**5. Techniques for injection**

for migraine headaches, local inflammation sensitizes sensory neurons and upregulates the recruitment of sensory nociceptors [31–38]. As alluded to earlier, migraine pathophysiology involves irritation of peripheral nerves. Specifically, it involves several branches of the trigeminal nerve. Subsequent repeated irritation of the nerve causes an augmented perception of pain. The trigger point hypothesis attempts to explain this cycle of inflammation and trigeminal neuronal hypersensitivity. It takes into account that patients are often able to describe the origin of their migraine pain in a specific area, and that each site of origin leads to a different constellation of symptoms. Among other mechanisms, irritation of extracranial nerves in the periphery can be caused by overactivity of surrounding musculature, tight fascial bands, and intimate neurovascular relationships. Therefore, irritation of peripheral nerves by adjacent muscular contraction or other contact points can cause release of inflammatory factors, triggering the onset of migraine headaches. In this context, onabotulinumtoxinA can be targeted to these potential trigger sites in an attempt to prevent or inhibit the inflammatory cycle leading to peripheral and central sensitization. This theory and its implication in the success or failure of migraine surgery should not influence the fact that anatomical knowledge of the nerve locations can improve BTX-A injection techniques. Even if some neurologists do not hold the peripheral nerve compression theory correct, evidence now shows that BTX-A is most effective when deposited closer to nerves, acting by means of either direct reduction of chemoreceptors on the nociceptor membrane surface, or indirect decrease in activity by

Trigger sites are identified by regions where the pain originates, rather than other final locations where the pain may travel. To assess which sites are active, a Migraine Diary should be completed by patients each day for at least 4 weeks. Since patients often do not pay especially close attention to the exact location where pain begins, this log is very useful in keeping track of trigger origin sites. In addition to the migraine diary, a thorough history should be obtained to differentiate between sites where pain begins and sites where pain may radiate to. Because trigger sites are where the pain originates, injection of targeted BTX-A should be focused in these sites and not where the pain ends. However, a more liberal approach to targeted injection is to inject all the regions. Currently, there are six major trigger sites relevant to available treatment methods, which can be categorized into several "regions": frontal (Site I), temporal (Site II), rhinogenic (Site III), occipital (Sites IV and VI), and auriculotemporal (Site V). **Site I** refers to headaches beginning in the lateral and central forehead areas, with central and cephalad radiation. Patients often describe the pain beginning above the eye and moving from outside to inside. At times, palpation with a single finger at the area of the supraorbital and supratrochlear nerve will reveal tender areas where the supraorbital nerve (SON) and supratrochlear nerve (STN) are involved. In some cases, hypertrophy of the corrugator supercilii muscle may be visible on physical exam. **Site II**, or the temporal trigger site, is associated with headaches originating in the temple. Often times, pain radiates toward the lateral temporal and posterior auricular areas. The temporalis muscle may be larger than normal, or tighter than usual. However, it is important to differentiate temporomandibular joint (TMJ) pathology, as it is not a trigger site for migraine headaches. In this region, the zygomaticotemporal branch of the trigeminal nerve (ZTBTN) is involved in the generation of pain. **Site III** refers to pain of nasoseptal origin. This pain is usually associated with weather changes and

reducing mechanosensitivity [25, 26].

132 Current Perspectives on Less-known Aspects of Headache

#### **5.1. PREEMPT injection paradigm [24]**

The injection protocol used in the phase III PREEMPT trials were based on, and developed upon, earlier phase II studies that demonstrated safety and efficacy in the use of onabotulinum toxin for chronic migraine patients. Using this PREEMPT injection paradigm, the phase III part 1 and part 2 studies confirmed significant reduction in the frequency of headache days and low rates of adverse events [9, 41]. At 24 weeks, pooled data from both trials reported a significant difference in the reduction of headache days compared to placebo. Specifically, those who underwent 24 weeks of BTX-A injection had a 7.4 day reduction, while placebo had a 4.7 reduction in headache days [10]. Thus, the PREEMPT injection protocol is a proven prophylactic treatment for chronic migraine patients.

As the first formal injection protocol described, the PREEMPT technique is a combination of a "fixed site" and "follow the pain" approaches. This was based on a number of earlier studies employing different approaches. From these studies, this combination approach was determined as the most optimal protocol to be used in the PREEMPT trials [24]. A total of 155 units are injected into 31 fixed sites, targeting a number of muscle groups. In addition to these fixed site and fixed dose (FSFD) sites, an additional eight sites and 40 units can be injected according to physician discernment in a "follow the pain" approach. Therefore, the PREEMPT injection paradigm uses a minimum of 155 units and a maximum of 195 units, which corresponds well with the determined optimal dosage range between 150 and 200 units [24]. **Figure 1** shows the PREEMPT injection protocol in each area. A standard 30-gauge 0.5-inch syringe is used, and an injection interval of 12 weeks is followed.

