US 20110250212A1 (19) United States (12) Patent Application Publication (10) Pub. N0.2 US 2011/0250212 A1 YEOMANS et al. (43) Pub. Date: Oct. 13, 2011

(54) THERAPY PROCEDURE FOR DRUG (60) Provisional application No. 60/794,004, ?led on Apr. DELIVERY FOR TRIGEMINAL PAIN 21, 2006, provisional application No. 60/711,950, ?led on Aug. 26, 2005. (76) Inventors: David C. YEOMANS, Sunnyvale, Publication Classi?cation CA (US); William H. FREY, II, Int. Cl. White Bear Lake, MN (US); Daniel (51) I. JACOBS, Mountain View, CA A61K 39/395 (2006.01) A61P 25/04 (2006.01) (Us) A61K 38/02 (2006.01) A61K 38/11 (2006.01) (21) App1.No.: 13/165,646 A61K 38/08 (2006.01) (52) US. Cl...... 424/172.1; 514/116; 514/185; (22) Filed: Jun. 21, 2011 514/18.4 (57) ABSTRACT Related US. Application Data The present invention relates to methods for the treatment or (63) Continuation of application No. 12/409,413, ?led on prevention of trigeminal nerve-associated pain, in particular Mar. 23, 2009, noW abandoned, Which is a continua chronic, acute and procedural-related pain. The methods tion of application No. 11/990,878, ?led on Aug. 19, comprise administration of agents to the trigeminal 2009, noW abandoned, ?led as application No. PCT/ nerve system Which results in analgesia to the facial or head US2006/033672 on Aug. 28, 2006. region. Patent Application Publication Oct. 13, 2011 Sheet 1 0f 8 US 2011/0250212 A1

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THERAPY PROCEDURE FOR DRUG described as “lightening bolt-like , machine gun-like” or DELIVERY FOR TRIGEMINAL PAIN “electric shock-like”. The pain is generally on one side of the face and is spasmodic, coming in short bursts lasting a feW CROSS-REFERENCE TO RELATED seconds Which may repeat many times over the course of a APPLICATIONS day. Trigeminal neuralgia can involve one or more branches of the trigeminal nerve and the causes are varied. Pharmaco [0001] This application is a national Phase ?ling under 35 logic treatments include anti-seiZure medications such as car USC §371 of International Application No. PCT/US2006/ 033672, ?ledAug. 28, 2006, Which is related to and claims the bamaZepine (Tegretol, Carbatrol), phenyloin (Dilantin), clon bene?t of US. Provisional Patent Application Ser. No. aZepam (Klonopin), (N eurontin), and lamtrignine (Lamictal), tricyclic antidepressants such as 60/711,950, ?led Aug. 26, 2005, and US. Provisional Patent (Elavil) and muscle relaxants such as baclofen. The treat Application Ser. No. 60/794,004, ?led Apr. 21, 2006, the ments generally have limited e?icacy and many patients entire contents of Which are hereby incorporated by reference eventually undergo an invasive procedure. The procedural herein in their entirety. interventions often involve the direct manipulation of the TECHNICAL FIELD trigeminal ganglion and include microvascular decompres sion, injection aimed at destroying pain ?bers, glyc [0002] The present invention relates generally to methods erol injection aimed at selectively destroying pain-transmit and compositions for the treatment of pain. More speci?cally, ting ?bers, percutaneous radiofrequency rhiZotomy, pulse the present invention relates to methods for the treatment radio frequency and gamma-knife. The pain relief from these prevention of trigeminal nerve-associated procedural, acute procedures canbe successful in a percentage of these patients, and chronic pain by administration and targeted delivery of but the relief can be short-lived and often facial pain returns. analgesic agents to the trigeminal nerve system resulting in Signi?cant procedural pain and long term morbidity may also localiZed pain relief With minimal untoWard central nervous be associated With such treatments. system effects or systemic side effects. [0006] Atypical Facial Pain (ATFP) is a syndrome encom passing a Wide group of facial pain problems. ATFP can have BACKGROUND OF THE INVENTION many different causes but the symptoms are all similar. Facial [0003] Pain is experienced When the free nerve endings pain, often described as burning, aching or cramping, occurs Which constitute the pain receptors in the skin as Well as in on one side of the face, often in the region of the trigeminal certain internal tissues are subjected to mechanical, thermal, nerve and can extend into the upper neck or back of the scalp. chemical or other noxious stimuli. The pain receptors (noci Although rarely as severe as trigeminal neuralgia, facial pain ceptors) can transmit signals along afferent neurons into the is continuous for ATFP patients, With feW, if any periods of central nervous system and then to the brain. The causes of remission. Some studies propose that ATFP is an early form pain can include in?ammation, injury, disease, muscle spasm of trigeminal neuralgia, but there is no agreement at this time. and the onset of a neuropathic event or syndrome. Ineffec Drug treatments forATFP are similar to What is prescribed for tively treated pain can be devastating to the person experienc trigeminal neuralgia including anti-seiZure medications and ing it by limiting function, reducing mobility, complicating tricyclic antidepressants With limited effectiveness. sleep, and dramatically interfering With the quality of life. [0007] Anesthesia dolorosa is one of the most dreaded [0004] The trigeminal sensory nerves (afferents) innervate complications of neurosurgery and is considered to be non and transmit to the brain most of the sensory signals from the reversible. The tWo main symptoms of anesthesia dolorosa face and anterior head. Pain involving the trigeminal nerve are facial numbness (much like the numbness from a dental and ganglion arises in many different medical situations and injection) and constant pain. The pain is usually presents unique problems to pain therapists and doctors. burning, pulling or stabbing but can also include a sharp, Chronic pain due to syndromes such as trigeminal neuralgia, stinging, shooting or electrical component. Pressure and atypical facial pain, anesthesia dolorosa, post-herpetic neu “heaviness” can also be part of the pain symptoms and often ralgia, cancer of the head and neck, migraine headaches, and there is eye pain. Cold can increase the feeling of numbness temporomandibular joint pain are examples of very different sometimes making the face feel froZen. Anesthesia dolorosa pain syndromes that all involve the trigeminal system and occurs When the trigeminal nerve is damaged by surgery, Which present clinical challenges that are peculiar to this physical trauma or as a complication of surgery to correct a nerve distribution. In addition to chronic pain states, there are condition such as trigeminal neuralgia. Topical treatments clinical situations Where facial and head pain is associated With are used to help manage the pain and discom With acute trauma such as an abscessed tooth, a headache or fort, While topical has been tested in a feW cases but a direct injury to the face and/or head such as a laceration or no single treatment has been found that resolves all of the pain a burn. Further, medical procedures such as common dental of this condition. Work and facial plastic and/or cosmetic surgery may elicit [0008] Post-herpetic neuralgia is pain that remains after the considerable pain, as Well as discomfort and anxiety. rash from shingles (herpes Zoster) has healed. Shingles is an [0005] Among syndromes associated With facial pain is infection of the nerves caused by the varicella-Zoster virus, trigeminal neuralgia, also called “tic duloreaux” Which is Which is the same virus that causes chickenpox. About one among the most debilitating facial pain syndromes. Trigemi third of the people Who get shingles Will get post herpetic nal neuralgia usually begins after the age of 40, is slightly neuralgia. The pain of post herpetic neuralgia may be con more common in Women and has an incidence of approxi stant, stabbing, aching, or burning and can last for months to mately 4-5 per 100,000 persons (Khorami and Totals (2001) years after the shingles outbreak. eMedicine Journal, Vol. 2). The primary symptom of trigemi [0009] It is predicted that approximately 65,000 Americans nal neuralgia is the sudden onset of severe, sharp facial pain, Will be diagnosed With head and neck cancers this year, this usually Without Warning. The quick bursts of pain are represents about 3% of all cancers diagnosed in the United US 2011/0250212 A1 Oct. 13, 2011

