AU2015255185A1 - Topical regional neuro-affective therapy - Google Patents

Abstract

A method of treating a disease state or condition in humans via topical brainstem afferent stimulation therapy via the administration of a drug to the back of the neck of a human patient at the hairline in close proximity to and under or on the area of skin above the brain stem to provide regional neuro-affective therapy is disclosed

Description

TOPICAL REGIONAL NEURO-AFFECTIVE THERAPY FIELD OF THE INVENTION [00011 The invention relates to topical regional neuro-affective therapy ("TRNA THERAPY") for the treatment of neuronal hyperexcitability and neurochemical dvsanction syndromes. This is accomplished via administration of effective amounts of these agents at the back of the neck at the hairline ("BONATH") BACKGROUND OF THE INVENTION 100021 The approximate 2 pound haman brain is comprised ofthe most complex material known to man, The neuron, the primary functional cell of the nervous system, operates on the basis of electrical impulses that result in the release of neurochenical substances (neurotransmitters) at specific receptors: dopamine serotonin acetycholne, norepinephrine. gammaamino btyic acid (GABA), and many others. There are estimated to be 80 100 billion (10 times the world population) neurons in the average human brain. These neurons, in tuin, make 200-300 billion coded connections with other neurons to accomplish the complex tasks of the human body t00031 The brainstem serves as the vital pathway for relay aQd processing of neural impulses flowing continuously between the brain and therest of the body. It is about the size of the thumb and contains the most dense and conltplicated wiring systems in the human body, hi addition to the axons and dendrites (wirs) that carry nerve impulses,; the brainstem also contains critical nuclei thit function as electrical generators and relays Sone of the nuclei are related to cranial nerv himctionwhile others serve as generators and impulse centers for pain perception,the autonomic system "fight or flight" response, wakefulness and alertness, as well as cardiac -respiratory and related autonoinic functions. 10004f in the prior art, there have been previous atteinpts to provide for a more efficacious and safe treatment using serotonin agonists specific for the 5HT I receptor subtype. 100051 For Example, U.S. Patent No, 5,863,935 to Robertson et al. describes certain compounds having "51T1-like" receptor agonist properties and their administration in a number of ways, including topical or intranasal application. f00061 Additionally. USatent No, 5,805,571 to List, describes a transdernal therapeutic system for the systemic administration of active substances wherein at least one of the active substances listed is a serotonin agonist of the group comprising indole derivatives; Typically, transdermal systems are not used in acute situations because they do not provide a immediate effect, but rather provide prophylaxis or prolonged CfTect through their stistained delivery process. Thansdenral systems such as that described in the 4571 patent to List require a period of time for the drug to pass through a barrier layer and onto/into the skin (ionophoresis throu gh concentrations gradients)which may take e g.a substantial period of time until the dose of drug that is absorbed is sufcient to alleviate the pain associated with the headache. These previously described transdemnal systems require the operation of a concentration gradient for the absorption of topically applied drug to enter the blodstream through the small blood vessels in the skin and soft tissues. After entry into the systemic circulation in sufficient quantity to establish a therapeutic level, drug is eventually delivered by the cerebral blood flow to the target sites. Accordingly, this process involves relative considerable time, not amenable for the acute relief of symptoms.a Frtheruaore, itis influenced by such factors as cardiac output and cerebrovascular disease that influence blood flow and tissue absorption 2 100071 The inventor has previously described the delhverv of animgan daa(s. tdiptans and ergot alkaloids) and muscle relaxants (e.g. Czanidine) through topical regional neuroaffective (TRNA) therapy by topical application (e g., as a cream/gel or a sustained release patch) applied at the back of the neck at the hairline (BONATH). The author has demonstrated the efficacy of this route of delivery for the treatment of igraine. another brainstem disorder, using sumatriptan andiianidin e compounded in an appropriate dernal penetration enhancing mediumi. [0108] The inventor's previous US, Patent Publication No, 20030013753 (filed June 5, 2002) and U.S. Patent Publication No. 20080090894 both of which are hereby incorporated by reference, disdose a unit dose of a topical fornulation for treating a migraine or cluster headache comprising a serotonin agonist incorporated into a phamnaceutically acceptable vehicle for topical administration onto the skin of a human patient. Preferably, uhenit dose providing the serotonin agonist is in a form that is immediately absorbable when said unit dose is applied onto human skin, Preferably, the serotonin agonist composes from about 0;5 to about 200 nug of sumatriptan, by weight based on the succinate salt, or a therapeutic equivalent dose of another topically absorbable pharmaceutically acceptable serotonin agonist. Preferably, the unit dose provides relief from a migraine or cluster headache within about 2 hours after topical administration to a human patient. {0009} The inventor's previous U.S. Patent Publication No. 20070065463 (filed June 21, 2004) discloses a topical frmmlation for treating migraines or cluster headachesmuscle sprains, muscle spasms, spasticity, tension headaches, tension related migraines and related conditions associated with muscle tension and pain comprising: a thrapeutikally effective amount of an active agent(s) incorporated into a pharmaceutically acceptable excipient for topical administration onto the skin of a human patient, the active agent(s) being selected from the group consisting of ) an ergot alkaloid; ii) a skeletal muscle relaxant: or ii) a combination of an ergot alkaloid and a skeletal muscle relaxant the active agent(s) being present