Patent Publication Number: US-2021177946-A1

Title: Therapeutic medications for the sphenopalatine ganglion

Description:
CROSS-REFERENCE 
     This application claims the benefit of U.S. Provisional Application No. 62/723,828, filed Aug. 28, 2018, and U.S. Provisional Application No. 62/918,602, filed Feb. 6, 2019, which applications are incorporated herein by reference. 
    
    
     BACKGROUND OF THE INVENTION 
     While pain syndromes, including headache and associated pain, affect a large percentage of the population, methods for treating pain are lacking. 
     SUMMARY OF THE INVENTION 
     Disclosed herein are methods of treating a neurological-related disorder comprising applying a therapeutically effective amount of botulinum neurotoxin to nerve ganglia including sphenopalatine ganglia and/or other ganglia of the head and neck. In some embodiments, the nerve ganglia is a parasympathetic nerve ganglia. In yet other embodiments, the nerve ganglia is a sphenopalatine ganglia, a ciliary ganglia, a submandibular ganglia, superior cervical ganglia, trigeminal ganglia and/or an otic ganglia. In still other embodiments, the nerve ganglia is a sphenopalatine ganglia. In some instances, the botulinum neurotoxin is applied to a pterygopalatine fossa. In still other instances, the botulinum neurotoxin is applied to the sphenopalatine ganglia. In still other embodiments, the botulinum neurotoxin is applied zygomatically, intranasally, through a hard palate technique, using a high tuberosity approach or combinations thereof. 
     In some instances, the neurological disorder is chosen from the group consisting of cluster headache, migraine headache, trigeminal neuralgia, herpes zoster pain, facial head or neck pain from various sources, complex regional pain syndrome, nasal contact point headache and vasomotor rhinitis, TMJ disorders, headaches, migraines, myofascial pain and dysfunction, anxiety, panic attacks, problems associated with Autonomic Sympathetic Overload, dizziness, vertigo, tinnitus, vomiting and nausea related to chemotherapy or other disorders, high blood pressure, atrial fibrillation increased appetite and obesity, loss of libido in women and combinations thereof. In yet other instances, the botulinum neurotoxin is chosen from the group consisting of botulinum neurotoxin type A, botulinum neurotoxin type B, botulinum neurotoxin type C, botulinum neurotoxin type D, botulinum neurotoxin type E, botulinum neurotoxin type F, botulinum neurotoxin type G, and combinations thereof. In some instances, the botulinum neurotoxin type B is administered with epinephrine. In still other instances, the botulinum neurotoxin type B further comprises a basic solution. In yet other instances, the amount of botulinum neurotoxin administered is between about 0.1 to about 1000 units. In still other instances, the amount of botulinum neurotoxin administered is between about 1 to about 1000 units. In still other embodiments, the amount of botulinum neurotoxin administered is between about 2 to about 50 units. 
     In some instances, the botulinum neurotoxin is administered over a period of time. In other instances, the botulinum neurotoxin is administered over one minute. In yet other instances, the volume of botulinum neurotoxin administered is between 0.1 to 10 cc. In some instances, the botulinum neurotoxin is further administered locally to the skin. In yet other instances, the botulinum neurotoxin is made from recombinant genetic methods. In still other instances, the botulinum toxin is isolated from  Clostridia botulinum  or  Clostridia berratti.    
     Also disclosed herein are methods and compositions for treating a pain syndrome comprising applying a therapeutically effective amount of botulinum neurotoxin to nerve ganglia including sphenopalatine ganglia and/or other ganglia of the head and neck. In some instances, the pain syndrome is chosen from the group consisting of migraine headaches, including migraine headaches with aura, migraine headaches without aura, menstrual migraines, migraine variants, atypical migraines, complicated migraines, hemiplegic migraines, transformed migraines, and chronic daily migraines; episodic tension headaches; chronic tension headaches; analgesic rebound headaches; episodic cluster headaches; chronic cluster headaches; cluster variants; chronic paroxysmal hemicrania; hemicrania continua; post-traumatic headache; post-traumatic neck pain; post-herpetic neuralgia involving the head or face; pain from spine fracture secondary to osteoporosis; arthritis pain in the spine, headache related to cerebrovascular disease and stroke; headache due to vascular disorder; reflex sympathetic dystrophy, cervicalgia; glossodynia, carotidynia; cricoidynia; otalgia due to middle ear lesion; gastric pain; sciatica; maxillary neuralgia; laryngeal pain, myalgia of neck muscles; trigeminal neuralgia; post-lumbar puncture headache; low cerebro-spinal fluid pressure headache; temporomandibular joint disorder; atypical facial pain; ciliary neuralgia; paratrigeminal neuralgia; petrosal neuralgia; Eagle&#39;s syndrome; idiopathic intracranial hypertension; orofacial pain; myofascial pain syndrome involving the head, neck, and shoulder; chronic migraneous neuralgia, cervical headache; paratrigeminal paralysis; sphenopalatine ganglion neuralgia; carotidynia; Vidian neuralgia; and causalgia; trigeminal neuralgia, herpes zoster; back pain and sciatica and combinations thereof. In yet other instances, the botulinum neurotoxin is chosen from the group consisting of botulinum neurotoxin type A, botulinum neurotoxin type B, botulinum neurotoxin type C, botulinum neurotoxin type D, botulinum neurotoxin type E, botulinum neurotoxin type F, botulinum neurotoxin type G, and combinations thereof. In some instances, the botulinum neurotoxin type B is administered with epinephrine. In still other instances, the botulinum neurotoxin type B further comprises a basic solution. 