States (American Cancer Society). Close to 60% of head and [0013] Pain treatment of almost any type usually includes neck cancer patients report long-term pain With up to 25% some form of analgesic agent or drug. Analgesic drugs are claiming moderate or severe pain (List and Stracks (2000) usually classi?ed into three groups: non- drugs, opioid Curr. Opin. Oncol., 121215-20). The trigeminal nerves and drugs, and co-analgesic drugs, also knoWn as adjuvants. Non ganglion are likely to mediate mo st of the head and facial pain opioid analgesic drugs include acetaminophen and non-ste in these patients and sometimes are directly affected by the roidal anti-in?ammatory drugs or NSAlDs. Opioid drugs, cancerous groWth. The recommended treatment for mo st can sometimes referred to as “”, include natural sub cer patients With mild to severe pain is opioid therapy such as stances such as , and semi-synthetic and synthetic , , , morphine, and substances. Co-analgesic medications are drugs that have a . Opioid therapy has a multitude of problems primary use other than pain relief, but also help produce analgesia for some painful conditions. including systemic effects aWay from the site of pain stimu lation. Furthermore, are highly addictive and patients [0014] Opioid drugs are commonly used to relieve pain. build up tolerance to the drugs quickly resulting in higher and HoWever, their usefulness is limited by the tolerance and higher doses being administered. dependence that normally develops on chronic treatment. Opioid drugs such as morphine can be addictive and can have [0010] Migraine headaches affect more than 29.5 million central nervous system-mediated side effects such as respira people in the United States. The typical migraine headache is tory and cardiac depressions and droWsiness. Additionally, throbbing or pulsatile, it builds up over a period of 1-2 hours opioid drugs suffer from frequent side effects such as nausea, and lasts from several hours to a Whole day. Pain intensity is vomiting and constipation. moderate to severe and can be debilitating and often causes [0015] Therapeutic drugs are delivered by a number of nausea and vomiting. Of particular interest to clinicians Who routes including, for example, oral administration, intrave study migraine headaches is the superior trigeminal division nous injection, intramuscular injection and subcutaneous (the ophthalmic division). This division innervates the fore injection. For patients suffering procedural, acute or chronic head, eyebroW, eyelid, anterior scalp, nose and contents of the pain associated With the trigeminal nerve, one of the main orbit thus giving an explanation for the pain localiZation problems With conventional drug delivery With analgesic along With the visual aura that is common With migraine agents is the lack of localiZed pain relief due to systemic headaches. Common treatments for migraine headaches distribution of the agent. Often larger dosages need to be include beta-blockers such as propranolol (lnderal) and administered to achieve an effective concentration of the drug Atenolol, tricyclic antidepressants, triptans, ergotamines, at a desired site. With higher doses of an analgesic agent, there anti-seiZure drugs and calcium channel blockers. Many of is the additional problem of limited e?icacy relative to the these drugs have systemic side effects and limited effective increase in undesired side effects due to the systemic distri ness. bution of the agent. Treatments consisting of localiZed but [0011] Acute facial pain can arise in patients undergoing invasive interventions directly to the trigeminal nerve have a common dental procedures such as tooth extraction, root signi?cant disadvantage due to the lack of selectivity and/or canal surgery and surgery for dental implants and dental reversibility of the intervention and the fact that these proce prostheses. Acute dental pain can also arise from dental/ dures can, by themselves, cause additional facial nerve prob gingival disease, other conditions such as an abscessed tooth lems including anesthesia doloroso, persistent numbness and or a bacterial infection or injury, that arise separately from nerve deafferentation. An additional problem With conven planned dental procedures. Most dentists use topical anes tional treatments for trigeminal nerve-associated pain, espe thetics such as benZocaine, eugenol and forms of xylocalne to cially With invasive procedures, is the high level of skill, numb various areas for minor procedures or before injection training and equipment required by the medical team Which of a . For most procedures a dentist Will inject can make treatment expensive and impractical for Widespread a local anesthetic such as , xylocalne and marcaine use. to create a nerve block at or around the site Where dental Work [001 6] lntranasal administration has been used for systemic needs to be done. Local numb the area Where they delivery of several therapeutic agents, for example, insulin, are injected and eliminate the acute pain of most procedures. thryrotropin-releasing hormone, and vasopressin. Using an In addition to the pain of administration, another main disad intranasal or other mucosal route for systemic delivery of a vantage of local anesthetics, especially for routine dental therapeutic agent alloWs for ease of administration and the procedures, is that numbness and loss of sensation in the ability to bypass intestinal degradation and ?rst pass hepatic facial region Will usually last for several hours after the dental metabolism of the therapeutic agent. There are times When it procedure is ?nished. is desirable to not have systemic distribution of a therapeutic [0012] Facial plastic surgery is becoming a very common agent or to have a therapeutic agent targeted to a localiZed or procedure With several million procedures done in the United regional area. For example, intranasal drug delivery has been States each year. The procedures range from necessary repair used to bypass the blood-brain barrier and deliver substances of damage such as lacerations or broken bones to elective to the central nervous system (CNS) and the brain. It has been cosmetic surgeries such as face lifts, rhinoplasties, skin reju demonstrated that large molecules such as polypeptides, pep venation, etc. For many of these procedures local anesthetics tides, oligonucleotides or DNA plasmids can be delivered are used (the patients are not under general anesthetic) and as directly to the CNS via speci?c uptake routes Within the nose With dental procedures, the local anesthetics can be painful to such as the axonal and perineural vascular/lymphatic path administer and include the problem of lingering numbness Ways of the olfactory and trigeminal nerves (Frey 11 (2002) lasting for hours after the procedure is ?nished. In addition, Drug Delivery Technology, 2:46-49; Thorne et al. (2004) depending on the surgery performed, patients experience Neuroscience, 127:481-496). HoWever, While there is evi varying levels of post-operative pain after the anesthetic dence that various therapeutic agents can be delivered to the Wears off. brain by an intranasal route and that the agents may travel US 2011/0250212 A1 Oct. 13, 2011