**Figure 1.** PREEMPT injection protocol. Locations of fixed site, fixed dose injections: (1a) procerus, (1b) corrugators, (1c) frontalis, (2) temporalis, (3) occipitalis, (4) cervical paraspinal, and (5) trapezius muscle. Follow-the-pain injection areas are indicated in red color.

#### *5.1.1. Frontal*

In the frontal region, a total of 35 units are injected in a shallow manner into four muscle groups. First, the corrugator muscle is injected bilaterally 1.5 cm above the medial superior edge of the orbital ridge, with 10 units into each side. In the midline, the procerus is injected with 5 units in a location midway between the two corrugator injections. Finally, injection of the frontalis is divided into four sites, with 20 units total. On one side, the medial injection is 1.5 cm above the corrugator injection, and the lateral injection is 1.5 cm away from the medial injection in the same horizontal plane. This is repeated on the opposite side of the forehead.

#### *5.1.2. Temporal*

In the temporal region, the temporalis muscle is the main muscle group targeted. Injection in this area consists of four sites on each side of the head. A total of 20 units are injected into each side. The first injection is behind the anterior border of the temporalis muscle. The second injection is 0.5 cm above and 1.5 cm posterior to the first injection. The third and fourth injection is 0.5 cm posterior and inferior to the second injection, respectively. This is repeated on the opposite side. As mentioned earlier, additional units can be injected on both or just one side, and is based on palpation for significant tenderness and pain that requires additional treatment.

### *5.1.3. Occipital*

had a 4.7 reduction in headache days [10]. Thus, the PREEMPT injection protocol is a proven

As the first formal injection protocol described, the PREEMPT technique is a combination of a "fixed site" and "follow the pain" approaches. This was based on a number of earlier studies employing different approaches. From these studies, this combination approach was determined as the most optimal protocol to be used in the PREEMPT trials [24]. A total of 155 units are injected into 31 fixed sites, targeting a number of muscle groups. In addition to these fixed site and fixed dose (FSFD) sites, an additional eight sites and 40 units can be injected according to physician discernment in a "follow the pain" approach. Therefore, the PREEMPT injection paradigm uses a minimum of 155 units and a maximum of 195 units, which corresponds well with the determined optimal dosage range between 150 and 200 units [24]. **Figure 1** shows the PREEMPT injection protocol in each area. A standard 30-gauge 0.5-inch syringe is

In the frontal region, a total of 35 units are injected in a shallow manner into four muscle groups. First, the corrugator muscle is injected bilaterally 1.5 cm above the medial superior edge of the orbital ridge, with 10 units into each side. In the midline, the procerus is injected with 5 units in a location midway between the two corrugator injections. Finally, injection of the frontalis is divided into four sites, with 20 units total. On one side, the medial injection is 1.5 cm above the corrugator injection, and the lateral injection is 1.5 cm away from the medial injection in the same horizontal plane. This is repeated on the opposite side of the forehead.

**Figure 1.** PREEMPT injection protocol. Locations of fixed site, fixed dose injections: (1a) procerus, (1b) corrugators, (1c) frontalis, (2) temporalis, (3) occipitalis, (4) cervical paraspinal, and (5) trapezius muscle. Follow-the-pain injection areas

In the temporal region, the temporalis muscle is the main muscle group targeted. Injection in this area consists of four sites on each side of the head. A total of 20 units are injected into each side. The first injection is behind the anterior border of the temporalis muscle. The second injection is 0.5 cm above and 1.5 cm posterior to the first injection. The third and fourth injection is 0.5 cm posterior and inferior to the second injection, respectively. This is repeated on the opposite side. As mentioned earlier, additional units can be injected on both or just one side, and is based on palpation for significant tenderness and pain that requires additional treatment.

prophylactic treatment for chronic migraine patients.

134 Current Perspectives on Less-known Aspects of Headache

used, and an injection interval of 12 weeks is followed.

*5.1.1. Frontal*

are indicated in red color.

*5.1.2. Temporal*

The occipitalis muscle group is injected with 15 units in three sites on each side, totaling 30 units. The first injection is 1 cm lateral to and above the occipital protuberance. The second injection is given 1 cm lateral and 1 cm above the first injection. Finally, the third injection is 1 cm medial and 1 cm above the first injection. Similar to the temple area injection, physicians can follow the pain by palpating for significant areas of tenderness, and inject additional units.