     INCORPORATION BY REFERENCE 
     All publications, patents, and patent applications mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication, patent, or patent application was specifically and individually indicated to be incorporated by reference. 
    
    
     DETAILED DESCRIPTION OF THE INVENTION 
     We have unexpectedly found that application of botulinum neurotoxin to the sphenopalatine ganglion, and/or one of the alternative ganglia, superior cervical ganglia, trigeminal ganglia, stellate ganglia and otic ganglia, results in improvement or positive change in the following: atrial fibrillation, angina, anorgasmic syndrome, anxiety, depression, dizziness or vertigo, esophageal spasm, hypertension, mood, libido, insomnia, myofascial pain and dysfunction, obstructive sleep apnea, glaucoma, glossodynia (commonly known as “Burning Mouth Syndrome”), nausea and vomiting, panic attacks, post-traumatic stress disorder (PTSD), tachycardia, tinnitus, TMJ disorder, vasomotor rhinitis, writer&#39;s cramp, and combinations thereof. 
     In addition, application of botulinum neurotoxin to the sphenopalatine ganglion, and/or one of the alternative ganglia, superior cervical ganglia, trigeminal ganglia, stellate ganglia and otic ganglia can be used to treat pain syndromes. In some embodiments, the pain syndromes include but are not limited to the following: migraine headaches, including migraine headaches with aura, migraine headaches without aura, menstrual migraines, migraine variants, atypical migraines, complicated migraines, hemiplegic migraines, transformed migraines, and chronic daily migraines; episodic tension headaches; chronic tension headaches; analgesic rebound headaches; episodic cluster headaches; chronic cluster headaches; cluster variants; chronic paroxysmal hemicrania; hemicrania continua; post-traumatic headache; post-traumatic neck pain; post-herpetic neuralgia involving the head or face; pain from spine fracture secondary to osteoporosis; arthritis pain in the spine, headache related to cerebrovascular disease and stroke; headache due to vascular disorder; reflex sympathetic dystrophy, cervicalgia; glossodynia, carotidynia; cricoidynia; otalgia due to middle ear lesion; gastric pain; sciatica; maxillary neuralgia; laryngeal pain, myalgia of neck muscles; trigeminal neuralgia; post-lumbar puncture headache; low cerebro-spinal fluid pressure headache; temporomandibular joint disorder; atypical facial pain; ciliary neuralgia; paratrigeminal neuralgia; petrosal neuralgia; Eagle&#39;s syndrome; idiopathic intracranial hypertension; orofacial pain; myofascial pain syndrome involving the head, neck, and shoulder; chronic migraneous neuralgia, cervical headache; paratrigeminal paralysis; sphenopalatine ganglion neuralgia; carotidynia; Vidian neuralgia; and causalgia; trigeminal neuralgia, herpes zoster; back pain and sciatica. Decreases in number or severity of migraine headache or cluster headache, facial head or neck pain from various sources, complex regional pain syndrome, and nasal contact point headache may occur with administration of a therapeutically effective amount of botulinum neurotoxin to the sphenopalatine ganglion, and/or one of the alternative ganglia, superior cervical ganglia, trigeminal ganglia, stellate ganglia and otic ganglia. 
     The effect of administration of a therapeutically effective amount of botulinum neurotoxin to the sphenopalatine ganglion, and/or one of the alternative ganglia, superior cervical ganglia, trigeminal ganglia, stellate ganglia and otic ganglia is completely unexpected as the mechanism of BoNT is completely different than lidocaine, cocaine and similar local anesthetics. BoNT works only at synapses whereas lidocaine works throughout a nerve, and BoNT is believed to work on cholinergic nerves, whereas local anesthetics work on all nerves: motor, sensory, parasympathetic and sympathetic. 
     Investigators have in the past applied botulinum neurotoxin to treat various diseases, but none have applied botulinum neurotoxin to nerve ganglia for the treatment of the disorders and diseases above. 
     For example, in 1994 Sanders and Shaari U.S. Pat. No. 5,766,605, Treatment of autonomic nerve dysfunction with botulinum toxin) discovered that BoNT could be used to treat disorders of the autonomic nerves. Indications included rhinorrhea, asthma, and decreasing sweating (hyperhidrosis). 