along perineural pathways, there is no known method utiliZ a peptidergic receptor . In yet other examples the ing these pathWays to speci?cally target the trigeminal nerve analgesic agent is a peptidergic receptor antagonist. In further system for localized or regional analgesia in individuals suf examples the analgesic agent is an antibody directed against fering from trigeminal nerve-associated pain. proalgesic antigens such as endothelin, nerve groWth factor, [0017] Despite a Wide range of medical treatments, vasoactive intestinal polypeptide (VIP) or pituitary adenylate trigeminal nerve-as sociated pain, in many different forms and cyclase-activating polypeptide (PACAP). In some examples situations, continues to affect millions of people. Thus neW the analgesic agent is an antibody directed against calcitonin methods for treating an individual for trigeminal nerve-asso gene-related (CGRP), cholecystokinin (CCK), Sub ciated pain are needed to directly target the trigeminal nerve stance P or galanin. In other examples the analgesic agent is a system With analgesic agents and deliver analgesia to facial or N-methyl-D-aspartate receptor blocker, a non-steroidal anti head regions With minimal central nervous system effects or in?ammatory drug, a steroid anti-in?ammatory drug, an ion systemic side effects. channel blocker, an antidepressant or an anti-seizure medica tion. In some examples the analgesic agent is an opioid. BRIEF SUMMARY OF THE INVENTION [0021] Some aspects of the invention include methods [0018] Provided herein are methods for treating an indi Wherein the analgesic agent is administered as a pharmaceu vidual for trigeminal nerve-associated pain, comprising: tical composition. Accordingly, provided herein are methods administering to the individual an effective amount of an for treating an individual for trigeminal nerve-associated analgesic agent Wherein the administration is targeted to the pain, comprising: administering to the individual an effective trigeminal nerve system and results predominantly in anal ge amount of a pharmaceutical composition comprising an anal sia to the facial or head region, particularly as compared to gesic agent Wherein the administration is targeted to the analgesic effects in other parts of the body. Some aspects of trigeminal nerve system and results predominantly in analge the invention include methods Wherein the trigeminal nerve sia to the facial or head region. Some aspects of the invention associated pain is selected from the group consisting of include methods Wherein the pharmaceutical composition is chronic, acute and procedural-related pain and combinations administered in a formulation selected from a group compris thereof. In some examples, the chronic pain is selected from ing a poWder, a liquid, a gel, an ointment, a suspension, a ?lm, the group consisting of trigeminal neuralgia, atypical facial a foil, a cream or a bioadhesive. Some aspects of the invention pain, anesthesia dolorosa, post-herpetic neuralgia, cancer of include methods Wherein the pharmaceutical composition the head and neck, migraine headaches, and temporoman further comprises a protease inhibitor, an absorption dibular joint pain. In some examples, the procedural-related enhancer, a vasoconstrictor or combinations thereof. In some pain is pain arising from dental, medical, surgical or cosmetic examples, the protease inhibitor is selected from a group procedures. In yet other examples, the acute pain is pain comprising antipain, arphamenine A and B, benZamidine arising from a laceration, a burn, a broken bone, an injury, a HCl, AEBSF, CA-074, calpain inhibitor I and II, calpeptin, headache, an abscessed tooth, dental disease, a bacterial pepstatin A, actinonin, , bestatin, chloroacetyl-HO infection or a sinus infection. Leu-Ala-Gly-NH2, DAPT, diprotin A and B, ebelactone A [0019] Provided herein are methods for treating an indi and B, foroxymithine, leupeptin, pepstatin A, phosphorami vidual for trigeminal nerve-associated pain, comprising: don, aprotinin, BBI, soybean trypsin inhibitor, phenylmeth administering to the individual an effective amount of an ylsulfonyl ?uoride, E-64, chymostatin, 1,10-phenanthroline, analgesic agent Wherein the administration is targeted to the EDTA and EGTA. In other examples the absorption enhancer trigeminal nerve system and results predominantly in anal ge is selected from a group comprising surfactants, bile salts, sia to the facial or head region and Wherein the analgesic agent bioadhesive agents, phospholipid additives, mixed micelles, is administered via mucosal and/ or dermal administration. In liposomes, or carriers, alcohols, enamines, cationic poly some examples the analgesic agent is administered intrana mers, NO donor compounds, long-chain amphipathic mol sally. In other examples the analgesic agent is administered ecules, small hydrophobic penetration enhancers; sodium or via buccal or sublingual administration. In other examples the a derivatives, glycerol esters of acetoacetic acid, analgesic agent is administered to conjunctiva or other cyclodextrin or beta-cyclodextrin derivatives, medium-chain mucosal tissues around the eye. In yet other examples the fatty acids, chelating agents, amino acids or salts thereof, analgesic agent is administered to the skin or dermal surface. N-acetylamino acids or salts thereof, mucolytic agents, In some examples, the analgesic agent is administered by enZymes speci?cally targeted to a selected membrane com more than one route. ponent, inhibitors of fatty acid synthesis and inhibitors of [0020] Provided herein are methods for treating an indi cholesterol synthesis. vidual for trigeminal nerve-associated pain, comprising: [0022] Provided herein are methods for treating an indi administering to the individual an effective amount of an vidual for trigeminal nerve-associated pain, comprising: analgesic agent Wherein the administration is targeted to the administering to the individual i) an effective amount of a trigeminal nerve system and results predominantly in anal ge pharmaceutical composition comprising an analgesic agent sia to the facial or head region. Some aspects of the invention Wherein the administration is targeted to the trigeminal nerve include methods Wherein the analgesic agent includes, but is system and results predominantly in analgesia to the facial or not limited to, a peptide, an amino acid, a polypeptide, an head region and ii) a vasoconstrictor Wherein administration or a small molecule compound Which has analgesic of the vasoconstrictor reduces systemic distribution of the properties. In some examples the analgesic agent is an opioid analgesic agent. In some examples the vasoconstrictor is peptide selected from a group comprising , selected from the group comprising phenylephrine hydro endorphins, , , , der chloride, tetrahydroZoline hydrochloride, naphaZoline morphin, oxytocin and analogues and derivatives thereof. In nitrate, oxymetaZoline hydrochloride, tramaZoline hydro some examples the analgesic agent is a peptide Which inhibits chloride, endothelin-l, endothelin-2, epinephrine, norepi peptidergic enZymes. In other examples the analgesic agent is nephrine and angiotensin. In some examples the vasocon US 2011/0250212 A1 Oct. 13, 2011

strictor is administered prior to the administration of the after thermal stimulation to the ear. Panel B shoWs baseline pharmaceutical composition. In other examples the vasocon and treated WithdraWal latencies after thermal stimulation to strictor is co-administered With the pharmaceutical composi the hindpaW. After taking baseline WithdraWal latencies, rats tion. In some examples administration of the vasoconstrictor Were intranasally administered 10 nmoles/kg met- results in a decreased effective dosage of the analgesic agent. and WithdraWal latencies Were retested. Each bar represents [0023] Provided herein are methods for treating an indi the average, across 4 animals, of latencies in response to vidual for trigeminal nerve-associated pain, comprising: stimulation at a particular time after the beginning of the set. administering to the individual an effective amount of a phar Thus, the ?rst White bar in each graph represents responses at maceutical composition comprising an analgesic agent the beginning of the baseline testing set; the ?rst black bar Wherein the peptide is administered by buccal or sublingual represents responses at approximately ?ve minutes after administration to the oral cavity and Wherein the agent pref administering met-enkephalin. Each successive bar repre erentially binds to opioid receptors Within the trigeminal sents responses at approximately 15 minutes after the previ nerve system and results predominantly in analgesia to the ous bar. facial or head region. Some aspects provide methods for [0028] FIG. 2 depicts the effect of intranasal administration treating an individual for trigeminal nerve-associated pain, of oxytocin on trigeminal nerve impulses in response to nox comprising: administering to the individual an effective ious laser pulses to the face in a rat model. Data demonstrating amount of a pharmaceutical composition comprising an anal average nerve impulses after noxious laser pulses to the face gesic agent Wherein the peptide is administered by transder pre- and post-treatment are shoWn. mal administration to the skin and Wherein the agent prefer [0029] FIG. 3 depicts the effect of intranasal administration entially binds to opioid receptors Within the trigeminal nerve of oxytocin on electrical stimulus-induced responses of system and results predominantly in analgesia to the facial or trigeminal nucleus caudalis Wide dynamic range neurons. head region. FIG. 3A shoWs responses (action potentials per 30 stimuli) to [0024] Provided herein are methods for treating an indi repeated stimulation of a rat’s face before and after oxytocin vidual for trigeminal nerve-associated pain, comprising: administration. FIG. 3B shoWs the approximate site (black administering to the individual an effective amount of a phar spot) of administration on the rat’s face of the electrical maceutical composition comprising an analgesic agent administration. FIG. 3C shoWs raW data recorded during elec Wherein the agent is administered by intranasal administra trical stimulation before oxytocin administration. FIG. 3D. tion to the nasal cavity and Wherein the agent preferentially shoWs raW data recorded during electrical stimulation 30 binds to opioid receptors Within the trigeminal nerve system minutes after intranasal oxytocin administration. and results predominantly in analgesia to the facial or head [0030] FIG. 4 depicts the effect of intranasal administration region. In some examples the administration is directed to the of on long-pulse laser-induced responses of inferior tWo-thirds of the nasal cavity. In other examples the trigeminal nucleus caudalis Wide dynamic range neurons. administration is directed to the inferior tWo-thirds of the FIG. 4A shoWs a baseline response before administration nasal cavity and is directed aWay from the olfactory region. With octreotide. FIG. 4B shoWs responses 5 minutes after [0025] Provided herein are methods for treating an indi octreotide administration. FIG. 4C shoWs responses 10 min vidual for trigeminal nerve-associated pain, comprising: utes after octreotide administration. FIG. 4D shoWs responses administering to the individual an effective amount of an 25 minutes after octreotide administration. FIG. 4E shoWs the analgesic agent Wherein the administration is targeted to the approximate site (black spot) of administration on the rat’s trigeminal nerve system and results predominantly in anal ge face of the electrical administration sia to the facial or head region, particularly as compared to [0031] FIG. 5 depicts the effect of intranasal administration analgesic effects in otherparts of the body. In some examples, of octreotide on electrical stimulus-induced Windup. FIG. 5A administration of an analgesic agent or a composition com shoWs the approximate site (black spot) of administration on prising an analgesic agent results in reduction of a pain rating the rat’s face of the electrical administration. FIG. 5B shoWs on the VAS of 30% or more. In other examples, administra responses before (solid squares) and 10 minutes after (open tion of an analgesic agent or a composition comprising an triangles) an intranasal administration of octreotide. FIGS. analgesic agent results in reduction of a pain rating on the 5C and 5D shoW the responses to the 1S’ and 15th stimuli VAS of 50% or more. before octreotide administration. FIGS. 5E and SF shoW the [0026] Provided are kits for carrying out any of the methods responses to the 1S’ and 15th stimuli 10 minutes after oct described herein. Kits are provided for use in treatment of reotide administration. trigeminal nerve-associated pain. Kits of the invention may comprise at least one analgesic agent in suitable packaging. DETAILED DESCRIPTION OF THE INVENTION Kits may further comprise a vasoconstrictor, at least one protease inhibitor, and/or at least one absorption enhancer. [0032] Described herein are methods for treating an indi Kits may further comprise a delivery device, including but not vidual for trigeminal nerve-associated pain. In general, the limited to, a device for intranasal administration. Kits may methods are based on the ?nding that molecules can travel further comprise instructions providing information to the along perineural pathWays to the trigeminal nerve and to the user and/or health care provider for carrying out any of the brain. Without Wishing to be bound by theory, it is believed methods described herein. that analgesic agents can be targeted to the trigeminal nerve system and that administration of the agents can result in BRIEF DESCRIPTION OF THE DRAWINGS analgesia and pain relief to an individual suffering acute, chronic or procedural facial or head pain. Furthermore, it is [0027] FIG. 1 depicts data demonstrating WithdraWal laten believed that targeted drug delivery to the trigeminal nerve cies after noxious thermal stimulation to the ears or hindpaWs system can limit systemic distribution of an analgesic agent in a rat model after intranasal administration of met-enkepha Which may decrease or eliminate undesirable central nervous lin. Panel A shoWs baseline and treated WithdraWal latencies system (CNS) effects or systemic side effects. In particular, it US 2011/0250212 A1 Oct. 13, 2011