in an effective concentration such that a unit dose of the 3 epical fermulation provides a therapeutic effect within about 2 hours after topical administration to the human patient, In certain preferred embodiments, the topical formulation comprises a skeletal muscle relaxat such as tizanidine, In certain preferred embodiments, the unit dose co prises from about 0,4 meg to 8 mng, preferably from about 02 mg go about 4 mg of tizanidine hydrochloride. n0010] bi instances where humans suffer from conditions involving neuronal hyperexcitability and/or a neurochemical dysfuction syndrome(s), adequate treatment is not generally available. Such conditions include headache including migraine, cluster, tension-type headache and the related menstrual conditions of menstrual migraine. In fact, other such conditions melude, but are not limited to, pain, anxiety reactions, panic attacks, seizures of both epileptic and nonepileptic (psychogenic) varieties; and acute head and face pain, syndromes such as trigeminal neuralgia, atypical facial pain occipital neuralgia,TMJ related pain, hot flashes, menstrual associated dysphoria, Multiple Sclerosis, and Parkinson's Dsease and similar or related syndromes, 100111 For example, Parkinson's disease is a common, debilitating, neurological condjtion of unknown cause, There is no known cure and treatment is directed at reducing symptoms It is considered the -result of a progressive degenerative process within the central nervous system (CNIS) A significant reduction in brain levels of the neuro-chemical dopamine is the hallmark characteristic of the disease process, Other brain chemicals are also affected, Pathological studies indicate death and loss of dopamine producing cells within the substsantia nigra of the brainstem, Loss of cells in the caudate and putaiMen (the striatun) which rAy on dopamine connections froni substantia iigra, the ascending nigra-striatal dopaminergic pathway also occurs, The resultant cardinal clinical signs of Parlinson's disease are, tremor, postural instability, bradykinesia/rigidity. Depression, autonomic dysimntion and memory disturbancecognitive problems are also common. Parkinson's disease is the third most common out-patient neurological diagnosis after headaches and seizures. 4 [001 2] The mainstay treatment of Parkinson's disease is aimed at normalizing the reduced central dopamnine levels Tis is accomplished by either providing exogenous levodopa orally for eventual conversion into dopamine in the brain r the use of dopamine agonists to augment the endogenous dopamine. COMT inhibitors are also used in the therapeutic regimen to reduce the breakdown of dopamine, allowing for higher and more persistent Ivels at the receptors, The problem with these traditional therapies is that they are unable to provide the stable doparine levels at the receptors which occur in the natural state, The fluctuations in dopamine levels resuh in fluctuations in clinical function: so called "on and off states. They also affect doparine receptor sensitivity in the long term such that "motor complic atins" and dyskinesias may occur after several years of therapy. This is particularly true with exogenous dopamine therapy and in patients diagnosed in their younger years. [001-1 Patients with end-f-iose wearing off phenomena, the most significant of which is "freezing, where one is essentially paralyzed and unable to move are significantly affected in their activities f0rm the sudden episodic dopamine deficiency at the receptor level j00141 Apomorphine hydrochloride (Apokyn by Veralis, which was recently acquired by Ipsen Pharmaceuticals) is given as subcutaneous injections to counter such "off period". It has also been administered via intraepritoneal infusion. The drug is reported to take effect within 1045 minutes and last for up to 1% hours This allows a patient to engage in pre-panned activities that would otherwise not have been pursued-going out to dinner, etc, The resultant sense of control over one's disease and associated reduced anxiety for such affected patients is inmeasurable: Apolkyn is marketed for use in the treatment of "acute, intermittent treatment of hylponobility; otT episodes (end-of-dose wearing off and unpredictable on/of episodes) associated with advanced Parkinson's disease'" 51 100151 Unfortunately, as an injection, Apokyn has not been a preferred form of treatment despite its efficacy, it is also associated with a relative high cost (approximately $10() for a 3md cartridge) not affordable for routine use by most patients, it involves a titration phase for tolerability and efficacy determination (2mg or ,2n to 6mg or 0,6mi) with a nurse at a doctor's office, further contributing to cost and time, Finally, Apokyn is associated with signi Icant nausea and voniting to the extent patients are required to take an anti-emetic (trimethobenzamide/Tigan 200-300mg 3x/day) for 3 days prior to the first injection and encouraged to continue the regimen for an additional 6 weeks. Despite using Tigan, a significant number of patients still experience nausea. and vomiting-3 1% and 11% respectively in reported clinical trials. Other anti-emetics with anti dopaminergic actions are contraindicated as they may worsen the symptoms of Parkinson's, Further, the requirement of medications to counter side-effects contributes to additional drug-drug interactions, Parkinson's patients are generally already on a significant degree of "poly-pharnacy 100161 The significant nausea and vomiting associated with aponorphine in f.raI and injectible f iss likely the result of its direct effect on the "chenoreceptor zone" of the area postrena in the floor of the Ith ventricle adjacent to the brainster Other conuonly reported adverse events in clinical trials also indicate stimulation of other brainstem structures, including the autonomic nervous system, by the apotnorphine in the cerebral blood dzziness yawning, sormnolence, rhinorrhea, sweating, flushing, pallor, hallucinations, edema, and chest pain 100171 Thus, in spite of its effectiveness and potential to improve the lives of persons affected by Parkinson's disease, for the above noted reasons, the use of injectible apomorp tine has been limited, Orat forms have not been pursued as they are even less well tolerated as the dose