#### *5.1.4. Cervical spine and paraspinal muscle groups*

In the area of the back of the neck, the PREEMPT protocol targets the semispinalis and splenius muscle groups. Injection consists of two sites on each side with 20 units total. On each side, the first injection is 3–5 cm inferior and just lateral to the occipital protuberance. Another injection is made 1 cm superior and lateral to the first.

#### *5.1.5. Trapezius*

The trapezius muscle is injected superiorly into three sites on each side, with 30 units total. The fixed dose is 5 units into each of the six total sites. One injection is made into the lateral portion of the muscle, another to the middle aspect, and one medially and superior within the medial portion of the muscle. With results from palpation for tenderness and pain, the physician can inject additional sites within the muscle group.

#### **5.2. ART injection technique: Anatomical, Regional, and Targeted [42]**

While the PREEMPT trials and its associated injection paradigm have paved the way for the development of BTX-A injection in migraine headaches, several other injection techniques have been developed, including the Anatomical, Regional, and Targeted (ART) injection paradigm. In contrast to the "fixed site" and "follow the pain" approach of the PREEMPT protocol, the ART technique offers a dynamic injection paradigm based on anatomical studies and surgical experiences in the decompression of nerves [42].

The ART injection paradigm can be described as Anatomical, Regional, and Targeted [42]. In this approach, injection is not necessarily targeted to a broad muscle group. Rather, this injection paradigm is designed based more on the *direct* effects of onabotulinum toxin on peripheral nerves, which have been previously described [25, 26, 43, 44]. As a result, injections rely heavily on accurate understanding of nerve anatomy and delivery of the toxin as close to the nerve as possible. The term "Anatomical" refers to injections based on the accurate location and depth of a nerve, and its surrounding musculature. "Regional" refers to focused injections at regions where pain originates (frontal, temporal, or occipital). "Targeted" refers to injections based on the topography of tender areas, which may not always correspond with known anatomical compression points. Therefore, the ART injection approach has the potential to be more individualized to each patient's unique picture of migraine pain.

While the PREEMPT injection paradigm dictates the exact dosage delivered to each site, the ART injection protocol is less strict on how much is injected. Previous studies have showed the optimal dosage range per injection cycle is between 150 and 200 units [24]. The standard ART dosage consists of 155 units delivered across several sites: 45 units into the frontal site, 25 units into the temples, 50 units to the GON, 10 units to the LON, 15 units split into the tails of the GON and LON, 5 units in the area of the AT nerve, and finally 5 units in the area of the tail of the AT nerve. This standard is the injection pattern given to patients who report pain in all trigger sites. However, upon physician discretion, more units can be delivered to certain areas, or none in certain trigger sites, according to what the patient reports.

#### *5.2.1. Site I: Frontal*

In Site I, injection of BTX-A is based on irritation of the supraorbital and supratrochlear nerves (SON and STN). In this site, the injection is more anatomical than targeted. If BTX-A is injected in areas of maximal tenderness here closer to the orbital rim, the risk for lid ptosis and diplopia is high. Therefore, injection is more fixed in this area. The corrugator supercilii muscle (CSM) is thought to compress the SON and STN, but any of the other glabellar muscles has the potential to as well (procerus, depressor supercilii). In addition, fibrous bands in the supraorbital foramen, or a boney foramen, could also be sources for proximal compression and pain. Before injecting into this area, the topographical anatomy of the corrugator muscle can be clearly visualized by asking the patient to frown. Of note, studies in plastic surgery literature have further outlined the anatomy of the corrugator, which is not followed accurately in the PREEMPT/Allergan injection protocol (**Figure 2**). The CSM begins 3 mm lateral to the midline and extends 43 mm laterally. Superiorly, it extends 33 mm from the pupil. An ice pack is used to cool the area before injection, as it is important to reduce anxiety and pain in the migraine patient. Digital occlusion of the supraorbital and supratrochlear vessels with the non-dominant thumb reduces the risk of "microhematomas". A short 0.5 inch 30-gauge needle with 0.1 cc graduation is used to inject 12.5 units into each side with a five-point standard injection (**Figure 3**). Based on correct anatomy, injection should be deeper medially and more superficial laterally. Single injections can be done on each side using a longer needle inserted superficially on the lateral side and extended deeply toward the medial side. Injection should be done as the needle is advancing, as it provides for the best control. If bleeding is present, gauze can be used, but it is critical not to press with excess pressure as the toxin can diffuse into unwanted areas in the upper lid.