is believed that higher concentrations of an analgesic agent at [0039] As used herein, “analgesia agent”, “analgesic a targeted site Will alloW for administration of loWer dosages agent” or “analgesic” refers to any biomolecule that alleviates of the analgesic agent to the individual. or prevents pain. [0033] The methods described herein involve administra [0040] As used here, “analgesic peptide” refers to any pep tion of a variety of different analgesic agents to a individual tide molecule that alleviates or prevents pain. for treatment of trigeminal nerve-associated pain. In general, [0041] As used herein, “” refers to a peptide the methods can administer to the trigeminal nerve an anal having a binding moiety and the capacity to gesic agent for prevention or treatment of facial or head pain. bind to an opioid receptor. An opioid peptide can be a natu Administration of analgesic agents targeted for a predomi rally occurring endogenous peptide, fragments, analogues or nantly regional analgesic effect can result in prevention or derivatives thereof. An opioid peptide can also be a non alleviation of pain Without numbness as compared to local endogenous peptide, fragments, analogues or derivatives anesthetics. Since the trigeminal nerve transmits most of the thereof. sensory signals of the face and head, administration of anal [0042] As used herein, “analogues and derivatives” refers gesic agents targeted to the trigeminal nerve can localiZe the to any peptide analogous to naturally occurring opioid pep analgesic effect to the face and head region, particularly as tides Wherein one or more amino acids Within the peptide compared to analgesic effects in other parts of the body. have been substituted, deleted, or inserted. The term also [0034] Targeted delivery can decrease the amount of agent refers to any peptide Wherein one or more amino acids have administered to an individual to achieve an analgesic effect, been modi?ed, for example by chemical modi?cation. In general, the term covers all Which bind to an opioid and can decrease the undesirable CNS effects or systemic side effects of many analgesic agents. More effective or ef?cient receptor and exhibit an opioid activity but Which may, if delivery of an analgesic agent to the trigeminal nerve can desired, have a different potency or pharmacological pro?le. decrease the total dose of an agent administered to a subject [0043] As used herein, “acute pain” refers to sudden, severe suffering from trigeminal nerve-associated pain. Effective pain from a speci?c cause (injury, infection, in?ammation, targeted delivery of an analgesic agent to the trigeminal nerve etc) that lasts a limited period of time (as opposed to chronic can decrease the systemic distribution of the agent Wherein pain). As used herein “chronic pain” refers to a persistent state CNS effects or systemic side effects are minimiZed or elimi of pain Whereby the cause of the pain cannot be easily nated. removed. Chronic pain is often associated With long-term incurable or intractable medical conditions or diseases. As [0035] In some aspects of the invention are included meth used herein “procedural pain” refers to pain arising from a ods for treating an individual for trigeminal nerve-associated medical, dental or surgical procedure Wherein the procedure pain comprising administering to the individual an analgesic is usually planned or associated With acute trauma. agent Wherein the administration is targeted to the trigeminal [0044] As used herein “systemic side effects” include, but nerve system and results predominantly in analgesia to the are not limited to, cardiovascular including peripheral vasodi facial or head region. In some examples, the analgesic agent can be a peptide, in particular an opioid peptide. The opioid lation, reduced peripheral resistance, and inhibition of peptide can be selected from a group comprising enkephalins, baroreceptors; dermatologic including pruritus (itching), ?ushing and red eyes; gastrointestinal including nausea and endorphins, ot-, dynorphins, endomorphins, vomiting, decreased gastric motility in stomach, decreased casomorphins, , , oxytocin and ana biliary, pancreatic and intestinal secretions and delays in food logues and derivatives thereof. In some examples, the peptide digestion in small intestine, diminished peristaltic Waves in can be targeted to opioid receptors on the trigeminal nerves. large intestine contributing to constipation, epigastric distress In other examples, more than one opioid peptide can be or biliary colic in biliary tract; respiratory including administered. In some examples, the analgesic agent can be a depressed respiratory rate; and urinary including urinary non-peptide, such as an amino acid, a polypeptide, an opiate, urgency and dif?culty With urination, and peripheral limb or a small molecule compound. heaviness. [0045] As used herein, “central nervous system effects” or DEFINITIONS “CNS effects” include, but are not limited to, narcosis, eupho ria, droWsiness, apathy, psychotic ideation, mental confusion, [0036] As used herein, unless otherWise speci?ed, the term alteration in mood, reduction in body temperature, feelings of “treatment” or “treating pain” refers to administration to an relaxation, dysphoria (an emotional state characteriZed by individual an agent of interest Wherein the agent alleviates or anxiety, depression, or unease), nausea and vomiting (caused prevents a pathology for Which the subject is being treated. by direct stimulation of chemoreceptors in the medulla). Treatment for trigeminal nerve-associated pain refers to the [0046] As used herein, “mucosal administration” or alleviation or prevention of trigeminal nerve-associated pain. “administered transmucosally” refers to delivery to the [0037] As used herein, “central nervous system” or “CNS” mucosal surfaces of the nose, nasal passageWays, nasal cav refers to that part of the nervous system that consists of the ity; the mucosal surfaces of the oral cavity including the brain and spinal cord. The CNS is one of the tWo major gingiva (gums), the ?oor of the oral cavity, the cheeks, the divisions of the nervous system. The other is the peripheral lips, the tongue, the teeth; and the mucosal surfaces of or nervous system Which is outside of the brain and spinal cord around the eye including the conjunctiva, the lacrimal gland, and includes the cranial nervesiof Which the trigeminal the nasolacrimal ducts, the mucosa of the upper or loWer nerve is a member. eyelid and the eye. [0038] Although analgesia in the strictest sense is an [0047] As used herein, “intranasal administration” or absence of pain, as used herein, “analgesia” refers to reduc “administered intranasally” refers to delivery to the nose, tion in the intensity of the pain perceived by an individual nasal passageWays or nasal cavity by spray, drops, poWder, Without causing general numbness. gel, inhalant or other means. US 2011/0250212 A1 Oct. 13, 2011