     Dr William Binder noted in the early 1990s that patients in whom he had injected botulinum toxin into their facial muscles to decrease wrinkles also had decreases in migraine headache. Patent U.S. Pat. No. 5,714,468 awarded to William Binder described how injections of botulinum toxin into muscles of the face or neck could alleviate migraine headaches. Since that time much research has corroborated these findings. 
     In 2002, Dr Ira Sanders discovered that application of BoNT to the nose or sphenopalatine ganglion (SPG) decreased all symptoms of allergic rhinitis (sneezing, itching, congestion and rhinorrhea) and asthma (U.S. Pat. Nos. 8,088,360, 9,314,513 8,092,781, 8,349,292, 7,879,340). 
     In 2003, Dr Ira Sanders discovered that botulinum toxin applied to the SPG could decrease migraine headaches (U.S. Pat. No. 9,504,735). More recently, Bratback et al. confirmed Dr Sanders&#39; invention by showing that 25 units of botulinum toxin applied bilaterally to the PPF and SPG can cause a 50% decrease in migraine headaches&#39; and a similar decrease in the number of cluster headaches. 
     In both studies the authors carefully chronicled all changes in the subjects yet other than headache, the improvement in other symptoms and conditions claimed in this invention were not seen. 
     Botulinum Neurotoxin 
     Wild type clostridial neurotoxins, specifically those from  Clostridia botulinum , are amphipathic protein conjugates with unique properties that make them beneficial in medical applications. First, in their natural or wild type form, they have specificity for neurons, particularly motor neurons. Second, they can block neuromuscular transmission for extended periods, from days to months depending on the serotype. Third, in most clinical applications they have been used at doses that are below the level of immunological recognition. Fourth, as they are remarkably safe for human use when injected into local areas such as muscles because there is little systemic spread of the toxin. 
     The clostridial neurotoxins include seven serotypes of botulinum neurotoxins, termed A-G (A, B, C1, D, E, F, and G) (Simpson, et al., Pharmacol. Rev., 33:155-188, 1981), and a single serotype of tetanus toxin (tetanus neurotoxin). These toxins all have a molecule size of  ˜ 150 kD and are comprised of a heavy-chain ( ˜ 100 kD) and a light chain ( ˜ 50 kD) that are covalently linked by a disulphide bridge at their N-terminals. The heavy chain consists of the binding domain (fragment C) at the C terminal and a translocation domain (fragment B, which is the amphipathic protein) at the N-terminal end. The light chain (fragment A) is the toxic domain, however, it also contains its own small amphipathic region. These neurotoxins are exceptional due to their specific binding to neurons and their specific catalytic action on the SNARE proteins, which are involved in neurotransmission. Botulinum neurotoxins A, C, and E cleave SNAP-25, in addition botulinum neurotoxin/C cleaves syntaxin 1. botulinum neurotoxins B, D, F, G and tetanus toxin cleave VAMP-2. 
     After a clostridial neurotoxin binds to the presynaptic surface, it is internalized by incorporation into endosomes. When the interior of the endosome reaches about pH 5.5, the amphipathic B-fragment merges with the membrane and forms a pore that allows the light chain to pass through to the cell&#39;s cytoplasm. While passing through the membrane the disulfide bond is broken and the light chain is released into the cytoplasm and exerts its toxic effect. 
     The toxic action of all clostridial neurotoxin light chains is to cleave proteins necessary for attachment of internal vesicles to the cell membrane. The production and docking of these vesicles is a highly regulated process that is present in all eukaryotic cells including single-cell organisms such as yeast. The vesicle membranes merge with the cell membrane thereby adding new membrane bound proteins while simultaneously discharging the vesicle&#39;s contents into the extracellular environment. In neurons, these vesicles contain neurotransmitters and neuropeptides. Botulinum neurotoxin A and E cleaves SNAP-25; botulinum neurotoxin C cleaves SNAP-25 and syntaxin 1; and tetanus neurotoxin and botulinum neurotoxin types B, D, F and G cleave VAMP (vesicle associated membrane protein, also called synaptobrevin). 
     There are 7 immunologically distinct toxins: A, B, C1, D, E, F and). These toxins bind to presynaptic membranes of target nerves and appear to work in a similar fashion (Brin, et al., “Report of the Therapeutics and Technology Assessment Subcommittee of the American Academy of Neurology”, Neurology, 40:1332-1336, 1990). Botulinum toxin shows a high affinity for cholinergic neurons. Botulinum toxin A produces a reversible, flaccid paralysis of mammalian skeletal muscle, presumably by blocking the exocytosis of acetylcholine at peripheral, presynaptic cholinergic receptors (Rabasseda, et al., Toxicon, 26:329-326, 1988). However, flaccid muscular paralysis is not necessary to achieve the reduction or prevention of migraine symptomatology. In fact, headache pain reduction may be observed at dosages of presynaptic neurotoxin which are lower or higher than dosages required to produce flaccid paralysis of skeletal muscle and without introduction of the neurotoxin into muscle tissue (Binder, U.S. Pat. No. 5,714,468). 