Injection into the frontalis muscle should be only in the upper half of the forehead (**Figure 3**). Injecting lower on the forehead leads to a higher rate of lid ptosis. A total of 15–20 units is injected. This injection not only targets the distal portions of the SON and STN, but relaxation of the frontalis muscle reduces cephalic pull that can cause tension in the proximal nerve areas.

#### *5.2.2. Site II: Temporal*

Injection into the temporal area is again more anatomical than targeted. The zygomaticotemporal branch of the trigeminal nerve (ZTBTN) emerges approximately 17 mm posterolateral and 6.5 mm cephalad to the lateral canthus. This point of exit from the temporalis muscle is seen consistently in cadaver studies [45]. A long 30-gauge needle should pierce the temporalis muscle 1 cm posterolateral to this point to deposit 12.5 units on each side (**Figure 4**). The injection should be fanned deeply in a 1.5 cm radius. Additionally, a single deep injection at the point of nerve exit over the deep temporal fascia should also be performed.

**Figure 2.** The location of the corrugator muscle.

the optimal dosage range per injection cycle is between 150 and 200 units [24]. The standard ART dosage consists of 155 units delivered across several sites: 45 units into the frontal site, 25 units into the temples, 50 units to the GON, 10 units to the LON, 15 units split into the tails of the GON and LON, 5 units in the area of the AT nerve, and finally 5 units in the area of the tail of the AT nerve. This standard is the injection pattern given to patients who report pain in all trigger sites. However, upon physician discretion, more units can be delivered to certain

In Site I, injection of BTX-A is based on irritation of the supraorbital and supratrochlear nerves (SON and STN). In this site, the injection is more anatomical than targeted. If BTX-A is injected in areas of maximal tenderness here closer to the orbital rim, the risk for lid ptosis and diplopia is high. Therefore, injection is more fixed in this area. The corrugator supercilii muscle (CSM) is thought to compress the SON and STN, but any of the other glabellar muscles has the potential to as well (procerus, depressor supercilii). In addition, fibrous bands in the supraorbital foramen, or a boney foramen, could also be sources for proximal compression and pain. Before injecting into this area, the topographical anatomy of the corrugator muscle can be clearly visualized by asking the patient to frown. Of note, studies in plastic surgery literature have further outlined the anatomy of the corrugator, which is not followed accurately in the PREEMPT/Allergan injection protocol (**Figure 2**). The CSM begins 3 mm lateral to the midline and extends 43 mm laterally. Superiorly, it extends 33 mm from the pupil. An ice pack is used to cool the area before injection, as it is important to reduce anxiety and pain in the migraine patient. Digital occlusion of the supraorbital and supratrochlear vessels with the non-dominant thumb reduces the risk of "microhematomas". A short 0.5 inch 30-gauge needle with 0.1 cc graduation is used to inject 12.5 units into each side with a five-point standard injection (**Figure 3**). Based on correct anatomy, injection should be deeper medially and more superficial laterally. Single injections can be done on each side using a longer needle inserted superficially on the lateral side and extended deeply toward the medial side. Injection should be done as the needle is advancing, as it provides for the best control. If bleeding is present, gauze can be used, but it is critical not to press with excess pressure as the toxin can diffuse

Injection into the frontalis muscle should be only in the upper half of the forehead (**Figure 3**). Injecting lower on the forehead leads to a higher rate of lid ptosis. A total of 15–20 units is injected. This injection not only targets the distal portions of the SON and STN, but relaxation of the frontalis muscle reduces cephalic pull that can cause tension in the proximal nerve areas.

Injection into the temporal area is again more anatomical than targeted. The zygomaticotemporal branch of the trigeminal nerve (ZTBTN) emerges approximately 17 mm posterolateral and 6.5 mm cephalad to the lateral canthus. This point of exit from the temporalis muscle is seen consistently in cadaver studies [45]. A long 30-gauge needle should pierce the temporalis muscle 1 cm posterolateral to this point to deposit 12.5 units on each side (**Figure 4**). The injec-

areas, or none in certain trigger sites, according to what the patient reports.

*5.2.1. Site I: Frontal*

136 Current Perspectives on Less-known Aspects of Headache

into unwanted areas in the upper lid.

*5.2.2. Site II: Temporal*

**Figure 3.** ART frontal trigger site injection. Image demonstrating injection sites over the corrugator muscle. The patient frowns to assist in finding the correct locations. The SON and STN nerves are targeted here, as well as the frontalis muscle.