[0048] The nasal cavity contains turbinate bones Which mammals as Well as in loWer animals. Examples of opioid protrude in to the nasal cavity and generally separate it into include, but are not limited to, codeine, , three regions. As used herein, the “inferior tWo-thirds of the oxycodone, loperimide, meperidine (Demerol), diphenoxy nasal cavity” refers to the portion of the nasal cavity Where the late, propoxyphene (Darvon), fentanyl, 4-methyl fentanyl, middle and inferior turbinate bones protrude and is the region hydrocodone, morphine, diacetylmorphine, , of the nasal cavity that is innervated by the trigeminal nerve hydromorphone (Dilaudid), , (Levo system. The superior third of the nasal cavity is de?ned by the Dromoran), , (Numorphan), superior turbinate bone Wherein the olfactory region is , , (Torbugesic), , located. , , , (Subox [0049] As used herein, “transdermal administration” or one), , , and the atypical opi “dermal administration” refers to delivery to the skin of the ates, and . face, neck, scalp or combinations thereof. [0056] Naturally occurring endogenous opioid peptides [0050] As used herein, “pharmaceutically acceptable car can generally be referred to as “endorphins” (endogenous rier” or “suitable carrier” refers to a carrier that is convention ) and include, but are not limited to, beta-endor ally used in the art to facilitate the storage, administration, phin, endomorphins, enkephalins, dynorphins, deltorphins, and/ or the healing effect of the agent. casomorphins, dermorphin and oxytocin. [0051] As used herein, “therapeutically effective dose”, [0057] Analgesic activity may be mediated by opiate recep “therapeutically effective amount” or “an effective amount” tors found Within the central nervous system and on periph refers to an amount of an analgesic agent that is useful for eral neurons throughout the body. Opioid peptides bind to the treating pain. same opiate receptors as opioid drugs. Both endog [0052] As used herein, “visual analogue scale” (VAS) enous peptide opioids and narcotic morphine-like analgesics refers to a commonly used scale in pain assessment. It is a 10 can alter the central release of neurotransmitters from afferent cm horizontal or vertical line With Word anchors at each end, nerves sensitive to noxious, i.e. painful, stimuli. After binding such as “no pain” and “pain as bad as it could be”. A subject With a receptor, opioid drugs or peptides may act to initiate or or patient is asked to make a mark on the line to represent pain block various biochemical and physiological sequences. intensity. This mark is converted to distance in either centi [0058] Several major categories of opioid receptors are meters or millimeters from the “no pain” anchor to give a pain knoWn: mu ([1), kappa (K), delta (6), and epsilon (e). In gen score that can range from 0-10 cm or 0-100 mm. The VAS eral, mu-receptors mediate analgesia, euphoria, respiratory may refer to an 11 point numerical pain rating scale Wherein and physical depression, miosis, and reduced G1 motility, 0 equals “no pain” and 10 equals the “Worst pain imaginable”. delta-receptors mediate analgesia, dysphoria, psychotomi [0053] It should be noted that, as used herein, the singular metic and respiratory effects and kappa-receptors mediate form “a”, “an”, and “the” includes plural references unless analgesia, sedation, miosis, respiratory depression and dys indicated otherWise. Additionally, as used herein, the term phoria. There is a differential distribution of these opiate “comprising” and its cognates are used in their inclusive receptors on nerves throughout the CNS and the peripheral sense; that is, equivalent to the term “including” and its cor neural system. In particular, mu and delta opioid receptors are responding cognates. found on the nociceptors in the trigeminal nerve but not on the olfactory nerve ?bers Within the nasal cavity. The differential Analgesic Agents distribution of opioid receptors can alloW for targeted admin [0054] Many different classes of molecules are potentially istration of opioid peptides to receptors Within the trigeminal useful for targeted administration to the trigeminal nerve nerve While delivery to the olfactory nerve and the brain is system for the treatment of pain. Certain molecular and bio minimized. logical characteristics make some therapeutic agents particu [0059] The peptides for use in the herein described methods larly unattractive for systemic administration and good can can be natural or synthetic, therapeutically or prophylacti didates for targeted delivery by transdermal and/or cally active, peptide fragments, peptide analogues, and transmucosal administration. One characteristic is poor bio chemically modi?ed derivatives or salts of active peptides. A availability of some systemically applied molecules and their variety of peptide analogues and derivatives are available and lack of ability to reach the target of choice, i.e. the trigeminal others can be contemplated for use Within the invention and nerve system. A second characteristic is the short half-life of can be produced and tested for biological activity according some molecules in the systemic circulation and the resulting to knoWn methods. Peptides for use Within the invention can lack of bioavailability at the desired target, i.e. trigeminal be peptides that are obtainable by partial substitution, addi nerve system. Brief half-lives are generally due to rapid deg tion, or deletion of amino acids Within a naturally occurring or radation of the molecule by enZymes, rapid uptake and tum native peptide sequence. Peptides can be chemically modi over in the kidney and/or liver, or excretion via the lung. ?ed, for example, by amidation of the carboxyl terminus Targeted delivery by transdermal and/ or transmucosal admin (iNRZ), the use of D amino acids in the peptide, incorpora istration can bypass some of these problems. HoWever, tar tion of small non-peptidyl moieties, as Well as the modi?ca geted delivery is not limited to molecules With these charac tion of the amino acids themselves (e.g. alkylation or esteri teristics, rather, these characteristics alloW targeted delivery ?cation of side chain R-groups). Such analogues, derivatives to the trigeminal nerve system, and limit the usefulness of the and fragments should substantially retain or enhance the compounds through other (e.g., systemic) routes of adminis desired biological activity of the native peptide. tration. [0060] All peptides described and/or contemplated herein [0055] Opioids are one of the classes of analgesic drugs can be prepared by chemical synthesis using either automated commonly used for treatment of moderate to severe pain. or manual solid phase synthetic technologies, generally These compounds include both plant-derived and synthetic knoWn in the art. The peptides can also be prepared recom alkaloids and also include endogenous peptides found in binantly, using techniques knoWn in the art. US 2011/0250212 A1 Oct. 13, 2011

[0061] A list of peptides is included in Table I, however one [0065] Endomorphins are amidated tetrapeptides and are skilled in the art Would know this list is not complete and one structurally unrelated to the other endogenous opioid pep could contemplate and produce additional peptides, ana tides. TWo peptides, -l and endomorphin-2 have logues and derivatives. Enkephalin Was isolated from mam been isolated from mammalian brain. Both peptides have malian brains and found to be a mixture of tWo pentapeptides similar characteristics including analgesia against heat Which differ only in the amino acid present at the 5-position. stimuli, mechanical stimuli and in?ammatory and neuro The tWo pentapeptides are methionine enkephalin (also pathic pain. (Zadina et al. (1997) Nature 386:499-502; Hack ler et al. (1997) Peptides 18:1635-1639) knoWn as met-enk or met-enkephalin) and leucine enkephalin [0066] peptides are novel opioid peptides (also knoWn as leu-enk or leu-enkephalin). Met-enkephalin derived from casein. Beta-casomorphins are the more exten has an amino acid sequence of Tyr-Gly-Gly-Phe-Met and sively studied opioid peptides arising from the proteolytic leu-enkephalin has an amino acid sequence of Tyr-Gly-Gly breakdoWn of food proteins. The [3-casomorphin peptide, Phe-Leu Wherein the Tyr, Met and Leu residues are all Tyr-Pro-Phe-Pro-Gly-Pro-Ile Was originally isolated from L-amino acids. The tyrosine moiety is important for activity bovine beta-casein, and subsequently peptides With the same and probably corresponds to the 3-hydroxyl group on the sequence Were identi?ed originating from ovine and buffalo morphine molecule. A is the precursor for beta-caseins. A human beta-casomorphin has been identi?ed met-enkephalin, leu-enkephalin and several other larger pep and has tWo amino acid differences from the bovine sequence, tides. The structure of proenkephalin A contains four copies Tyr-Pro-Phe-Val-Glu-Pro-Ile. Several other casomorphin of met-enkephalin and one copy of leu-enkephalin, along peptides have been isolated including [3-casomorphin 1-3, With a heptapeptide (met-enk-Arg-Phe) and an octapeptide [3-casomorphin 1-4, [3-casomorphin 1-5 and [3-casomorphin (met-enk-Arg-Gly-Leu). A series of peptides containing met 1-8. enkephalin at the N-terminus also possess opioid activity, and [0067] Dermorphin is a seven amino acid peptide, origi include peptide F and peptide E. Peptide F contains tWo nally isolated from Phylomedusa sauvagei frog skin. It is a met-enkephalin sequences one at each end, While peptide E ligand Which binds With high a?inity to the mu opioid recep contains met-enkephalin at the N-terminus and leu-enkepha tor and has many biological roles including analgesia, endo lin at the C-terminus. crine modulation, immunomodulation, increased K+ conduc [0062] In addition to naturally occurring enkephalins, tance and inhibition of action potentials. enkephalin analogues and derivatives are knoWn in the art, [0068] Oxytocin is a nine amino acid cyclic peptide hor including, for example, derivatives and analogues Which are mone that is released from the posterior lobe of the pituitary speci?c for different types of opiate receptors. (Hruby and gland and stimulates the contraction of smooth muscle of the Gehrig (1 989) Medicinal Research Reviews 91343-401). Fur uterus during labor and facilitates release of milk from the thermore, enkephalin peptides can be modi?ed by replace breast during nursing. Studies have shoWn that oxytocin can ment and/or modi?cation of speci?c amino acids, as it is also play an important role in nociceptive modulation. The knoWn in the art that these modi?cations decrease the rate of mu receptors as Well as oxytocin receptors appear to be the hydrolysis and degradation of enkephalins by proteases. predominant receptor bound by oxytocin and that they both [0063] [3-endorphin is a 31-amino acid peptide formed are involved in oxytocin’s physiological effects. (Wang et al. from a larger precursor, pro-opiomelanocortin. [3-endorphin (2003) Regal. Pepi, 115:153-159; ZubrZycka et al. (2005) contains a tetrapeptide sequence (Tyr-Gly-Gly-Phe) Which is Brain Res. 1035:67-72). common to the enkephalin peptides and this tetrapeptide [0069] Accordingly, in some aspects of the invention, the sequence appears to be essential to the function of these analgesic agent can be an opioid peptide selected from the peptides. ot-endorphin is a 16-amino acid peptide that is also group comprising leu-enkephalin, met-enkephalin, met-enk formed from precursor pro-opiomelanocortin. Arg-Phe, met-enk-Arg-Gly-Leu, peptide E, peptide F, [3-en [0064] Dynorphins are another class of endogenous opio ids that exist in multiple forms in the central nervous system. dorphin, ot-endorphin, A1-17, , beta Dynorphins derive from precursor (proen , ot-neoendorphin, dynorphin A1-8, dynorphin kephalin B). Dynorphin, also knoWn as Dynorphin A1-17, is A 1-13, endomorphin-l, endomorphin-2, [3-casomorphin, a Well-knoWn opioid peptide that has the sequence Tyr-Gly [3-casomorphin 1-3, [3-casomorphin 1-4, [3-casomorphin 1-5, Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys-Leu-Lys-Trp-Asp [3-casomorphin 1-8, dermorphin, I, deltorphin II, Asn-Gln. Smaller peptides such as dynorphinA1-8 and three dermenkephalin, , oxytocin and analogues and leu-enkephalins are also contained Within proenkephalin B derivatives thereof. In some examples more than one peptide and are abundant in the neural lobe of the pituitary gland. is administered. In other examples, an opioid peptide is DynorphinA1-13 has been found in the striatonigral pathWay administered in combination With a second agent. In some and may provide a feedback mechanism for regulating examples, the opioid peptide is administered in combination dopaminergic activity in the striatum. With more than one additional agent.