     Although the molecular basis for the sensation of migraine pain is not clear (Goadsby, et al., N. Eng. J. Med., 346:257-270, 2004), Botulinum toxin might exert its analgesic effect by blocking the release of nociceptive and inflammatory agents that are released during migraine, and not by blocking the release of acetylcholine. Because Botulinum toxin does not act on acetylcholine directly, but on the SNARE protein complex that mediates vesicle fusion, the release of other molecules which is also mediated by the SNARE protein complex is also affected by the toxin (Aoki, Current Medicinal Chemistry, 11:3085-3092, 2004). In fact, studies have shown that Botulinum toxin can also block the release of substance P, which is associated with neurogenic inflammation and pain generation (Aoki, Current Medicinal Chemistry, 11:3085-3092, 2004), glutamate, also associated with nociception (Cui, et al., Pain, 107:125-133, 2004), epinephrine, norepinephrine, and calcitonin gene-related peptide (Aoki, Current Medicinal Chemistry, 11:3085-3092, 2004). Botulinum toxin A does not appear to cause degeneration of nervous or muscular tissue and has been approved for use in certain therapies by the U.S. Food and Drug Administration. 
     In addition to Botulinum toxin A, other presynaptic neurotoxins have also been suggested to be useful for the treatment of disease, given the functional characteristics they share with Botulinum toxin (Binder, U.S. Pat. No. 5,714,468). One of these presynaptic neurotoxins is Tetanus neurotoxin, which is produced by  Clostridium tetani  (DasGupta, et al., Biochemie, 71:1193-1200, 1989), and shows significant sequence homology with serotypes A and E of Botulinum toxin. In particular, fragment Ibc of the Tetanus toxin, which is obtained by peptide digestion of the toxin, appears to act peripherally to produce flaccid paralysis (Fedinic, et al., Boll.lst. Sieroter Milan, 64: 35-41, 1985; and, Gawade, et al., Brain Res., 334:139-46, 1985). 
     Pterygopalatine Fossa (PPF) 
     The pterygopalatine fossa (PPF) is an inverted pyramidal space located inferior to the orbital apex, which contains the sphenopalatine ganglion (SPG), also known as pterygopalatine ganglion, Meckel&#39;s ganglion, or Sluder&#39;s ganglion. The PPF contains various arteries, veins, lymphatics, and nerves. Preganglionic parasympathetic facial nerve fibers synapse in the PPF, while postganglionic sympathetic fibers from the superior cervical ganglion and sensory fibers from the maxillary nerve pass through the ganglion without synapsing. The PPF communicates with the orbit, nasal cavity, and oral cavity, and through the orbit with the maxillary sinus and upper teeth, which makes it an important cranial neurovascular crossroad. 
     In Sluder&#39;s original 1908 article, he described a variety of neuralgic, motor, sensory, and gustatory symptoms, referred to as Sluder&#39;s neuralgia, which are now called cluster headaches. Dr. Sluder was the first to propose and use transnasal injections of cocaine to anesthetize the SPG, and described using a straight needle to enter the naris, reach the PPF, push posteriorly 0.66 cm, and inject topical cocaine to bathe the ganglion. Four years later, Sluder reported that injecting a 5% solution of phenol (carbolic acid), a neurolytic substance, dissolved into alcohol instead of cocaine provided longer term pain relief from these neuralgias in 10 of his patients. 
     In 1925, Ruskin became the first to use SPG blocks for trigeminal neuralgia. He also introduced transoral approaches for blocking the ganglion. Since the early 1900s, the SPG has been targeted to relieve head pain; among the earliest of these treatments involved applying numbing medications on cotton swabs to the back of the nose. Another technique later used was injecting patients through an area on the cheek, using alcohol. 
     Byrd and Byrd described over 2,000 patients who had undergone the procedure, on whom the SPG block had been performed over 10,000 times. Despite this success and for reasons that are unclear, the use of SPG blocks dwindled and not much was published in the literature until the 1980s. 
     It has long been known that lidocaine, cocaine or similar local anesthetics can block the nerves in the PPF. These drugs work by numbing the membrane of the neuron and prevent transmission of impulses across thee neurons. The blocks appear to reset the autonomic nervous system turning off Sympathetic Overload (dominance) and allowing Parasympathetic response to dominate. 
     It has been found that application of lidocaine to the PPF or the surrounding bony canals leading to this fossa have unexpected results. Specifically, patients injected with lidocaine have improvement in cluster headache, migraine headache, trigeminal neuralgia, herpes zoster pain, facial head or neck pain from various sources, complex regional pain syndrome, nasal contact point headache and vasomotor rhinitis. 
     In addition, it has been found that lidocaine applied to the SPG can also improvement facial head or neck pain from various sources, complex regional pain syndrome, nasal contact point headache, mucosal headache, TMJ disorders, headaches, myofascial pain and dysfunction, anxiety, panic attacks and other problems associated with Autonomic Sympathetic Overload, vomiting and nausea related to chemotherapy or other disorders. 
