the botulinum toxin is injected into 4 or 6 injection sites in the occipital muscle at a dose of 5 U to 10 U, preferably 5 U or 7.5 U or 10 U, per injection site, wherein the total dose injected in the occipital area is 20 U to 60 U,(iv) in the cervical area, the botulinum toxin is injected into 2 or 4 injection sites in the cervical paraspinal muscles at a dose of 5 U to 10 U, preferably 5 U or 7.5 U or 10 U, per injection site, wherein the total dose injected in the cervical area is 10 U to 20 U, and wherein the total dose administered to the frontal, temporal, occipital and cervical areas is 78 U to 182 U and the total number of injection sites in the frontal, temporal, occipital and cervical areas is 16 to 25.

[0085] The method according to the second aspect of the present invention may be a method of preventing or reducing the occurrence of migraine in a patient or a method of reducing the seventy of one or more symptoms associated with a migraine of a patient. Preferably, the method is a method for the preventive treatment of migraine of a patient.

[0086] The method according to the second aspect of the present invention is closely related to the use according to the first aspect of the present invention. Thus, all definitions, explanations, advantages, description of preferred embodiments and features etc. given herein with respect to the use according to the first aspect of the present invention equally apply to the method according to the second aspect of the present invention.EXAMPLES

[0087] The present invention is further illustrated by exemplary injection schemes suitable for treating migraine headaches. The botulinum toxin (BoNT) used in the examples is Xeomin®. However, other botulinum toxins, in particular botulinum toxin of type A (in free or complexed form) may also be used.EXAMPLE 1Injection schemes A and B of the present invention

[0088] According to a first injection scheme (referred to as injection scheme A), a total of 195 units (U) of botulinum toxin are injected in 25 injection sites distributed across four areas of the head (frontal, temporal, occipital, and cervical areas) and the shoulder area. As a variation thereof, it is also possible to omit injections into the shoulder area, i.e. into the trapezius muscle. In a second injection scheme (referred to as injection scheme B), a total of 155 units (U) of botulinum toxin are injected in 21 injection sites distributed across four areas of the head (frontal, temporal, occipital, cervical). As a variation thereof, it is also possible to use additional injections into the shoulder area, as defined in connection with the first aspect of the present invention. The total units (U), number of injection sites, and units and volume per injection site are shown in Table 1.Table 1. Injection schemes A and B

[0089] As can be seen from Table 1 , a volume of 0.1 ml per 5 U and a volume of 0.2 ml per 10 U is used in injection schemes A and B. This means that a botulinum toxin formulation with a concentration of 50 ll / rnl is used in these exemplary schemes.However, while 50 ll / ml is the preferred concentrations, other concentrations may also be used.

[0090] The exact location of the individual injection points in the frontal, temporal, occipital, and cervical treatment areas is shown in FIG. 1 (see upper panel "A" for injection scheme A and lower panel "B" for injection scheme B). As can be seen from FIG. 1 , muscles to be treated in the frontal area are the following: procerus (injection site A), corrugator supercilii (injection sites B1 and B2), and frontalis (injection sites C1 to C4). Details about how the injections in the frontal area are preferably carried out are provided in Table 2. Sensory nerves aimed to be reached by BoNT in the frontal area are nervus supratrochlearis and nervus supraorbitalis.Table 2. Frontal area

[0091] In the temporal area, injection sites D1 to D3 are used to treat the temporal muscle (see FIG. 1 ). Details about how the injections in the temporal area are preferably carried out are provided in Table 3. Sensory nerves aimed to be reached by BoNT in the temporal area are nervus zygomaticotemporalis and nervus auriculotemporalis.Table 3. Temporal area

[0092] In the occipital area, the occipital muscle is to be treated (injection sites E1 to E3 in FIG. 1A; injection sites E1 and E2 in FIG. 1 B). Details about how the injectionsin the occipital area are preferably carried out are provided in Table 4. Sensory nerves aimed to be reached by BoNT in the occipital area are greater and lesser occipital nerve.Table 4. Occipital area

[0093] In the cervical area, the cervical paraspinal muscles are to be treated (injection sites F1 and F2 in FIG. 1 ). Details about how the injections in the cervical area are preferably carried out are provided in Table 5. Sensory nerves aimed to be reached by BoNT in the cervical area are greater occipital nerve and third occipital nerve.Table 5. Cervical area