TABLE I

Name Amino Acid Sequence

Leu-enkephalin Tyr-Gly-Gly-Phe-Leu SEQ ID NO: 1

Met-enkephalin Tyr-Gly-Gly-Phe-Met SEQ ID NO: 2

Peptide F SEQ ID NO: 3

Met US 2011/0250212 A1 Oct. 13, 2011

TABLE I — cont inued

Name Amino Acid Sequence

[5-endorphin (human) Thr-Pro-Leu-Val—Thr—Leu-Phe—Lys-Asn-Ala-Ile GenBank Ile-Lys-Asn-Ala-Tyr-Lys—Lys—G1y-Glu 764134 ot-endorphin Tyr-Gly-Gly-Phe-Met—Thr—Ser-G1u—Ser-Gln-Thr- SEQ ID NO: 5 Pro-Leu-Val-Thr-NH2

Dynorphin A Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys SEQ ID NO: 6 Leu-Lys-Trp-Asp-Asn-Gln

Dynorphin B Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Gln-Phe-Lys-Val- SEQ ID NO: 7 Val-Thr ot-neoendorphin Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro-Lys SEQ ID NO: 8

[5-neoendorphin Tyr-Gly-Gly-Phe-Leu-Arg-Lys-Tyr-Pro SEQ ID NO: 9

Dynorphin Al-8 Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile SEQ ID NO: 10

Dynorphin Al Tyr-Gly-Gly-Phe-Leu-Arg-Arg-Ile-Arg-Pro-Lys- SEQ ID NO: 11 l3 Leu-Lys

Endomorphin-l Tyr-Pro-Trp-Phe-NH2 SEQ ID NO: 12

Endomorphin-2 Tyr-Pro-Phe-Phe-NH2 SEQ ID NO: 13

Dermorphin Tyr- (D)Ala-Phe-Gly-Tyr-Pro-Ser-NH2 SEQ ID NO: 14

[5-casomorphin Tyr-Pro-Phe-Pro-Gly-Pro-Ile SEQ ID NO: 15 (bovine)

[5-casomorphin Tyr-Pro-Phe-Val-Glu-Pro-Ile SEQ ID NO: 16 (human)

[5-Casomorphin Tyr-Pro-Phe SEQ ID NO: 17 l-3

[5-Casomorphin Tyr-Pro-Phe-Pro SEQ ID NO: 18 l-4

[5-Casomorphin Tyr-Pro-Phe-Pro-NH2 SEQ ID NO: 19 l-4, amide

[5-casomorphin Tyr-Pro-Phe-Pro-Gly SEQ ID NO: 20 l-5

[5-Casomorphin Tyr-Pro-Phe-Pro-Gly-Pro-Ile-Pro SEQ ID NO: 21

Deltorphin I Tyr- (D)Ala—Phe-Asp-Val—Val—Gly-NH2 SEQ ID NO: 22

Deltorphin II Tyr- (D)Ala—Phe—G1u—Va1—Val—Gly-NH2 SEQ ID NO: 23

Dermenkephalin Tyr- (D) Met—Phe-His—Leu-Met-Asp-NH2 SEQ ID NO: 24

Dermorphin Tyr- (D)Ala-Phe-Gly-Tyr-Pro-Ser SEQ ID NO: 25

Morphiceptin Tyr-Pro-Phe-Pro-NH2 SEQ ID NO: 26

Oxytocin Cys-Tyr-Ile-Gln-Asn-Cys—Pro—Leu-G1y SEQ ID NO: 27

[0070] Other analgesic or potentially analgesic agents can , peptidergic receptor antagonists, amino acid recep include opioids, amino acids, non-opioid peptides, polypep tor agonists, N-methyl-D-aspartate receptor blockers, nico tides, non-peptidic compounds and small molecule com tinic agonists, non-steroidal anti-in?ammatory drugs pounds. These agents may have an analgesic effect by inter (NSAIDs), steroid anti-in?ammatory drugs, ion channel acting With opiate receptors, non-opiate receptors and/ or ion blockers, antidepressants, anti-seizure medications, antibod channels. These agents can include, but are not limited to, ies directed toWard proalgesic antigens and antibodies peptidergic channel modulators, peptidergic enzyme inhibi directed to other neuropeptides. Channel modulators may tors, analgesic enzymes, trophic factors, peptidergic receptor include snail toxins, such as omega-conotoxin MVHA, and US 2011/0250212 A1 Oct. 13, 2011