     In addition, in patients whose SPG has been blocked there was a feeling of calmness or peace. Many patients find decreases in tension, depression, insomnia and anxiety. High blood pressure tends to stabilize and A-fib may improve. Patients may experience decreased appetite with weight loss. Women tend to have a positive effect on their libido, sometimes very soon after administration and some Anorgasmic women have reported developing normal or heightened sexual release. 
     Relatively recently, the FDA has approved catheters (thin plastic tube placed in the nose) to facilitate insertion of numbing medication injected in and around the SPG. Three catheters approved are Sphenocath®, Allevio®, and Tx 360®. Anesthetics used in SPG injections to control head pain include bupivacaine and lidocaine. 
     In a preferred embodiment, the presynaptic neurotoxin of the invention is Botulinum toxin. In a particularly preferred embodiment of the invention, the presynaptic neurotoxin is Botulinum toxin A. Botulinum toxin A is presently supplied and commercially available as “Botox”® by Allergan, Inc. of Irvine, Calif., Xeomin® of Merz Pharma of Germany, and as “Dysport”® by Ipsen, of Berkshire, UK. In another embodiment of the invention, the presynaptic neurotoxin is Botulinum toxin B. Botulinum toxin B is commercialized as “Neurobloc”®/“Myobloc”® by Solstice Neuroscience, Inc, of San Francisco, Calif. Botox® has been FDA approved to treat, among other things, cervical dystonia, brow furrows, blepharospasm, strabismus, and hyperhidrosis. 
     The potency of a toxin is expressed as a multiple of the LD50 value for a reference mammal. One “unit” of toxin is the amount of toxin that kills 50% of a group of mammals that were disease-free prior to inoculation with the toxin. For example, one unit of Botulinum toxin is defined as the LD50 upon intra peritoneal injection into female Swiss Webster mice weighing 18-20 grams each. One nanogram of the commercially available Botulinum toxin A typically contains about 40 mouse units. The potency in humans of the Botulinum toxin A product currently supplied by Allergan, Inc. as “Botox”® is estimated to be about LD50=2,730 units. 
     Assuming an approximate potency of LD50=2,730 units, the presynaptic neurotoxin can be administered in a dose of up to about 1,000 units; however, dosages of as low as about 1 unit will have therapeutic efficacy. It is important to note that the potency of a single unit is variable among the commercial formulations. The potency of 1 U of onabotulinumtoxinA (Botox) is about equal to 1 U of incobotulinumtoxinA (Xeomin), 3 U of abobotulinumtoxinA (Dysport) and 40 to 50 U of rimabotulinumtoxinB (Neurobloc). However, it is very important to recognize that this ratio of equivalence cannot be employed. For injections, botulinum toxins type A are diluted with 0.9% sodium chloride solution. 
     The injections will be repeated as necessary. As a general guideline, Botulinum toxin A administered into or near muscle tissue has been observed to produce flaccid paralysis at target site muscles for up to about 3 to 6 months. However, increased duration up to 9-12 months have been reported with autonomic applications such as hyperhidrosis. 
     In a preferred embodiment of the invention, commercially available Botox® can be reconstituted with sterile non-preserved saline prior to injection. Each vial of Botox® contains about 100 units of clostridium Botulinum toxin type A purified neurotoxin complex. Dilutions will vary depending upon the commercial preparation. 
     The preferred target administration sites for the current invention are the contents of the PPF including but not limited to the SPG, maxilllary nerve and sympathetic neurons. 
     For example, in one embodiment 100 units of Botulinum toxin A are reconstituted in 4 cc of normal saline, a specific syringe with demarcations at 0.1 cc of 2.5 units, and at 0.2 cc of 5 units will be used. In another embodiment in which 100 units of Botulinum toxin A are reconstituted in 1 cc of normal saline, the syringe with demarcations at 0.1 cc of 10 units; and at 0.2 cc of 20 units will be used. These delivery tools allow for accurate delivery and recording of the dose given. 
     Injections are preferably made every 3-12 months or upon return of symptoms. The dose injected on one side can vary from about 0.1-1000 units, preferably about 5-50 units, and more preferably about 20-30 units for botulinum neurotoxin type A, for example onabotulinumtoxin A (Botox). In some instances and depending upon the type of botulinum neurotoxin used, the amount employed would increase, for example, for rimbotulinumtoxin B (Neurobloc) the amount administered would be approximately 50-times the amount of botulinum neurotoxin relative to onabotulinum toxin A (botox), i.e., from about 5-50,000 units, preferably about 250-2500 units, and more preferably about 1000-1500 units for botulinum neurotoxin type B. Injections can be unilateral or bilateral depending on the nature and location of the lesion. Injections can be done simultaneously on both sides or separately. 