[0094] In the shoulder area, the trapezius muscle is to be treated in injection scheme A (injection sites G1 in FIG. 1A). This area is not treated in injection scheme B. Details about how the injections in the shoulder area are preferably carried out are provided in Table 6. Sensory nerves aimed to be reached by BoNT in the shoulder area are plexus-like connections between the branches of the cervical plexus (CII-CV) and sensory fibers of the accessory nerve.Table 6. Shoulder area

[0095] The above-described exemplary injection schemes according to the present invention can be utilized for the treatment of migraine (both episodic and chronic migraine) as determined in two parallel-group treatment, multicenter, double-blind,randomized, three-arm clinical trials investigating the efficacy and safety of intramuscular BoNT type A injections compared with placebo injections in decreasing the number of monthly migraine days in participants aged 18 years and older with either chronic or episodic migraine. The trials are identical in design except for the study population, which requires a diagnosis of episodic or chronic migraine to participate in the respective trial. Once eligibility has been confirmed by a 30-day baseline period, participants are randomly assigned to one of the three treatment groups and attend a treatment session where the study doctor injects either BoNT type A Scheme A, B, or placebo.

[0096] Injections are repeated after 12 weeks, and the efficacy is assessed by comparing the number of monthly migraine days during the baseline period with the mean number of monthly migraine days during month 3 after the second injection session (weeks 21 -24 after randomization). All participants have the opportunity to receive two further injection treatments at week 24 and 36 to generate long-term safety data. Participants who have previously received BoNT scheme A or B continue in their arm, while participants who have previously received placebo are injected according to BoNT scheme A.

[0097] Perimenstrual Migraine: perimenstrual migraine days are assessed for 5 days, 2 days before and 3 days after start of menstruation, for each menstruation period as reported from premenopausal participants. This is determined by month 1 to 6 and normalized to 5 days for each month. Baseline is derived similarly from the screening period. The changes from baseline are analyzed by month with a baseline adjusted ANCOVA model. Perimenstrual acute migraine medication days are derived and analyzed analogously. For the menstruation periods during EP, these perimenstrual migraine days and perimenstrual acute migraine medication days are derived analogously. Standard descriptive analyses are provided.EXAMPLE 2Injection schemes C and D of the present invention

[0098] According to two alternative injection schemes of the present invention (referred to as injection schemes C and D), the aforesaid areas (frontalis, temporal, occipital, cervical, and shoulder) are injected with a fixed number of 22 intramuscular injections and a total dose of 200 U (injection scheme C) and 150 U (injection scheme D), respectively, with only two different doses per injection site (i.e. , 5 U in frontalis and 10 U in all other muscles for injection scheme C; 3.75 U in frontalis and 7.5 U in all other muscles for injection scheme D). The location of the individual injection sites in each of these areas is shown in FIG. 2 (see top panel "C / D"; the injection pattern for injection schemes C and D are identical), and the total units (U) and number of injection sites per muscle area as well as the units and volume per injection site is shown in Table 7.Table 7. Injection schemes C and D*5 U (0.05 ml of 100 ll / rnl) into 4 injection sites in the frontalis and 10 U (0.01 ml of 100 ll / rnl) into two injection sites in the glabellar area (Corrugator supercilii)**3.75 U (0.05 ml of 75 ll / rnl) into each of 4 injection sites in the frontalis and 7.5 U (0.01 ml of 75 ll / rnl) into each of two injection sites in the glabellar area (Corrugator supercilii)EXAMPLE 3Injection schemes E and F of the present invention

[0099] In two further alternative injection schemes of the present invention (referred to as injection schemes E and F), the aforesaid areas (frontalis, temporal, occipital, cervical, and shoulder) are injected with a fixed number of 29 and 19 injection sites, each injected with 5 units (0.1 ml), resulting in a total of 145 U (injection scheme E) and 95 U (injection scheme F) (see Table 8). The position of the individual injection points in each area is shown in FIG. 2E (panel "E" of FIG. 2 corresponding to injection scheme E) and FIG. 2F (panel "F" of FIG. 2 corresponding injection scheme F), respectively.Table 8. Injection schemes E and FSTATEMENTS REGARDING INCORPORATION BY REFERENCE AND VARIATIONS

[0100] All references throughout this application, for example patent documents including issued or granted patents or equivalents; patent application publications; and non-patent literature documents or other source material; are hereby incorporated by reference herein in their entireties, as though individually incorporated by reference, to the extent each reference is at least partially not inconsistent with the disclosure in this application (for example, a reference that is partially inconsistent is incorporated by reference except for the partially inconsistent portion of the reference).