requirements are high. Intra-peritoneal and intravenous injections are impractical 100I81: Apomorphine hydrochloride is a non-ergoline dopamine agonist that is lipophilic and soluble in water at 80 degrees Celsius, In vitro tests show it has a high affinity for the 6 D4 dopamine receptor and moderate fbr the D2, D3, and D$ receptors, It also has moderate affinity for some alpha-adrenergic receptors, t has a low affinity for the dopamine DI and serotoniA receptorsAlthough the precise mechanism of action of apomorphine is unknown, it is believed to work through the stinuhation of post-synaptic dopamine D2 receptors in the striatun, the caudate and putamen, 10019} The significant nausea and vomiting associated with apomorphine in oral and injectible forms is likely the result of its direct effect on the chemoreceptorr zone" of the area postrema in the floor of the Pith ventricle adjacent to the brainstem. Other commonly reported adverse events in einical trials also indicate stimulation of other brainsten structures, including the auonoric nervous system, by the apomorphine in the cerebral blood: dizziness; yawning somnolence .rhinorhm 'eating, flushing pallor, hallucinations, edema, and chest pain. [0020] For the above reasons, despite its efficacy and potential to improve the lives of persons affected by Parkinson's disease, the use of injectible apororphine has been limited. Orl forms have not been pursued as they are even less well tolerated as dose requirements are high. hntra-peritoneal and intravenous injections are impracical but have been pursued. Intra-peritoneal apomorphine via continuous infusion pump (such as for insuini) is used in Europe' SUMMARY OF THE INVENTION [09211 R is an object of die present invention to provide a method of treatment in humans with topical brainstem deafferentation therapy via the regional administration of a compound useful for the treatment of such diseases or conditions that may be treated via such therapy. [00221 It is an object of the present invention to provide a method for the treatment of neuaonal hyperexcitability and neurochemical dysfinctionssyndromes including but not -7 limited to pain, anxiety reactions, panic attacks, seizures of both epileptic and non epileptic (psychogenic) varieties;. and acute bead and face pain syndromes such as trigeminal neuralgia, atypical facial pain, occipital neuralgia, TMJ related pain, hot flashes, menstrual associated dysphoria, Multiple Sciemis, and Parkinson's Disease and similar or related syndromes 1131it msa object of the invention to Provide a topical fhrulato t of a dopalunine agonist(s) usefl in the treatment of Parkinsons disease and/or related syndromnes/diseases. f0024) It is a further object of the invention to provide a method of treatment of Parkinson's disease and related syndromes/diseases via the topical administration of one or more dopamine agonists, 100251 It is a Anther object of the invention to provide a topical formulation of a dopamine agonist(s) useful in the treatment of Parkinson's disease and/or related syndromes/diseases. [00261It is a Airther object of the invention to provide a method of treatment of impotence with erectile dysfunction in men via the topical administration of one or more dopamine agonists, f00271 It is a flurthe object of the, present invenltionl to providea method for the treatment of neuronal hyiperexcitabdity and neurochemical dysfunction syndromes in humans suffering from Parkinson's disease and/or related syndromes/diseases via topical brainstem afferent stimulation therapy via the regional administration of a compound useful for the treatment of such diseases or conditions that may be treated via such therapy 100281 It is a father object of the present invention to provide a method of treatment of impotence/erectile dysfunction in men and/or related syndromes/diseases via topical 8 brainstern afferent stinulation therapy via the regional administration of a compound usedI for the treatment of such diseases or conditions that may be treated via such therapy 0029] The above objects and others are attained by virtue of the present invention, which is directed in part to a method of treating a disease state or condition in humans via transdermal regin al neuro-affective (TRNA) or regional neuro-affective (RNA) therapy viaadinistration of a. drug at the back of the neck at the hairline (BONATH). The drug is seleted from, eg, an antiiePeppuc. an uxiolytic, a neuroleptic an anti-psychotic an analgesc an anti-inflarnmatory, an antiPPakinson's disease/syndome drug, a sexual dysfunction drug, a drug for the treatment of dystonia, a drug for the treatment of spastic conditions, a drug for the treatment of benign essential/fanilial tremor, a drug for the treatment of tremor related to MS, a drug for the treatment of chronic encepahalopathies, a drug for the treatment of congenital CNS degeneration conditions/cerebrpalsy, a drug for the treatment of cerebellar degeneration syndromes, a drug for the treatment of neuropathic and/or neurogenic pain a drug for smoking cessation, a drug for appette suppression, a drug for neurodegenerative conditions, a drug for the treatment of multiple serosis, a drug for the treatment of insonmia,a drug for the treatment of fatigue, a drug for the treatment of vertigonaiea and/or diziness, a dug thr the treatment of' writers cramp and restless leg syndrome, a drug for the treatment of ADD/ADHD, and other dnugs which an beneficially be administered at the back of the neck at the hairline in close proximity to and under or on the area of skin above the brain stem to provide regional neuroaffective therapy to the pattit 10301 The invention is also directed to a topical formulation, comprising a drug selec ed fom an ant epleptican anxiolytic, a neuroleptic., an antiqpsychotic, an analgesic§ an anti-inflammatory, an anti-Parkinson's disea/syndrome drug, a sexual dysfunction drug, a &ug for the treatment of dystonia, a drug for the treatment of spastic conditions, a drug for the treatment of benign essential/familial tremor, a drug for the treatment of tremor related to MS, a drug for the treatment of chronic encepahalopathies, a drug for the treatment of congenital CNS degenerauon conditions/cerebral palsy, a drug for the 9 treatment oficereheiar degeneration syndromes, a drug for th.e treatment of neuropathic and/or neurogenic pain, a drug for smoking cessation, a drug for appetite suppression, a drug for neurodegenerative conditions,A drug for the treatment of multiple sclerosis, a drug for the treatment of insomnia, a drug for the treatment of fatigue, a drug for the treatment of vertigo, nausea and/or dizziness, a drg for the treatment of writer's crrnp and restless leg syndrome, a drug for the treatment of ADD/ADHD and combinations of any of the foregoing, in a formulation suitable for administration at the the back of the neck at the hairline in close pronxiity to andm uder or on the area of skin above the brain stem of a human patient to provide regional neuroaffective therapy to the patient. The topical formulation may be prepared as an immediate, controlled or sustained release formulation. 