     In another embodiment of this technique, an injection of epinephrine can precede, or be given simultaneous or even after the BoNT injection. The epinephrine contracts blood vessels, thereby decreasing the soft tissue volume within the pterygopalatine fossa. It also aids in preventing or minimizing any bleeding in the fossa. In addition, it decreases the extracellular space and fluid exchange in the area, decreasing the spread of the toxin. 
     In another embodiment the local and systemic spread of toxin can be minimize, a non-limiting example being serotype B a used. Type B is marketed in liquid form with preservation aided by an acidic pH of 5.6. This particular product is known for its pain on injection and for seemingly substantial systemic spread to autonomically innervated structures, a non-limiting example being the salivary glands which decreases salivation which the patient experiences as dry mouth. To combat these side effects, the type B BoNT solution may be combined with epinephrine described above. In the particular case of BoNT the acidic nature of the solution may cause inflammation with increased fluid release and uptake by local blood vessels. This increased fluid exchange could remove BoNT type B from the area and allow it to enter the systemic circulation. To minimize this, a basic solution to neutralize the acid pH and decrease the acidic nature of the injection. This decreases pain and the inflammation in the area. 
     The application of BoNT by needle injection can be done in at least four ways. 
     Zygomatic 
     In the suprazygomatic approach the patient is placed supine with the head in a neutral position. The needle entry point is found at the angle formed by the superior edge of the zygomatic arch below and the posterior orbital rim forward. The needle (22 to 25 gauge) is inserted perpendicular to the skin and advanced to reach the greater wing of the sphenoid at a depth of approximately 10-15 mm). The needle is then reoriented in a caudal and posterior direction and advanced a further 35-45 mm to reach the pterygopalatine fossa. After a negative aspiration test for blood, solution is slowly injected. Nerve stimulation may help locate the pterygopalatine fossa: Nerve stimulation is associated with paresthesia coinciding with the stimulating frequency of the nerve stimulator. In anesthetized children, stimulation of the temporal muscle that results in a mandibular contraction may be noted. The disappearance of the muscle contraction heralds the passage through the temporal muscle and entrance into the pterygomaxillary fossa. 
     In an alternative embodiment the needle can be inserted below the zygomatic arch (infrazygomatic). 
     Intransal 
     Preferably the nose is decongested with phenylephrine or epinephrine and anesthetized with lidocaine. A flexible or rigid scope is passed into the nasal cavity such that it visualizes the mucosa posterior to the middle turbinate. A syringe contained BoNT diluted with preferably 1-4 cc of normal saline is attached to a long needle preferably about 3.5 cm and preferably 27 gauge. The needle is introduced into the nasal cavity and advanced until the needle tip is at the posterior border of the middle turbinate. The needle is then slowly advanced 1-10 mm through mucosa behind the middle turbinate. The needle is aspirated and then injection is made. 
     Palatal 
     The exit of the pterygopalatine canal is identified on the hard palate about mid-way between the 2 nd  or 3 rd  molar and the midline. A needle is advanced into the foramen in a posterosuperior direction at an angle of 45-60 degrees from the horizontal plane of the hard palate. At 20-30 mm the needle is aspirated and then injection is made. 
     High Tuberosity 
     A 25-gauge long needle is recommended for this injection but a 27-gauge is acceptable. 1  The penetration site for the maxillary block is the height of the mucobuccal fold distal to the maxillary second molar. Prior to placing topical anesthetic, it is important to use a finger to feel along the facial aspect of the maxilla to find the zygomatic process, which is usually located above the first maxillary molar. It is important to insert distal to the zygomatic process or the maxillary bone may be scraped during administration. The angle of the syringe should be 45° from the mid-sagittal plane, as well as 45° apically from the maxillary occlusal plane. A helpful visual guide for this angle is a line running from the lateral periphery of the ala of the nose to the inside corner of the opposite eyebrow. The average depth of penetration for the maxillary block is 30 mm. With a 32 mm long needle, 2 mm of needle should remain visible outside the tissue. The bone should not be contacted on this injection, and the needle should progress smoothly through the tissues. The clinician should know the exact length of the needle, as different manufacturers produce different needle lengths. If both aspirations are negative, the injection anesthetic should be slowly deposited, re-aspirating every ¼ of the cartridge to make sure a blood vessel has not been penetrated. The clinician should administer this injection slowly (taking more than 60 seconds to deliver the full amount) because of the highly vascular nature of the pterygopalatine fossa. 
     Injections are preferably made every 3-9 months or upon return of symptoms. 
     The dose injected on one side can vary from 1-1000 units, preferably 1-50 units, and more preferably 20-30 units. Injections can be unilateral or bilateral. 