[0101] The terms and expressions which have been employed herein are used as terms of description and not of limitation, and there is no intention in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments, exemplary embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention. The specific embodiments provided herein are examples of useful embodiments of the present invention and it will be apparent to one skilled in the art that the present invention may be carried out using a large number of variations of the product, product components, methods steps set forth in the present description. As will be obvious to those skilled in the art, products and methods useful for the present invention can include a large number of optional composition and processing elements and steps.

[0102] As used herein, the singular forms "a", "an", and "the" include plural reference unless the context clearly dictates otherwise. Also, the terms "a" (or "an"), "one or more" and "at least one" can be used interchangeably herein.

[0103] Whenever a range is given in the specification, for example, a dosage range, a time range, or a composition or concentration range, all intermediate ranges and subranges, as well as all individual values included in the ranges given are intended to be included in the disclosure. It will be understood that any subranges or individual values in a range or subrange that are included in the description herein can be excluded from the embodiments herein.

[0104] All patents and publications mentioned in the specification are indicative of the levels of skill of those skilled in the art to which the invention pertains. References cited herein are incorporated by reference herein in their entirety to indicate the state of the art as of their publication or filing date and it is intended that this information canbe employed herein, if needed, to exclude specific embodiments that are in the prior art.

[0105] As used herein, "comprising" is synonymous with "including,", "containing," or "characterized by," and is inclusive or open-ended and does not exclude additional, unrecited elements or method steps. As used herein, "consisting of" excludes any element, step, or ingredient not specified in the said embodiment. As used herein, "consisting essentially of" does not exclude materials or steps that do not materially affect the basic and novel characteristics of the embodiment. In each instance herein any of the terms "comprising", "consisting essentially of" and "consisting of" may be replaced with either of the other two terms. The invention illustratively described herein suitably may be practiced in the absence of any element or elements, limitation or limitations which is not specifically disclosed herein.

[0106] One of ordinary skill in the art will appreciate that starting materials, biological materials, reagents, synthetic methods, purification methods, analytical methods, assay methods, and biological methods other than those specifically exemplified can be employed in the practice of the invention without resort to undue experimentation. All art-known functional equivalents, of any such materials and methods are intended to be included in this invention. The terms and expressions which have been employed are used as terms of description and not of limitation, and there is no intention that in the use of such terms and expressions of excluding any equivalents of the features shown and described or portions thereof, but it is recognized that various modifications are possible within the scope of the invention. Thus, it should be understood that although the present invention has been specifically disclosed by preferred embodiments and optional features, modification and variation of the concepts herein disclosed may be resorted to by those skilled in the art, and that such modifications and variations are considered to be within the scope of this invention as defined by embodiments herein.

[0107] Without wishing to be bound by any particular theory, there may be discussion herein of beliefs or understandings of underlying principles relating to the products and methods disclosed herein. It is recognized that regardless of the ultimatecorrectness of any mechanistic explanation or hypothesis, an embodiment of the invention can nonetheless be operative and useful.

[0108] In general, the terms and phrases used herein have their art-recognized meaning, which can be found by reference to standard texts, journal references and contexts known to those skilled in the art.