1031) The drug formulations useful in the present invention may be in a foni selected from a topical fornuaitn (eig, a crean, ointment or gel); a transdennal device; or an irnpliantable or injectable formulation. 00321 The inventmn is further directed to the use of a drug selected from the group consisting of anti-epileptic, an anxiolytic, a neur& leptic, an anti-psychotic, an analgesic, an antiinflammatory, an antiParkinson's disease/syndrome drug, a sexual dysfunction drug, a drug for the treatment of dystonia, a drug for the treatment of spastic conditions, a drug for the treatment of benign essential/faimilial tremor, a drug for the treatment of tremor related to MS, a drug for the treatment of chronic encepahalopathies, a drug for the treatment of congenital CNS degeneration conditions/cerebral palsy, a drug for the treatment of cerebellar degeneration syndromes, a drug for the treatment of neuropathic and/or neurogenic pain, a drug for smoking cessation, a drug for appetite suppression, a drug for neurodegenerative conditions, a drug for the treatment of nltiple sclerosis, a drug for the treatment of insomnia, a drug for the treatment of fatigue, a drug for the treatment of vertigo, nausea and/or dizziness, a drug for the treatment of writer's cramp and restless leg syndrome a drug for the treatment of ADD/ADHD, in the preparation of a medicament for providing regional neuro-affective therapy to human patient, wherein the drug is administered at the back of the neck at the hairline in close pr ximiity to and t under or on the area of skin above the brain stem to provide regional neuro-affective therapy to the patient, 100-3 In certain embodiments, the drug is applied to the posterior cervical region of the human in order to effect the brainstem afferent stimulation therapy; Most preerably, the topical formulation or transdernal therapeuic system is applied to the back of the neck; preferably in close proximity to or on the area of skin above the brain stem. (00341 In other embodiments the drug is admistered via implantation or injection at the ack of the neck at the hairline (BONATH) in such embodiments, the therapy is accomplished via the availability of the drugs) at the free nerve endings under the epidermis, I such embodiments, the drug may be incorporaed into an implantation device or may be incorporated into a carier such as a gel or manix that will provide a prolonged release/effect of the dopamine agonist at the site The carrier may be a hydrophilic or hydrophobic material colloidal material, and may be in a state ranging from a viscous liquid to a solid polymeric insert. [0035] Certain embodiments of the invention are directed to a method of treatment, comprising deliverig a drug(s) through regional neuro-at5ective therapy by application as a cream/gel or a sustained release patch applied at the back of the neck at the hairline (BONATT), or via administration under the skin at the BONATH via an implantable or injectable drug formulation or device, 10tt361 In certain embodiments, themethod frther provides for a tIheirapeuticoally effective treatment through transdermal regional neuro-affective (TRNA) therapy by application of a drug(s) as a cream/gel or a sustained release patch applied at the back of the nteck at the bardine(BONATH) without the side-effects and the other drnwbacks of the current injection method. [00371 In certain embodiments, the drug is a dopamine agonist such as apomorphine (Apokyn@, APO-go@). pram ipexole (Mirapexin@) ropinirole (Requip@) bromocriptine 11 (Parioded@), cabergoline (Cabaser@, Dostinex@), pergolide (Permax@, Celance@) rotigotine (Neupro@), mixtures of any f the foregoing, or otter dopamine agonists known to those skilled in the art. 100381 In other embodime nts, the drag is onodsuch as morphine, co-de" dihydrocodeine, hydrocodone , hydromorphone ncomorphine, oxycodone, oxymorphone, fntanyl, alphamethylfentany , alfentanil , sufentanil, remifentanil carfentanyl ohmefentanyl. thebaine, oripavi ne diacetymnorphine (heroin), phenylpiperidines such as pethidine (meperidine) and ketobemidone, .allylprodine prodine, propoxyphene , dextropropoxyphene, dextromoraiide, bezitrarnide, piritramide, methadone, dipipanone, levomethadyl Acetate (LAAM), loperamnide, diphenoxylat, dozocine, pentazocine, phenazocine, buprenorphine , dihydroetorphine etorphine , butorphanol. nalbuphine, levorphanol, evomethorpham, lefetamine, meptazinol, tilidiae, tranadol, taentadol, mixtures thereof; and the like. 14O39)in yet other embodiments, the drug isTarpentadol (a centrally acting oral analgesic having two mechanisms of action combining muopioid receptor agonism and norepinephrine reuptake inhiblion) [O4j Alternatively, the drug is an opioid antagonist, for example, naloxone natrexone nalmefene, or mixtures thereof 01041] in yet other embodiments, the drg is a selective norepinephrine reuptake inhibitor such as Atomoxetine (Strattera@), Mazindl{Mazanore, Sanorex@) Nisoxetine (LY-94939), Reboxetine (Edronax@, Vestra@), Viloxazine ('Vivala&@), mixtures hlereof, and the like. 1100421 In yet otter .odiments, the drg is a benzodiazepine, such as lorazeparn (Aivan@), diazepam (Valium@), elonazepam (KIonopin@), chlordiazepoxide (Librium@) aprazolam (XanaxT), mixtures thereof, and the like, In other embodinients, the drug is a neuroleptic or psychotropic such as chlorpromazine (Thorazine®), 12 haloperidol (Hnadol@) rspeidone (Risperdai@), oanzapine (Zyprexa@) and