     It is another embodiment of this invention to apply BoNT topically to the SPG. The SPG can be anesthetized by topical application of local anesthetics to the mucosa of the nasal cavity. This is done in the region immediately posterior to posterior end of the middle turbinate (termed the SPG area). This is because the SPG underlies the mucosa in this area. Moreover, topical diffusion is possible as there is no bone underneath the mucosa in this region. Moreover, local anesthetics are small molecules which are known to pass through mucosa easily. In contrast, BoNT is a large molecule that passes through mucosa poorly and diffuses slowly. However, in 1994, Sanders and Shaari showed that botulinum toxin could pass through nasal mucosa to block neurons suppling nasal secretory glands. 
     In one embodiment, BoNT is applied to the SPG area by contact with a cotton tipped applicator. This is like techniques used to apply local anesthetics to this area. The cotton is saturated with a solution of BoNT. It is held against the mucosa for 1 minute to 1 hour. The BoNT solutions are more concentrated or have higher doses than injection as topical delivery is less efficient and much of the solution never leaves the cotton. Dosage is preferably 1 to 1000 units dissolved in from 0.1 to 10 cc, more preferably 5 to 100 units dissolved in 0.5 to 5 cc. 
     A practitioner familiar with the art would know of obvious variations of this topical technique including other physical carriers (sponges) and other materials. 
     EXAMPLES 
     Example 1. Migraine 
     A 50-year-old female has 10-15 episodes of migraine headache every month. Her physician uses 1 cc of normal saline in a 5 cc syringe to dilute a 100 unit vial of BoNT. The physician injects via the zygomatic technique and deposits 0.25 cc into the PPF. Over the next month the patient&#39;s frequency of headache decreases to 5 per month and they are of lesser intensity. 
     Example 2. Cluster Headache 
     A 40-year-old male has 5 episodes of cluster headache every month. His physician uses 2 cc of normal saline in a 5 cc syringe to dilute a 100 unit vial of BoNT. The physician injects via the palatal technique and deposits 0.5 cc into the PPF. Over the next month the patient&#39;s frequency of headache decreases to 1 per month and they are of lesser intensity. 
     Example 3. Dizziness, Vertigo 
     A patient experiences acute onset of vertigo 2 days after noting an upper respiratory tract infection. The physician dilutes a 100 unit vial of BoNT with 4 cc of normal saline in a 5 cc syringe attached to a 3.5 inch 27 gauge spinal needle. The physician inserts the needle into one nostril via the intranasal technique and deposits 1 cc into the PPF. Over the next week the patient experiences only slight improvement in symptoms so the physician performs an intra-nasal injection on the opposite side. Within a week after the second injection the vertigo is eliminated and the dizziness decreases to a lesser intensity. 
     Example 4. Tinnitus 
     A patient experiences chronic tinnitus which keeps him awake at night. An audiogram shows bilateral high frequency sensorineural hearing loss. The physician dilutes a 100 unit vial of BoNT with 2 cc of normal saline in a 5 cc syringe with a 1.5 inch 27 gauge needle. The physician injects 0.5 cc in the PPF bilaterally. The patient notes decreased tinnitus over the next week and resolution of his insomnia which lasts 6 months. 
     Example 5. Insomnia 
     A patient experiences chronic tinnitus which keeps him awake at night. An audiogram shows bilateral high frequency sensorineural hearing loss. The physician dilutes a 100-unit vial of BoNT with 2 cc of normal saline in a 5 cc syringe with a 1.5 inch 27 gauge needle. The physician injects 0.5 cc in the PPF bilaterally. The patient notes decreased insomnia over the next week which lasts 9 months. 
     Example 6. Decreased Libido 
     A 30-year-old post-menopausal female has noted decreased libido over the past year. The physician dilutes a 100 unit vial of BoNT with 4 cc of normal saline in a 5 cc syringe attached to a 3.5 inch 27 gauge spinal needle. The physician inserts the needle into one nostril via the intranasal technique and deposits 0.5 cc into the PPF. The injection is repeated on the opposite side. Over the next month the patient reports increased libido which lasts six months. 
     Example 7. Anorgasmic Syndrome 
     A 50-year-old post-menopausal female has noted decreased the inability to achieve orgasm despite adequate stimulation over the past year. The physician dilutes a 100 unit vial of BoNT with 4 cc of normal saline in a 5 cc syringe attached to a 3.5 inch 27 gauge spinal needle. The physician inserts the needle into one nostril via the intranasal technique and deposits 0.5 cc into the PPF. The injection is repeated on the opposite side. Over the next month the patient reports orgasm during sexual activity. This improvement lasts 5 months. 
     Example 8. Trigeminal Neuralgia 
     A 30-year-old male has lancinating pain around the right side of his face while chewing. He is diagnosed with trigeminal neuralgia. His physician uses 2 cc of normal saline in a 5 cc syringe to dilute a 100 unit vial of BoNT. The physician injects via the palatal technique and deposits 0.5 cc into the PPF unilaterally on the side of the pain. Over the next month the patient&#39;s frequency of pain decreases 80% and this lasts 12 months. 