**Figure 4.** ART temporal trigger site injections. Figure demonstrating the relationship between the auriculotemporal nerve (AT), zygomaticotemporal nerve (ZTBTN), and the superficial temporal artery. It is important to note that the ZTBTN is on a different fascial plane, and does not normally contact the AT nerve or temporal artery. Injection sites include: (1) 1.5 cm posterolateral emergence of ZTBTN from deep temporal fascia. (2) fascial band compression at proximal AT. (3) Distal AT area corresponding to crossing with the superficial temporal artery.

The auriculotemporal nerve (AT) is another potential source of nerve irritation in the temporal area. This nerve is referred to as **Site V**. Injection at this site is more targeted than anatomical. BTX-A delivery should be guided by the patient's descriptions of tender areas, which may not always correspond with areas of anatomical compression. Injections should be in two sites: one near the proximal AT area where fibrous bands can compress the nerve, and one near the distal AT where it crosses the superficial temporal artery [42] (**Figure 4**).

#### *5.2.3. Site III: Nasoseptal*

BTX-A cannot be delivered to this area. A computed tomography scan should be done to elucidate areas of turbinate contact or other masses. Currently, the only treatment for this site is surgical correction.

#### *5.2.4. Site IV: Occipital*

Injection in Site IV is based on irritation of the occipital nerves: greater occipital nerve (GON), lesser occipital nerve (LON), and the third occipital nerve (TON). Although the LON can be referred to as **Site VI**, its treatment is considered together with other occipital sites. The GON is most commonly the primary site of pain. This injection is both targeted and anatomical. The nerve consistently pierces the semispinalis capitis muscle at a point 1.5 cm lateral to the midline and 3 cm below to the occipital protuberance (**Figure 5**). However, the area of maximal tenderness is often 0.5–1 cm lateral to this point. Therefore, BTX-A injection should be targeted to this area. When injecting this nerve, it is critical to inject deeply enough to pierce the trapezius fascia, where the nerve resides. A sturdier 27-gauge long needle is used to ensure penetration of the thick fascia, with 25 units injected into each side. The LON is injected similarly in a targeted and anatomical approach, using 10 units total for both sides (**Figure 5**). The point of maximal tenderness often corresponds anatomically within 0.5 cm of the emergence of the LON behind the sternocleidomastoid muscle [46]. The LON emerges 6.4 cm lateral to the posterior midline drawn through cervical spine, and 7.5 cm caudal from a horizontal line drawn between the most superolateral aspects of the external auditory canals [47]. Additionally, patients sometimes describe pain in the areas corresponding to the distal tails of the GON and LON. In these areas, terminal branches of the occipital artery intertwine with the occipital nerves.

The auriculotemporal nerve (AT) is another potential source of nerve irritation in the temporal area. This nerve is referred to as **Site V**. Injection at this site is more targeted than anatomical. BTX-A delivery should be guided by the patient's descriptions of tender areas, which may not always correspond with areas of anatomical compression. Injections should be in two sites: one near the proximal AT area where fibrous bands can compress the nerve, and one near the

**Figure 4.** ART temporal trigger site injections. Figure demonstrating the relationship between the auriculotemporal nerve (AT), zygomaticotemporal nerve (ZTBTN), and the superficial temporal artery. It is important to note that the ZTBTN is on a different fascial plane, and does not normally contact the AT nerve or temporal artery. Injection sites include: (1) 1.5 cm posterolateral emergence of ZTBTN from deep temporal fascia. (2) fascial band compression at

BTX-A cannot be delivered to this area. A computed tomography scan should be done to elucidate areas of turbinate contact or other masses. Currently, the only treatment for this site

Injection in Site IV is based on irritation of the occipital nerves: greater occipital nerve (GON), lesser occipital nerve (LON), and the third occipital nerve (TON). Although the LON can be referred to as **Site VI**, its treatment is considered together with other occipital sites. The GON is most commonly the primary site of pain. This injection is both targeted and anatomical. The nerve consistently pierces the semispinalis capitis muscle at a point 1.5 cm lateral to the midline and 3 cm below to the occipital protuberance (**Figure 5**). However, the area of maximal tenderness is often 0.5–1 cm lateral to this point. Therefore, BTX-A injection should

distal AT where it crosses the superficial temporal artery [42] (**Figure 4**).

proximal AT. (3) Distal AT area corresponding to crossing with the superficial temporal artery.

*5.2.3. Site III: Nasoseptal*

138 Current Perspectives on Less-known Aspects of Headache

is surgical correction.

*5.2.4. Site IV: Occipital*

**Figure 5.** ART occipital trigger site injection sites and landmarks. Occipital protuberance (triangle), GON (black oval), tail of GON (black square), LON (gray oval), tail of LON (gray square), 3rd occipital nerve (white circle).