quetiapine (Seroque@). [00431 In yet other embodiments, the drug is a norepinephrine-dopamine reuptake inhibitor (NDR), such as Amineptine (Survectcr@). Bupropion (Wellbutrin@ Zyban®), Dexmethylphenidate (Focahi), Methyiphenidate (Ritalin. ConcertaO Nomifenine (Merital@V mixtures there and the ike [00441 In yet other embodiments, the drug is a serotonin-norepinephrine reuptake inhibitor (SNl), such as Desvenlafaxine (Pristiq. u oxetine (Cymbaa) Miinacipran (btel@, Saveha@), Venlafaxine (Etfexox®.mixtures thereof; and the like, 100451 I1yet other embodiments, the drug is a tricydic antidepressant (NCA), such as Antriptyline (Iavii@), Butriptyline (Evadene@t Evadyne®\ Clomipramine (Anaf-ranil@), Desipramine (Norpramin@P, Pertofrane,), Dosulepin (Prothiade®), Doxepin (dapdine, Sinequan@) linipramine (Torranil®) Loepramine (Feprapax, Gamanil@, Lomont@), Nortriptyline (Aventyl®, Nortrilen®, Pamelor@), Protriptyuine (Vivactib@) Trimipramine (Surmonti@). mixtures thereof, and the like, [0046] In yet other embodiments, the drug is a tetracyclic antidepressant, such as Amgxapine (AsendinV), Maprotifine (Ludiomil@), Mianserin (Tolvon®), mixtures theref, and the like, 0(47] In yet other embodiments, the drug is an atypical antipsychot, such as Ziprasidone (Geodon@, ZeldoxO), Nefazodone (Serzone@), and the like, [0048] In yet other embodiments, the drug is an anti-epileptic drug such as Valproic acid (Depacon@Depakotett Leviteracetem (Keppra), Lamotrigene (Lanietal®), Topiramate (Topamax®X Pregabalin (Lyrica@), Gabapentin 13 (Neurontin®),Carbamazepine (Tegreto@), Oxcarbazepine (Trilepta@), Phenobarbital and other barbiturates, Tiagabine (Gabatri @) RetigabineM(Valeant Pharmaccutials) LacosamidcTM (Schwarz Biosciences), and Peramnpanelr (Eiisai) are in development as anti-epileptics and neuromodulators fbr other associated neurological, pain, and psychiatric conditions, and thus are further examples of potentially useful drugs in the present inventiott j0049J in yet ether embodiments, the drug is an analgesic/antinflammatory agent such as acetaminophen; prednisone, solumedrol, and other steroids; naproxen, aspirin, voltaren ketoprofen, ibuprofen, and other NSAID's, 10A501 in yet other embodiments, the drug is an appetite suppressant such as Sibutramine(Meridia@, ieducti I@), which is a centrally acting serotonin-norepinephrine reuptake inhibitor that is structural related to amphetamines but having a distinct rCmchanism of action, Other potentially useful drugs for anti-obesity include Rimonabant (Acormplia), substances related to amphetamine such as phentemine and/or e rine andor dexfenflane, (the combination popularly referred to phen fen) may also be useful in the treatments of the present invention. It is believed that the present method of treatment would avoid the potential heart value damage found with these combinations when administered orally (PO05I For purposes of the present invention, a "topical fbomulation" includes, for exam pie, ointments creams, lotions, pastes, gels, etc, which releases one or more drugs (e.g., dopamine agonists) at a predetermined rate over a defied period of time to a defined site of application. [00521 For purposes of the present invention, an "injectable"fruiation includes, for example, an injectable solution, suspension, get or the like and may be in immediate release form or may provide a controlled or sustained release of the drug at the site of administration. 14 0053J For purposes of the present invention, an "implantable" formulation includes, for example; a solid, semisolid or liquid drug fonnulation which can be administered at the site of adminiNtraion (eBg, 3ONATH) either via injection and/or via surgical implantation. The solid may comprise microspheresmicrocapsules, pellets, discs, and the like, The implantable fonnulations of the inventon nay provide a controlled or sustained release of the drug at the site of administration [00541 For purposes of the present invention, a "tansdennal therpeutic systems defined as a drug-containing device (including e g patch, disc, etc.) which releases One or more drugs at a predetermined rate over a defined period of time to a defined site of application. [00551 For purposes of the present invention transdermal" delivery is the delivery by passage of a drug through the skin and into the bloodstream ('traditional" transdermal delivery) and is termaed ctransdermal systemic drug delivery (TSD therapy). {0056] For purposes of the present invention, the term "topical transdermal therapy" is synonomrnous with the more accurately termed topical regional neuro-affeetive therapy (or "TRNA therapy"), This term describes important aspects of this delivery method: topical, regional (near brainstem and cervical spinal cord), and affecting the free nerve endings of the afferent nervous svsten 100571 For purposes of the present invention "therapeutically effective" or "effective" amount is mcant to be a nontoxic hut sufficient amount of a compound to provide the desired therapeutic effect, e.g, avoidance of the onset of a mignaine and or increased alleviation of the migraine and/or cluster headache. In the present case, for example, it is the dose of serotonin agonist that will be effective in relieving symptoms of the migraine or cluster headache. An "effective" amount of a permeation enhancer as used herein, for example, means an amount that will provide the desired increase in skin permeability and, correspondingly, the desired depth of penetration, rate of administration, and amount of drug to be delivered. 