Claims

CLAIMS1. A botulinum toxin for use in the preventive treatment of migraine, wherein the botulinum toxin is injected at least into the frontal, temporal, occipital and cervical areas of the head, wherein(i) in the frontal area, the botulinum toxin is injected into (a) 6 injection sites at a total dose of 30 U to 40 U or (b) 7 injection sites at a total dose of 28 U to 42 U, wherein in case of (a) the botulinum toxin is injected into 2 injection sites in the corrugator supercilii muscle at a dose of 7.5 U to 10 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 3.75 U to 5 U per injection site, and wherein in case of (b) the botulinum toxin is injected into 1 injection site in the procerus muscle at a dose of 4 U to 6 U into 2 injection sites in the corrugator supercilii muscle at a dose of 4 U to 6 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 4 U to 6 U per injection site,(ii) in the temporal area, the botulinum toxin is injected into 4, 6 or 8 injection sites in the temporalis muscle at a dose of 5 U to 10 U per injection site, wherein the total dose injected in the temporal area is 20 U to 60 U,(iii) in the occipital area, the botulinum toxin is injected into 4 or 6 injection sites in the occipital muscle at a dose of 5 U to 10 U per injection site, wherein the total dose injected in the occipital area is 20 U to 60 U,(iv) in the cervical area, the botulinum toxin is injected into 2 or 4 injection sites in the cervical paraspinal muscles at a dose of 5 U to 10 U per injection site, wherein the total dose injected in the cervical area is 10 U to 20 U, and wherein the total dose administered to the frontal, temporal, occipital and cervical areas is 78 U to 182 U and the total number of injection sites in the frontal, temporal, occipital and cervical areas is 16 to 25.

2. The botulinum toxin for use according to claim 1 , wherein(i) in the frontal area, the botulinum toxin is injected into (a) 6 injection sites at a total dose of 30 U to 40 U or (b) 7 injection sites at a total dose of 28 U to 42 U, wherein in case of (a) the botulinum toxin is injected into 2 injection sites in the corrugator supercilii muscle at a dose of 7.5 U to 10 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 3.75 U to 5 U per injection site, and wherein in case of (b) the botulinum toxin is injected into 1 injection site in the procerus muscle at a dose of 4 U to 6 U into 2 injection sites in the corrugator supercilii muscle at a dose of 4 U to 6 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 4 U to 6 U per injection site,(ii) in the temporal area, the botulinum toxin is injected into 6 or 8 injection sites in the temporalis muscle at a dose of 7.5 U to 10 U per injection site, wherein the total dose injected in the temporal area is 45 U to 60 U,(iii) in the occipital area, the botulinum toxin is injected into 4 or 6 injection sites in the occipital muscle at a dose of 7.5 U to 10 U per injection site, wherein the total dose injected in the occipital area is 40 U to 60 U,(iv) in the cervical area, the botulinum toxin is injected into 2 or 4 injection sites in the cervical paraspinal muscles at a dose of 5 U to 10 U per injection site, wherein the total dose injected in the cervical area is 15 U to 20 U, and wherein the total dose administered to the frontal, temporal, occipital and cervical areas is 128 U to 182 U and the total number of injection sites in the frontal, temporal, occipital and cervical areas is 18 to 25.

3. The botulinum toxin for use according to claim 1 or 2, wherein(i) in the frontal area, the botulinum toxin is injected into 7 injection sites at a total dose of 35 U, wherein the botulinum toxin is injected into 1 injection site in the procerus muscle at a dose of 5 U, into 2 injection sites in the corrugator supercilii muscle at a dose of 5 U per injection site, and into 4injection sites in the frontalis muscle at a dose of 5 U per injection site,(ii) in the temporal area, the botulinum toxin is injected into 6 injection sites in the temporalis muscle at a dose of 10 U per injection site, wherein the total dose injected in the temporal area is 60 U,(iii) in the occipital area, the botulinum toxin is injected into 4 or 6 injection sites in the occipital muscle at a dose of 10 U per injection site, wherein the total dose injected in the occipital area is 40 U to 60 U,(iv) in the cervical area, the botulinum toxin is injected into 4 injection sites in the cervical paraspinal muscles at a dose of 5 U per injection site, wherein the total dose injected in the cervical area is 20 U, and wherein the total dose administered to the frontal, temporal, occipital and cervical areas is 155 U to 175 U and the total number of injection sites in the frontal, temporal, occipital and cervical areas is 21 to 23.

4. The botulinum toxin for use according to claims 1 or 2, wherein(i) in the frontal area, the botulinum toxin is injected into 6 injection sites at a total dose of 30 U to 40 U, wherein the botulinum toxin is injected into 2 injection sites in the corrugator supercilii muscle at a dose of 7.5 U to 10 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 3.75 U to 5 U per injection site,(ii) in the temporal area, the botulinum toxin is injected into 6 injection sites in the temporalis muscle at a dose of 7.5 U to 10 U per injection site, wherein the total dose injected in the temporal area is 45 U to 60 U,(iii) in the occipital area, the botulinum toxin is injected into 6 injection sites in the occipital muscle at a dose of 7.5 U to 10 U per injection site, wherein the total dose injected in the occipital area is 45 U to 60 U,(iv) in the cervical area, the botulinum toxin is injected into 2 injection sites in the cervical paraspinal muscles at a dose of 7.5 U to 10 U per injection site, wherein the total dose injected in the cervical area is 15 U to 20 U, and wherein the total dose administered to the frontal, temporal, occipital and cervicalareas is 135 U to 180 U and the total number of injection sites in the frontal, temporal, occipital and cervical areas is 20.