     Example 9. Temporomandibular Joint (TMJ) Pain 
     A 40-year-old female has pain localized to her left ear when chewing. Her dentist diagnoses TMJ. The dentist dilutes a 100-unit vial of BoNT with 2 cc of normal saline in a 5-cc syringe with a 1.5 inch 27 gauge needle. He anesthetizes the mucosa and then performs a high tuberosity injection of 1 cc on the left side. Over 2 weeks thee TMJ pain diminishes and the effect lasts 8 months. 10. Hypertension. A 60 ear male has hypertension with a blood pressure reading of 140/90. The physician dilutes a 100 unit vial of BoNT with 4 cc of normal saline in a 5 cc syringe attached to a 3.5 inch 27 gauge spinal needle. The physician inserts the needle into one nostril via the intranasal technique and deposits .5 cc into the PPF. The injection is repeated on the opposite side. In 2 weeks his blood pressure reading is 120/70 and is no longer hypertensive. The effect lasts 3 months. 
     Example 11. Atrial Fibrillation 
     A 70 ear male has atrial fibrillation. The physician dilutes a 100 unit vial of BoNT with 4 cc of normal saline in a 5 cc syringe attached to a 3.5 inch 27 gauge spinal needle. The physician inserts the needle into one nostril via the intranasal technique and deposits 0.5 cc into the PPF. The injection is repeated on the opposite side. In 2 weeks his atrial fibrillation has been eliminated. The effect lasts 6 months. 
     Example 12. Anxiety and Depression 
     A 60 year old female suffers from anxiety and depression. The physician dilutes a 100 unit vial of BoNT with 4 cc of normal saline in a 5 cc syringe attached to a 3.5 inch 27 gauge spinal needle. The physician inserts the needle into one nostril via the intranasal technique and deposits 0.5 cc into the PPF. The injection is repeated on the opposite side. Over the next month the patient reports that the anxiety and depression is largely eliminated. This improvement lasts 5 months. 
     Example  13 . Panic Attacks 
     A 40-year-old female military veteran has anxiety and panic attacks. His physician uses 2 cc of normal saline in a 5-cc syringe to dilute a 100 unit vial of BoNT. The physician injects via the palatal technique and deposits 0.5 cc into the PPF bilaterally. Over the next 2 months the number and severity thee panic attacks decreases 80% and this lasts 12 months. 
     Example 14. Post Traumatic Stress Disorder (PTSD) 
     A 30-year-old male military veteran has PTSD. His physician uses 2 cc of normal saline in a 5-cc syringe to dilute a 100 unit vial of BoNT. The physician injects via the palatal technique and deposits 0.5 cc into the PPF bilaterally. Over the next 2 months the patient&#39;s severity of PTSD decreases 80% and this lasts 12 months. 
     Example 15. Vomiting and Nausea 
     A 40-year-old female has cancer and is undergoing chemotherapy. After each dose of chemotherapy, she experiences 1 week of nausea and vomiting. The physician dilutes a 100-unit vial of BoNT with 4 cc of normal saline in a 5 cc syringe attached to a 3.5 inch 27 gauge spinal needle. The physician inserts the needle into one nostril via the intranasal technique and deposits 0.5 cc into the PPF. The injection is repeated on the opposite side. Over the next month the patient reports decreased nausea and vomiting which lasts six months. 
     Example 16. Glaucoma 
     A 30-year-old male has been diagnosed with glaucoma. His physician uses 2 cc of normal saline in a 5-cc syringe to dilute a 100-unit vial of BoNT. The physician injects via the palatal technique and deposits 0.5 cc into the PPF bilaterally. Over the next month the patient&#39;s frequency of pain decreases 80% and this lasts 12 months. 
     Example 17. Maxillary Cancer 
     A 60-year-old male has cancer involving his right maxillary sinus with severe continual pain and inability to swallow. His physician dilutes 2 100-unit vial of BoNT with 1 cc of normal saline each and places them in a 5-cc syringe with a 1.5 inch 27 gauge needle. He anesthetizes the mucosa and then performs a high tuberosity injection of 1 cc on the left side. Over 3 days the pain diminishes to a tolerable level. 
     Example 18. Herpes Zoster 
     A 40-year-old male has herpes zoster of the face affecting his rights eye with severe pain. The nasal cavity is anesthetized with lidocaine 1% with epinephrine 1:100,000. A cotton tipped applicator is saturated with 1 cc of a solution of normal saline containing 100 units of BoNT. The applicator is introduced into the nasal cavity and the cotton is held against the SPG area mucosa for 1 hour. In 2 days, the pain of the herpes zoster has decreased by 50%. 
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     While preferred embodiments of the present invention have been shown and described herein, it will be obvious to those skilled in the art that such embodiments are provided by way of example only. Numerous variations, changes, and substitutions will now occur to those skilled in the art without departing from the invention. It should be understood that various alternatives to the embodiments of the invention described herein may be employed in practicing the invention. It is intended that the following claims define the scope of the invention and that methods and structures within the scope of these claims and their equivalents be covered thereby.