15 [0058I For purposes of the present invention, the term "delivers" when used with respect to the topical formulation or transdermal therapeutic system means that the fommuation or system provides a mean relative release rate or flux of the drug out of the fornilation or system and thrngh th skin of the patent. [00591 -By "predetermined area of skin" is intended a defined area of intact unbroken living skin. In certain embodiments of the present invention, the predetermined area will be ni the range of about I em2 to about 100 c 2, preferably in the range of about 10 cm2 to about 100 cm2,more preferably in the range of about 20 m2 to about 60 cm2, However, it will be appreviated by those skilled in the art of topical delivery that the area of skin through which drug is administered nay vary significantly, depending on the formulation, dose, the app ication of the formulation, and the like, [00601 "Penetration enhancement" or "permeation enhancement" for purposes of the present invention relates to an increase in the permeability of skin to a pharmacologically active agent ie so as to increase the rate at which the drug permeates through the skin and enters the bloodstream The enhanced permeation effected through the use of such enhancers can be observed by measuring the rate of diffusion of drug through animal or human skin using a diffusion cell apparatus. [00611 For purposes of the present invention, the "brainstem afferent stimulation therapy rgiui" is defined as the skin region of the head and/or At thle fbontotentporaI region and/or upper posterior cervical area. In certain preferred embodinents, the treatment area is the post cervical area in close proximity to the brain stem, Preferably this area is a relatively haidless area of the patient's head and/or neck. [0062J For purposes of the present invention, the drug may be in the form of the base or may be provided as a pharmaceutical acceptable salt (inorganic or orrganic) or complex It may be in an opticaly pure form or a mixture of stereoisomers 16 DETAILED DESCRIPTION 004j3 An important aspect of the benefits of "TRNA" or "RNA" BONATH" therapy in CNS drug delivery for brainstem related disorders ies in the anatomy of the region The free nerve endings with receptors for the neuro-chemaicals dopamine, serotonin, norepinephrine. and others are located just below the surface of the skin, easily assessable to drugs compounded in an appropriate dernal penetration enhancing medium and topically appfled to the skin {00641 An important component of the brainstem autonomic nervous system is the "flight or fight" (sympathetic) response responsible for protecting an individual from danger. Programmed to act "automatically" without time-consuning thought, it results in physiological and emotional manifestations reflective of either fleeing from or fighting/confronting perceived danger. Often, the difference between the two is not clearly delineated, as in most situations, the response is mixed. 100651 Norepinephrine (noradrenaline) and serotonin are considered the principal neuro transmitters involved with the sympathetic autonomc sys t em "fight or flight" response, Dopamine and acetylcholine (primarily affects the parasympathetic system) also play roles The collections of neuronal nuclei responsible for the production of these neurotransmitters reside in the brainsten. The locus ceme us contains neurons which produce norepinephrine, the dosal raphe is responsible for serotonin production, and the substantial nigra, for dopamine. Acetylcholine is produced in a more widespread fashion. 100661 It is now widely accepted that mood disorders are related to dysregulation of neurornmitters-Ybrain chemical imbalance ".Drug therapies are directed at "re establishing neurochemical balance" in the brain through the use of serotonin re-uptake inhibitors (SSRI s) and serotonin and norepinephrine re-uptake inhibitors (SNRPs). Although these drugs are effective, they take several weeks to months to show significant benefit, Furthermore, their clinical effect is most pronounced for the chronic symptoms 17 related to depression and anxiety. They are ineffective or less effective than desired for the episodic acute symptoms of anxiety reactions and panic attacks which commonly accompany these chronic conditions, To this end, acute treatment for break-through episodes has been in the form of oral or injectible anxiolytics, depending on severity of symptoms: Commonly used drugs are the benzodiazepines: lorazepam (Ativan), diazepam (Valium), clonazepami (Klonopin) chiordiazepoxide (Librium), and alprazolam (Xanax), For particularly severe symptoms, neuroleptics and psychotropls may also be used: chlorpromazine (Thorazine).halperidol (Haldol) risperidone (Risperdal) olanzapine (Zyprexa) and quetiapine Seroquel). 100671 Oral and injectible anxiolytics and neuroieptcs/psychtropics must rely on systemic blood (and therefore, blood levels) for eventual effect on the brain, This is associated with undesirable systemic side-effects, particularly fatigue and lethargy acutely post-dose. With chronic use, psychological dependency, tardive dyskinesia, Parkinsonisrm, obesity, and insulin resistance may be encountered, With oral preparations, there is delay(/2 to several hours) before significant cynical effect. In some situations, this degree of delay is unacceptable as profound clinical deconmpensation may result. An example is a panic attack in a predisposed individual that leads to a psychoic breakdown or a non-epiieptic/psychogenic seizure. The clinical consequence for such an affected individual is significant There is also the additional financial expense of an emergency room visit or hospitalization. [00681 Mood changes with symptoms of anxiousness, sadness, and elation are part of the human experience. These normal emotions of life become problematic when they become severe, persistent, and interfere with functional abilityIt is at this point that medical intervention needs to be considered. Whether one gets to the point of requiring medical therapy is dependent on several factors, One is the innate nature of the person's make-up how they are "wired and programmed" to deal with the issues of life. Somoe of this relates to family history, growth and development pre and post-natally (intra-utedne insult and birth trauma) and one's basic emotional and philosophical outlook, The external factors consist of stressors impinging on the individual: relational, physical (illness and disability), financial, work-related, etc, In this regard, it is not just the degree of stress that is important but also the length of time associated Certain life events are universaly stressful for all individuals: death of a loved one, divorce losing a job, Still, how these events specifically impact an individual depends on one's coping mechanisms and the specifies of the event for that individual [00691 Psychologists have devised a "life crisis unit" sCle (LCUTs for enotionally significant life stress events The scale ranges from 0 to 100, with the more emotionally significant events in the higher range, it has been determined that ifan individual accumulates 250-300 points over a relatively short period, 3-4 months, they are at risk for a nervous breakdown and/or significant physical illness. Accordingly, individuals at risk from innate make-up are particularly prone to decompensation when such external stress etonts come in to their lives. These are the people who experience frequent panic attacks and emotional breakdowns. Their lives are significantly disrupted and they may become emotionally disabled. 