5. The botulinum toxin for use according to claim 1 , wherein(i) in the frontal area, the botulinum toxin is injected into 7 injection sites at a total dose of 35 U, wherein the botulinum toxin is injected into 1 injection site in the procerus muscle at a dose of 5 U, into 2 injection sites in the corrugator supercilii muscle at a dose of 5 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 5 U per injection site,(ii) in the temporal area, the botulinum toxin is injected into 4, 6 or 8 injection sites in the temporalis muscle at a dose of 5 U per injection site, wherein the total dose injected in the temporal area is 20 U to 40 U,(iii) in the occipital area, the botulinum toxin is injected into 4 or 6 injection sites in the occipital muscle at a dose of 5 U per injection site, wherein the total dose injected in the occipital area is 20 U to 30 U,(iv) in the cervical area, the botulinum toxin is injected into 2 or 4 injection sites in the cervical paraspinal muscles at a dose of 5 U per injection site, wherein the total dose injected in the cervical area is 10 U to 20 U, and wherein the total dose administered to the frontal, temporal, occipital and cervical areas is 85 U to 125 U and the total number of injection sites in the frontal, temporal, occipital and cervical areas is 17 to 25.

6. The botulinum toxin for use according to any one of claims 1 to 5, wherein (i) the botulinum toxin is not injected into any further injection points or (ii) the botulinum toxin is further injected into the shoulder area, wherein(v) in the shoulder area, the botulinum toxin is injected into 2, 4 or 6, preferably 2 or 4, injection sites in the trapezius muscle at a dose of 5 U to 10 U per injection site, wherein the total dose injected in the shoulder area is 10 U to 30 U, preferably the botulinum toxin is injected into 2 injection sites in the trapezius muscle at a dose of 5 U to 10 U, preferably 7.5 U or 10 U, per injection site, wherein the total dose injected in the shoulder area is 10 U to20 U, or the botulinum toxin is injected into 4 injection sites in the trapezius muscle at a dose of 5 U to 10 U, preferably 5 U or 7.5 U, per injection site, wherein the total dose injected in the shoulder area is 20 U to 30 U.

7. The botulinum toxin for use according to claim 1 , wherein the botulinum toxin is injected into 25 injection sites in the frontal, temporal, occipital, cervical and shoulder areas at a total dose of 195 U, wherein(i) in the frontal area, the botulinum toxin is injected into 7 injection sites at a total dose of 35 U, wherein the botulinum toxin is injected into 1 injection site in the procerus muscle at a dose of 5 U, into 2 injection sites in the corrugator supercilii muscle at a dose of 5 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 5 U per injection site,(ii) in the temporal area, the botulinum toxin is injected into 6 injection sites in the temporalis muscle at a dose of 10 U per injection site, resulting in a total dose injected in the temporal area of 60 U,(iii) in the occipital area, the botulinum toxin is injected into 6 injection sites in the occipital muscle at a dose of 10 U per injection site, resulting in a total dose injected in the occipital area of 60 U,(iv) in the cervical area, the botulinum toxin is injected into 4 injection sites in the cervical paraspinal muscles at a dose of 5 U per injection site, resulting in a total dose injected in the cervical area of 20 U, and(v) in the shoulder area, the botulinum toxin is injected into 2 injection sites in the trapezius muscle at a dose of 10 U per injection site, resulting in a total dose injected in the shoulder area of 20 U, and, preferably, wherein the location of the injection sites is as shown in Figure 1A.