their derivatives, saxitoxin and tetrodotoxin. Enzyme inhibi polypeptide, a non-peptidic compound or a small molecule tors may include cyclosporin A, bestatin, bestatin analogue compound. In some examples, tWo agents are administered in Z4212 (N-[(2S,3R)-3-Amino-2-hydroxy-4-(4-3. methylsul combination. In other examples, more than tWo agents are phonyl-phenyl)-1 -oxobutyl]-1-aminocyclopentanecarboxy administered in combination. The agents may be adminis lic) and bestatin analogue Z 1796 ((2S)iN-[(2S,3R)-3 tered at the same time or may be administered at different Amino -2 -hydroxy-4-(4 -methylsulphonyl-phenyl)- 1 - times. oxobutyl]-L-leucine). Analgesic enzymes may include endothelin-1 peptidase. Trophic factors may include glial Administration derived neurotrophic factor (GDNF) and brain-derived neu rotrophic factor (BDNF). Peptidergic receptor agonists may [0072] Chronic, acute or procedural pain associated With include somatostatin and its synthetic analogue octreotide, the trigeminal nerve system is experienced in many syn nocistatin, galanin and neuropeptide Y. Peptidergic receptor dromes and diseases including, but not limited to, trigeminal antagonists may include calcitonin gene-related peptide neuralgia, atypical facial pain, anesthesia dolorosa, post-her receptor antagonist CGRP(8-37), cholecystokinin (CCK) petic neuralgia, cancer of the head and neck, migraine head receptor antagonists such as Tyr-(D)Phe-Gly-(D)Trp aches, other types of headaches, temporomandibular joint NMeNle-Asp-Phe-NH2 or PD134308, neurokinin-l receptor pain, injuries to the face and/or head, injuries or infections of (substance P receptor) antagonists such as spantide II ((D) the teeth, common dental procedures and facial surgeries NicLysl, 3-Pal3, D-Cl2Phe5, Asn6, D-Trp7.9, Nle11-sub such as cosmetic plastic surgery. It is believed that analgesic stance P), vasoactive intestinal peptide (VIP) receptor antago agents can be targeted to the trigeminal nerve system and that nists such as (Ac-Try1, D-Phe2)-GRF-(1-29) (Where GRF is this directed administration can result in analgesia and pain groWth hormone releasing factor) and galanin receptor relief for a individual suffering acute, chronic or procedural antagonists such as RWJ-57408). Amino acid receptor ago facial or head pain. nists may include gamma-amino butyric acid (GABA) and [0073] The trigeminal nerve (?fth cranial nerve or CN V) is glycine. N-methyl-D-asparate (NMDA) receptor blockers the largest of the 12 cranial nerves and it is the principal may include and dextromethorphan. Anti-seizure general sensory nerve to the head, particularly the face and is medications that decrease pain may include gabapentin, lam the motor nerve to the muscles of mastication. The trigeminal otrigine, tiagabine, topiramate, , oxcarba nerve innervates tissues of a mammal’s (e.g. human) head Zepine, clonaZepam, valproic acid, and phenyloin. Nicotinic including skin of the face and scalp, oral tissues and tissues of agonists may include nicotine and . Typical and and surrounding the eye. The trigeminal nerve has three major atypical non-steroidal anti-in?ammatory drugs may include branches or divisions: the ophthalmic, the maxillary, and the , acetaminophen, choline and magnesium salicylates, mandibular divisions. Thus, some aspects of the present choline salicylate, , potassium, invention include methods for treating an individual for diclofenac sodium, diclofenac sodium With misoprostol, trigeminal nerve-associated pain comprising administering di?unisal, , calcium, ?urbiprofen, ibu to the individual an analgesic agent Wherein the administra profen, indomethacin, , , magnesium tion of the analgesic agent is targeted to one or more of the salicylate, meclofenamate sodium, , meloxi three major branches of the trigeminal nerve including the cam, , , naproxen sodium, , ophthalmic, maxillary, and mandibular divisions. , , , , , [0074] The ophthalmic division is the superior division of sodium, . Steroid anti-in?ammatory the trigeminal nerve, it is the smallest of the three branches drugs may include predni sone and dexamethasone. Ion chan and is Wholly sensory. The ophthalmic nerve has three nel blockers may include selective blockers of TrpV1 , TrpV2, branches knoWn as the nasociliary nerve, the frontal nerve, Nav1.3, Nav1.7, Nav1.8, Nav1.9 andASICs (acid sensing ion and the lacrimal nerve Which participate in the sensory supply channels), as Well as P, Q, and N type calcium channels, such to the skin of the forehead, upper eyelid and nose. The naso as , and non-speci?c sodium channel blockers, ciliary nerve further divides into the anterior ethmoidal nerve such as , lidocaine, , mepivacaine, prilo and the infratrochlear nerve, While the frontal nerve divides calne, bupivacaine and eidocaine. Antidepressants may into the supratrochlear and supraorbital nerves. The supratro include amitriptyline, nortryptiline, , paroxetine, chlear nerve supplies the middle part of the forehead, and the citralopram, venlafaxine, clomipramine, and bupropion. supraorbital nerve supplies the lateral part and the front of the Antibodies directed toWard proalgesic antigens may include scalp. The lacrimal nerve, supplies the lacrimal gland and the antibodies to endothelin, nerve groWth factor, vasoactive lateral part of the upper eyelid. Thus, in some aspects, meth intestinal peptide (VIP) and pituitary adenylate cyclase-acti ods of the invention involve administration of an analgesic vating polypeptide (PACAP). Antibodies directed toWard agent to the one or more of the nerves branching from the other neuropeptides may include antibodies to CGRP, CCK, ophthalmic nerve including the nasociliary nerve, frontal substance P and galanin. Other compounds may include, but nerve, lacrimal nerve, anterior ethmoidal nerve, infratro are not limited to, SNC 80, DPI-125, clonidine, dexmedeto chlear nerve, supratrochlear nerve and supraorbital nerve. midine, calcitonin, baclofen, d-cycloserine, ergotamine, [0075] The maxillary division is the intermediate division serotonin agonists and 5HT drugs. One skilled in the art of the trigeminal nerve. It has three cutaneous branches: the Would knoW this list is not complete and it is believed that one infraorbital nerve Which participates in the sensory supply to could contemplate and produce additional peptides, polypep the skin on the lateral aspect of the nose, upper lip, and loWer tides, non-peptidic compounds, small molecule compounds, eyelid; the Zygomaticofacial nerve, Which supplies the skin of analogues and derivatives thereof Which have analgesic prop the face over the Zygomatic bone; and the Zygomaticotempo erties. ral nerve Which supplies the skin over the temporal region. [0071] Accordingly, in some aspects of the invention, the Thus, in some aspects, methods of the invention involve analgesic agent is an amino acid, a non-opioid peptide, a administration of an analgesic agent to the one or more of the US 2011/0250212 A1 Oct. 13, 2011

nerves branching from the maxillary nerve including infraor that are involved in pain (nociception) are termed “nocicep bital, Zygomaticofacial and Zygomaticotemporal. tors”. In contrast, there are no nociceptors or other soma [0076] The mandibular division is the inferior division of tosensory primary afferents in the olfactory nerve Which is the trigeminal nerve. It has three sensory branches: the buccal essentially devoted to the sense of smell and pheromone nerve supplies the skin of the cheek over the buccinator detection. The anterior ethmoidal nerve, a branch of the naso muscle. It also supplies the mucous membrane lining of the ciliary nerve, innervates, among other tissues, the ethmoidal cheek and the posterior part of the buccal surface of the sinus and regions of the inferior tWo-thirds of the nasal gingiva (gum). The auriculotemporal nerve supplies parts of mucosa, including the anterior portion of the nasal septum the auricle, the external acoustic meatus, the tympanic mem and the lateral Wall of the nasal cavity. The maxillary division brane (eardrum) and the skin in the temporal region. The has several branches that innervate the nasal cavity and inferior alveolar nerve further divides into the incisive nerve sinuses, including the nasopalatine nerve, the greater palatine and the mental nerve. The incisive nerve supplies the incisor nerve, the posterior superior alveolar nerves, the middle supe teeth, the adjacent gingiva, and the mucosa of the loWer lip rior alveolar nerve and the anterior superior alveolar nerve. and the mental nerve supplies the skin of the chin, the skin and The maxillary sinus is innervated by the posterior, middle and mucosa membrane of the loWer lip and gingiva. The lingual anterior superior alveolar nerves. The mucous membrane of nerve supplies general sensory ?bers to the anterior tWo thirds of the tongue, the ?oor of the mouth, and the gingiva of the nasal septum is supplied chie?y by the nasopalatine nerve the mandibular teeth. Thus, in some aspects, methods of the and the lateral Wall of the nasal cavity is supplied by the invention involve administration of an analgesic agent to one greater palatine nerve. or more of the nerves branching from the mandibular nerve [0079] Accordingly, some aspects of the invention include including buccal, auriculotemporal, inferior alveolar, inci methods for treating an individual for trigeminal nerve-asso sive, mental and lingual. ciated pain comprising administering to the individual an [0077] Accordingly, some aspects of the invention include analgesic agent to mucosa tissue Within the nasal cavity. In methods for treating an individual for trigeminal nerve-asso some examples, the methods include administration of an ciated pain comprising administering to the individual an analgesic agent to the inferior tWo-thirds of the nasal cavity analgesic agent to mucosa tissue or epithelium Within the oral Wherein the analgesic agent is targeted to mucosal tissue cavity, Within or around the eye or to the skin. The methods innervated by the trigeminal nerve and aWay from the olfac can include administering an agent to oral tissues Wherein the tory nerve. In some examples, the methods include adminis analgesic agent is targeted to mucosal tissue innervated by a tration of an analgesic agent to the inferior tWo-thirds of the trigeminal division, for example the mandibular division. The nasal cavity Wherein the analgesic agent preferentially binds oral mucosal tissues include, but are not limited to, the gin to opioid receptors Within the trigeminal nerves. In some giva (gums), the ?oor of the oral cavity, the cheeks, the lips, examples, the methods also include administration of an anal the tongue, the teeth or a combination thereof. The methods gesic agent to the inferior tWo-thirds of the nasal cavity can include administering an agent to conjunctiva or other Wherein the analgesic agent preferentially binds to non mucosal tissues around the eye Wherein the analgesic agent is opioid receptors Within the trigeminal nerve system. Thus, in targeted to mucosal tissue or epithelium innervated by a some aspects of the invention, methods involve administra trigeminal division, for example the ophthalmic or maxillary tion of an analgesic agent to one or more of the nerves branch division. The tissues or epithelium include, but are not limited ing from the maxillary division that innervate the nasal cavity to, the conjunctiva, the lacrimal gland, the nasolacrimal ducts, including nasopalatine, greater palatine, posterior superior the mucosa of the upper or loWer eyelid, the eye, or a combi alveolar, middle superior alveolar and anterior superior nation thereof. An agent that is administered to the conjunc alveolar. tiva but not absorbed completely through the conjunctival [0080] Intranasal drug delivery has been a topic of research mucosa can drain through the nasolacrimal ducts into the and development for many years, although it has been only nose Wherein it can be absorbed by mucosal tissue innervated Within the past decade that carrier systems have been devised by the trigeminal nerve Within the nasal cavity. The methods Which make delivery of substances effective. (Sayani and can include administering an agent to skin of the face or head Chien (1996) Critical Reviews in Therapeutic Drug Carrier Wherein the analgesic agent is targeted to tissue innervated by Systems, 13185-184.) one of the trigeminal divisions. The agent can be administered [0081] Intranasal delivery of analgesic agents has a number to the skin of the face, scalp or temporal region. Suitable skin of advantageous features including comparatively high bio of the face includes skin of the chin, the upper lip, the loWer availability, rapid kinetics of absorption and avoidance of lip, the forehead, the nose, the cheek, the skin around the eyes, liver ?rst-pass effect. In regard to patient compliance and ease the upper eyelid, the loWer eyelid or combinations thereof. of use, intranasal administration provides a simple, rapid and Suitable skin of the scalp includes the front of the scalp, the non-invasive mode of application. In particular, intranasal scalp over the temporal region, the lateral part of the scalp, or delivery can alloW for targeted delivery of an analgesic agent combinations thereof. Suitable skin of the temporal region to the nasal cavity and to the trigeminal nerve system to treat includes the temple and the scalp over the temporal region and or prevent trigeminal nerve-associated pain. Furthermore, combinations thereof. targeted delivery to the trigeminal nerve system and prefer [0078] Within the nasal cavity, the trigeminal nerve inner ably not the olfactory region can reduce the amount of drug vates mainly the inferior tWo-thirds of the nasal mucosa, entering the CNS or systemic circulation thereby reducing or While the olfactory nerve innervates the superior upper third eliminating CNS effects or systemic side effects. Targeted of the nasal mucosa. There are primary afferent somotosen delivery to the trigeminal nerve system can reduce the effec sory neuronal ?bers in the trigeminal nerve Which alloWs for tive dosage necessary to achieve analgesia in the facial or craniofacial somatosensory information including touch, head regions Wherein loWer effective dosages Will further temperature, proprioception (position sense) and pain. Those reduce CNS or systemic side effects. US 2011/0250212 A1 Oct. 13, 2011