100701 These individuals require prompt recognition with the institution of kadsy appropriate therapy. Untreated, they are prone to the phenomenon of pervasive dysfunction from persistent neuronal hyperexitabilityfdysfunction, This, in turm may result in re-programming of neural circuits with accompanying permanent psychological and behavioral changes This progression of events is akin to the process of "kindling" Which occurs in epileptic conditions: untreated or inadequately treated seizure foci spread to other areas of the brain and become increasingly resistant to therapy The new foci of neuronal hyperxexcitability may be adjacent to the original or cross over the corpus ealiosurn as a "mirror focus". 100711 A similar phenomenon occurs in migraine, a condition with increased propensity to neuronal hyper-excitability in the brainstern with peripheral and cortical sensitivity to triggers, If treatment is rendered late or inadequately> there is a greater likelihood for more severe and persistent symptoms, In this regard, yoig migraneurs also need to be identified early and treated to reduce life-long disability from chronic, severe migraines 19 [00721 The "fight or flight" sympathetic system response, interpreted as stress, is in the nost basic sense, a fear- based reaction; fear of the uncertainty related to significant life stress events. The experienced fear may be real or perceived but the effect is the same perceived danger as the individual's sense of control and stability is threatened. Interestingly, as the LCU scale suggests the more emotional significant the event the more likely it results in a stress reaction. Even "positive' stress Cob promotion with increased responsibilities) may have negative effects similar to the negative event of being fred from ajob, In this respect "stress" may be defied -as any change that significantly alters ones status quo and questions the individuals sense of security and stability physically, emotionaly, or relationally, 7 As thesympathetic nervous system serves to protect the individual, it is easy to understand that it is also intimately involved with pain perception in addition to the psychological response.n fact, the two systems go hand-in-hand: the more severe the perceived pain, the greater the emotional toll arnd likelihood for depression; and vice versa, a depressed individual perceives pain more acutely than one who is not it is also recognized that "emotional" pain (heartbreak) disrupts brainstem function and more significantly affects the individual than physical pain such as that associated with a heart attack or a broken ann. The emotions of fear, betrayal, and abandonment may be attached to the former. The neuro-transmitters norepinephrine and serotonin have both been recognized to play significant roles in the human psychological and pain response- Drugs which modulate, increase, and balance the levels of these two brain chemicals have been approved for both mood and pain syndromes, 100741 The SNIR1s duloxitine (Cynbata@) and venlafaxine (Effexor@), as well as the older tricyclic antidepresants, such as anytriptilene (Elavil@), have shown benefit for depression and for neuropathic pain, with or without associated mood dysfunction, 100751 There have also recently come on the scene, drugs in die category of neuro modulators" which treat neurochemical imbalance and dysfunction syndromes indirectly 20 Gabapentin (Neurontin®) and pregabalin (Lrica@) are specific caium channel modulators which influence serotonin and norepinephrine release at their repective receptors, They are indicated for such diverse and seendngly different conditions as: focal onset seizures, post-herpetic neuralgia, diabetic peripheral neuropathy, fibromyalgia, anxiety, and drug withdraw syndromes, The commonality in these conditions is that there has occurred some component of neurologic injury with resultant persistent neuronal hyper-excitability and dysfunction, The abnormally increased activity of these neuronal populations in tum results in neurochemical imbalhmce, These neuro modulating drugs act to suppress such activity and reestablish neAotransrnitter equilibrium, The resultant specific symptom reduction or resolution depends on the specific location and fumctions of the affected neuronal population 100761 Many anti-epileptic drugs have also been found of benefit in psychological conditions manifesting significant fluctuations and swings in mood. Bipolar affective disorder (manic-depressive disorder) is such a disorder, alluing there is likely neuronal hyper-excitability involved with these conditions. Thus, it is the specific population of neurons and their comections which determine the symptoms experienced by the patient The seizure drugs valproic acid (Depakote@) and uanotrigene (Lamictal@) are both indicated for hipolar affective disorder in addition to their initial indications for epilepsy, Anti-epileptic drgs, together with anti-depressants and anxiolytics are used in the treatment of Tnon-epileptic"/psychogenic seizures, an involuntary, conversion reaction disorder with significant psychological disability-The anti-epileptics, Depakote and Topamax are also FDA approved for migraine headache prophylaxis, suggesting the association of hyper-excitable neuronal populations requiring stabilization with this condition (00771 Approved medical therapy for Parkinson's disease (PD) in the United States is limited to oral and subcutaneous (sub-Q) injection. T'e tablet, in ordinary or oral dissolving form (ODT)p is used to deliver levodopa to the centralnervous system (CNS) in combination with carbidopa (Sinemet@) or with a COMT inhibitor (Comtan@); dopamine agonists, MAO inhibitor, COMT inhibitors, and other agents also use the oral 21.