8. The botulinum toxin for use according to claim 1 , wherein the botulinum toxin is injected into 21 injection sites in the frontal, temporal, occipital, and cervical and areas, and not in the shoulder areas, at a total dose of 155 U, wherein(i) in the frontal area, the botulinum toxin is injected into 7 injection sites at a total dose of 35 U, wherein the botulinum toxin is injected into 1 injectionsite in the procerus muscle at a dose of 5 U, into 2 injection sites in the corrugator supercilii muscle at a dose of 5 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 5 U per injection site,(ii) in the temporal area, the botulinum toxin is injected into 6 injection sites in the temporalis muscle at a dose of 10 U per injection site, resulting in a total dose injected in the temporal area of 60 U,(iii) in the occipital area, the botulinum toxin is injected into 4 injection sites in the occipital muscle at a dose of 10 U per injection site, resulting in a total dose injected in the occipital area of 40 U,(iv) in the cervical area, the botulinum toxin is injected into 4 injection sites in the cervical paraspinal muscles at a dose of 5 U per injection site, resulting in a total dose injected in the cervical area of 20 U, and, preferably, wherein the location of the injection sites is as shown in Figure 1 B.

9. The botulinum toxin for use according to claim 1 , wherein the botulinum toxin is injected into 22 injection sites in the frontal, temporal, occipital, cervical and shoulder areas at a total dose of 200 U, wherein(i) in the frontal area, the botulinum toxin is injected into 6 injection sites at a total dose of 40 U, wherein the botulinum toxin is injected into 2 injection sites in the corrugator supercilii muscle at a dose of 10 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 5 U per injection site,(ii) in the temporal area, the botulinum toxin is injected into 6 injection sites in the temporalis muscle at a dose of 10 U per injection site, resulting in a total dose injected in the temporal area of 60 U,(iii) in the occipital area, the botulinum toxin is injected into 6 injection sites in the occipital muscle at a dose of 10 U per injection site, resulting in a total dose injected in the occipital area of 60 U,(iv) in the cervical area, the botulinum toxin is injected into 2 injection sites in the cervical paraspinal muscles at a dose of 10 U per injection site, resultingin a total dose injected in the cervical area of 20 U, and(v) in the shoulder area, the botulinum toxin is injected into 2 injection sites in the trapezius muscle at a dose of 10 U per injection site, resulting in a total dose injected in the shoulder area of 20 U, and, preferably, wherein the location of the injection sites is as shown in Figure 1 C.

10. The botulinum toxin for use according to claim 1 , wherein the botulinum toxin is injected into 22 injection sites in the frontal, temporal, occipital, cervical and shoulder areas at a total dose of 150 U, wherein(i) in the frontal area, the botulinum toxin is injected into 6 injection sites at a total dose of 30 U, wherein the botulinum toxin is injected into 2 injection sites in the corrugator supercilii muscle at a dose of 7.5 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 3.75 U per injection site,(ii) in the temporal area, the botulinum toxin is injected into 6 injection sites in the temporalis muscle at a dose of 7.5 U per injection site, resulting in a total dose injected in the temporal area of 45 U,(iii) in the occipital area, the botulinum toxin is injected into 6 injection sites in the occipital muscle at a dose of 7.5 U per injection site, resulting in a total dose injected in the occipital area of 45 U,(iv) in the cervical area, the botulinum toxin is injected into 2 injection sites in the cervical paraspinal muscles at a dose of 7.5 U per injection site, resulting in a total dose injected in the cervical area of 15 U, and(v) in the shoulder area, the botulinum toxin is injected into 2 injection sites in the trapezius muscle at a dose of 7.5 U per injection site, resulting in a total dose injected in the shoulder area of 15 U, and, preferably, wherein the location of the injection sites is as shown in Figure 1 D.11 . The botulinum toxin for use according to claim 1 , wherein the botulinum toxin is injected into 29 injection sites in the frontal, temporal, occipital, cervical andshoulder areas at a total dose of 145 U, wherein(i) in the frontal area, the botulinum toxin is injected into 7 injection sites at a total dose of 35 U, wherein the botulinum toxin is injected into 1 injection site in the procerus muscle at a dose of 5 U, into 2 injection sites in the corrugator supercilii muscle at a dose of 5 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 5 U per injection site,(ii) in the temporal area, the botulinum toxin is injected into 8 injection sites in the temporalis muscle at a dose of 5 U per injection site, resulting in a total dose injected in the temporal area of 40 U,(iii) in the occipital area, the botulinum toxin is injected into 6 injection sites in the occipital muscle at a dose of 5 U per injection site, resulting in a total dose injected in the occipital area of 30 U,(iv) in the cervical area, the botulinum toxin is injected into 4 injection sites in the cervical paraspinal muscles at a dose of 5 U per injection site, resulting in a total dose injected in the cervical area of 20 U, and(v) in the shoulder area, the botulinum toxin is injected into 4 injection sites in the trapezius muscle at a dose of 5 U per injection site, resulting in a total dose injected in the shoulder area of 20 U, and, preferably, wherein the location of the injection sites is as shown in Figure 1 E.