[0082] Accordingly, some aspects of the present invention vated by any one of the trigeminal divisions or a combination include methods for treating an individual for trigeminal thereof to treat or prevent trigeminal nerve-associated pain in nerve-associated pain comprising administering to the indi the facial or head regions. vidual an analgesic agent by intranasal administration [0088] Accordingly, some aspects of the present invention Wherein the administration is targeted to the trigeminal nerve include methods for treating an individual for trigeminal system and results predominantly in analgesia to the facial or nerve-associated pain comprising administering to the indi head region, particularly as compared to analgesic effects in vidual an effective amount of an analgesic agent to the skin of other parts of the body. The methods can administer an anal the face, head or scalp Wherein the administration is targeted gesic agent to the nasal cavity of an individual, in particular to to the trigeminal nerve system and results predominantly in the inferior tWo-thirds of the nasal cavity, to promote delivery analgesia to the facial or head region. In some examples, the to the trigeminal nerve system With minimal delivery to the analgesic agent is administered to particular sites on the face olfactory nerve. or scalp to promote delivery to particular trigeminal divisions. [0089] In some aspects of the invention a vasoconstrictor is [0083] Within the oral cavity, the buccal or sublingual used to decrease systemic distribution of the analgesic agent. delivery routes are convenient choices for drug delivery as The vasoconstrictor can be included in a pharmaceutical com they are user-friendly and non-invasive. Some of the advan position to decrease systemic distribution of the analgesic tages include i) less proteolytic activity in the oral cavity as agent. Alternatively, the vasoconstrictor may be delivered to compared to some other routes thereby avoiding the problems the mucosal or dermal surface separately from the pharma of enzymatic degradation of peptide and protein drugs and ii) ceutical composition. Vasoconstrictors are compounds that bypassing the liver ?rst pass effect. In particular, buccal or constrict blood vessels and capillaries and decrease blood sublingual delivery can alloW for targeted delivery of an anal How. They can be used to increase concentration of an agent gesic agent to the oral mucosa and to the trigeminal divisions at a desired site by inhibiting movement of the analgesic agent that innervate the oral mucosa to treat or prevent trigeminal nerve-associated pain. Targeted delivery to a trigeminal divi into the bloodstream and thereby reducing systemic distribu tion of the agent Vasoconstrictors can be used to decrease the sion can reduce the effective dosage necessary to achieve effective dosage of agent needed to achieve analgesia by analgesia in the facial or head regions Wherein loWer effective limiting systemic distribution and concentrating the agent in dosages Will further reduce CNS effects or systemic side the trigeminal nerve. A vasoconstrictor can be administered effects. before administration of the analgesic agent or can be co [0084] Accordingly, some aspects of the present invention administered With the analgesic agent. Vasoconstrictors may include methods for treating an individual for trigeminal include, but are not limited to, phenylephrine hydrochloride, nerve-associated pain comprising administering to the indi tetrahydroZoline hydrochloride, naphaZoline nitrate, vidual an analgesic agent by buccal or sublingual administra oxymetaZoline hydrochloride, tramaZoline hydrochloride, tion Wherein the administration is targeted to a trigeminal endothelin-1, endothelin-2, epinephrine, norepinephrine and division and results predominantly in analgesia to the facial or angiotensin. head region. The methods involve administration of an anal [0090] In some examples of the invention, methods involve gesic agent to the oral cavity of an individual to promote administration of a vasoconstrictor to the oral cavity of an delivery to the trigeminal nerve With minimal systemic dis individual prior to administration of an analgesic agent to the tribution. oral cavity, Wherein administration of the vasoconstrictor [0085] Drug delivery to the mucosal tissue around the eye decreases systemic distribution of the analgesic agent thereby or to the conjunctiva is another convenient choice for drug minimiZing undesirable CNS effects or systemic side effects. delivery that is non-invasive. In particular, administration to In other examples, methods involve administration of a vaso the mucosa or epithelium of the eyelids, the conjunctiva or the constrictor and an analgesic agent to the oral cavity of an lacrimal system can alloW for targeted delivery of an analge individual. A vasoconstrictor may be administered to the oral sic agent to the mucosa and tissues innervated by trigeminal cavity of an individual prior to or at the same time as an divisions to treat or prevent trigeminal nerve-associated pain. analgesic agent, Wherein administration of the vasoconstric Targeted delivery to a trigeminal division can reduce the tor decreases systemic distribution of the analgesic agent effective dosage necessary to achieve analgesia in the facial thereby decreasing the effective dosage amount of analgesic or head regions Wherein loWer effective dosages Will further agent necessary to achieve analgesia to the facial or head reduce CNS effects or systemic side effects. region. [0086] Accordingly, some aspects of the present invention [0091] In some examples of the invention, methods involve include methods for treating an individual for trigeminal administration of a vasoconstrictor to the nasal cavity of an nerve-associated pain comprising administering to the indi individual prior to administration of an analgesic agent to the vidual an effective amount of an analgesic agent to the con nasal cavity, Wherein administration of the vasoconstrictor junctiva or other mucosal tissues around the eye Wherein the decreases systemic distribution of the analgesic agent thereby administration is targeted to a trigeminal division and results minimiZing undesirable CNS effects or systemic side effects. predominantly in analgesia to the facial or head region. The methods can co -administer a vasoconstrictor and an anal [0087] Transdermal drug delivery or administration of a gesic agent to the nasal cavity of an individual, Wherein therapeutic agent to the skin has become a proven technology administration of the vasoconstrictor decreases systemic dis over the last 20 years. Transdermal drug delivery offers con tribution of the analgesic agent thereby minimiZing undesir trolled release of a drug to the patient and transdermal patches able CNS or systemic side effects. The methods can admin are user-friendly, convenient, painless, and offer multi-day ister a vasoconstrictor to the nasal cavity of an individual prior do sing Which usually results in improved patient compliance. to or co-administer With an analgesic agent, Wherein admin Administration to the skin by transdermal delivery can alloW istration of the vasoconstrictor decreases systemic distribu for targeted delivery of an analgesic agent to the skin inner tion of the analgesic agent thereby decreasing the effective