12. The botulinum toxin for use according to claim 1 , wherein the botulinum toxin is injected into 19 injection sites in the frontal, temporal, occipital, cervical and shoulder areas at a total dose of 95 U, wherein(i) in the frontal area, the botulinum toxin is injected into 7 injection sites at a total dose of 35 U, wherein the botulinum toxin is injected into 1 injection site in the procerus muscle at a dose of 5 U, into 2 injection sites in the corrugator supercilii muscle at a dose of 5 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 5 U per injection site,(ii) in the temporal area, the botulinum toxin is injected into 4 injection sites in the temporalis muscle at a dose of 5 U per injection site, resulting in a total dose injected in the temporal area of 20 U,(iii) in the occipital area, the botulinum toxin is injected into 4 injection sites in the occipital muscle at a dose of 5 U per injection site, resulting in a total dose injected in the occipital area of 20 U,(iv) in the cervical area, the botulinum toxin is injected into 2 injection sites in the cervical paraspinal muscles at a dose of 5 U per injection site, resulting in a total dose injected in the cervical area of 10 U, and(v) in the shoulder area, the botulinum toxin is injected into 2 injection sites in the trapezius muscle at a dose of 5 U per injection site, resulting in a total dose injected in the shoulder area of 10 U, and, preferably, wherein the location of the injection sites is as shown in Figure 1 F.

13. The botulinum toxin for use according to any one of claims 1 to 12, wherein the volume per injection point is between 0.05 mL and 0.2 ml, preferably between 0.10 ml and 0.20 ml.

14. The botulinum toxin for use according to any one of claims 1 to 13, wherein the migraine is chronic migraine or episodic migraine.

15. The botulinum toxin for use according to any one of claims 1 to 14, wherein the botulinum toxin is of type A, or wherein the botulinum toxin is in a form that is free of complexing proteins or is in the form of a complex that contains complexing proteins, or wherein the botulinum toxin is of type A and is in a form that is free of complexing proteins or is in the form of a complex that contains complexing proteins.

16. A method for treating a patient with migraine headaches, the method comprising administration by injection of botulinum toxin at least into the frontal, temporal, occipital and cervical areas of the head of the patient, wherein(i) in the frontal area, the botulinum toxin is injected into (a) 6 injection sites at a total dose of 30 U to 40 U or (b) 7 injection sites at a total dose of 28 U to 42 U, wherein in case of (a) the botulinum toxin is injected into 2 injection sites inthe corrugator supercilii muscle at a dose of 7.5 U to 10 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 3.75 U to 5 U per injection site, and wherein in case of (b) the botulinum toxin is injected into 1 injection site in the procerus muscle at a dose of 4 U to 6 U into 2 injection sites in the corrugator supercilii muscle at a dose of 4 U to 6 U per injection site, and into 4 injection sites in the frontalis muscle at a dose of 4 U to 6 U per injection site,(ii) in the temporal area, the botulinum toxin is injected into 4, 6 or 8 injection sites in the temporalis muscle at a dose of 5 U to 10 U per injection site, wherein the total dose injected in the temporal area is 20 U to 60 U,(iii) in the occipital area, the botulinum toxin is injected into 4 or 6 injection sites in the occipital muscle at a dose of 5 U to 10 U per injection site, wherein the total dose injected in the occipital area is 20 U to 60 U,(iv) in the cervical area, the botulinum toxin is injected into 2 or 4 injection sites in the cervical paraspinal muscles at a dose of 5 U to 10 U per injection site, wherein the total dose injected in the cervical area is 10 U to 20 U, and wherein the total dose administered to the frontal, temporal, occipital and cervical areas is 78 U to 182 U and the total number of injection sites in the frontal, temporal, occipital and cervical areas is 16 to 25.

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