route. Apomnorphine, as subsQ injection. (Apokyn@), is approved for the acute treatmecnt of episodes of hypomoilityoffperiods associated with PD. In Europe, aponorphine is also given by intra-peritoneat pump. All current treatment modalities are considered "systemic" in that ultimate therapeutic effect relies on blood flow: first the general circulation, the, the cerebral blood, to reach target sites in CNS This also holds true for the transdermal dopamine agonist (rntigotine) patch, Neupro®, which, applied to the skin, required absorption into sub-Q vessels for eventual delivery to CNS Neupro was remOved from the US. market after technical problems with crystallization within the patch matrix but remains available in Europe, Studies are undemy to reintroduce it in the US. [00781 The widespread presence of active drug in systemic and cerebral blood is likely the primary source of side-effects associated with PD drugs. As stimulation of dopamine receptors and other ueuro-chemicai effects occur at regions other than those targeted, unwanted drug etTects occur. Furtherwith reliance on blood flow for therapeutic effect, idiosyncrasies in the cardiovascular and cerebrovascular systems need to be considered Heart disease and atheroscleross, both conmton in elderly PD patients, can significantly affect systemic drug delivery. With oral delivery of PD medications, gastrointestinal (G) disease affecting GI transit, absorption, and hepatic metabolism are concems, 10O79J Systemic delivery of PD drugs also raises the concem of "non-ihysiologic effects" as active drug is delivered to downstreamn" neuro-anatormical structures in advance of those "upstreamxn" Within the dopaninergic system, normal physiological sequence of neuro-chemical flow and effect is fTom brainstem? substantiala nigra) to striatum (caudate and put amen) by ascending nigra-striatal pathways, Accordingly. therapeutic etTect would seem best realized when PD drug effect follows the same neuro physiological sequence This may part icu laly ho d true for dopamine precursors and agonists. The long term dopanmine therapy effects of "receptor hypersensitivity," manifest as motor complications and "on-off phenomena," may be the conseqence of persistent fluctuating, non-physiologic "downstream" dopamine receptor stimuIation, (080) All currently approved therapies for the conditons described above reach the central nervous system through the systemic circulation. Cerebral blood flow to brainstem stctures is through the posterior circulation via the vertebral and baiar arteries and their branches. In view of the undesirable sideeffects associated with tids form of drug delivery to the brain, the present invention is directed in part to the targeted regional delivery to the brainsten 100811 To understand tie concept of"peripheral deoafferentatisn" as it applies to the brainstem and how topical drug delivery to the back of the neck works requires a review of the neuro-anatomy and the neuro-physiology of the regionAs indicated above, this area of the nervous system is very complicated, compact and highly inter-active and inter-related. 100821 The Trigeninal Nerve System is a component of the brainstem which coordinates pain input from the face, head, and the back of the neck. As such, it intimately influences the production of other symptoms associated with syndromes attributed to dysfuction within the trigenminal complex, These include the photophobia, phonophobia, nausea, anxiety, aldynia, and other focal sensory symptoms which may accompany a migraine attack. Similarly, episodes of trigeminal neuralgia (tic douloreux) frequently involve significant affective (emotional) and visceral components, Because of proximity and connections to other structures in the brainstem, abnornalities of temperature regulation, thirst, alertness, and mood are common. Some of these symptoms may be as equally disabling as the head and face pain, 100831 In addition to receiving pain and sensory (at'erent) input from the face, nasal and para-nasal sinuses, the teeth, scalp, the dura of the anterior and middle cranial fossa, the trigeminal system receives similar input from the soft tissues of the posterior cervical region The free nerve endings in the back of the neck are just below the surface of the skin, easily accessible to topically delivered drugs formulated in an appropriate dernal penetration enhancing compounding medium. The free nerve endings, via the small unw 23 myelinated and myelinated "C ibers" (pain fibers) carry pain impulses through afferent sensory ncrves back to the Trigeminal Nucleus Caudalis (NC), TNC is the pain processing center extending from the pons through the entire extent of the brainstem to the upper cervical spinal cord, After synapsing at the thalarnus, pain impulses from TNC travel to the sonat\osensory cortex, where pain is perceived. 100841 As providing important afferent input to the brain, the trigeniinal system also receives afferent input from the rest of the body, Affarent input is defined as any neural impulses coming back to the brain foEm the body. As such it provides information to the brain for processing and interpretation: pain, sensation, autonomic functions Euferent output, on the other hand, consists of impulses originating in the central nervous system (brain, brainsten, and spinal cord) flowing to the body forfinction: movement response, action, i0851 The ay nerve includes both efferent and afferent fibers and i 1txY'ea ower bramnstemt (medulla oblongata) via 8-10 radicles. The af'ferent fibers arise in th jduar and the nodose vagus ganglia. The somratic afferentt fibers tenninate in the nucleus ofthe trigeminospinal tract (TNC)+ Both the jugular and the nodse ganglia are oneted with the superior cervical sympathetic ganion through intercommunica rmi. The superior cervical sympathetic ganglion is located between the intemal carid actry and the jugular vein on the vental aspects of the transverse processes of the 2, 3rd, and the 4th ceral vertebrae. it is the largest of the sympathetic tmunk gangia [01861 Sympathetic roots arising &om the ganglion join the st and the 2nd cervical nerves; frequently the 3rd, and occasionally, the 4th in addition to nerve fibers which extend rostrafly from the superior cervical sympathetic ganglion, the sympathetic innervation of the head includes fibers which join the plexi on the common carotid and vertebrtal arteries, The one on the vertebral atery is continuous with the plexus on the siar artery, Rami derived front the internal carotid plexus join the tngeminal nerve and hecavernous plezxus in addition to the other structure such as the abduceos and deep peovsal nerves, From the cavemous plexus, located in the middle cranial fossa, 24 sympathetic fibers join the oculomotor, trochlear, and the ophthalmic nerves. Fibers from the plexts also accompany blood vessels into the hypophysis, The spheno-palatine gangion, located in the pterygo-palatine fossa, receives sympathetic fibers from the face with rani distributed to the mucous membranes of the nares, mouth, the pharynx and some orbital structures 100871 From the above it is clear that cervical nerve function is intimately related to vagal afferents and afferents from the facehead, and the dura of cranial fosswe associated with migraine and other head and face pain syndromes, 100881 It has been long reported that vagal nerve stimulation (VNS) in the neck down regulates abnormal discharges from epileptic foci and treats seizures VNS is now approved as adjumct to medical therapy in certain forms of iniractable epilepsy, It is also of benefit in severe depression resistant to traditional drug therapy; Studies with VNS in migraine, anxiety, and fibroiyalgia have been underway and have shown Prelininary promise in benefit. 1908I9) The nechanis m of action appears to be the down-regulation of hyperexcitable, dysfunctional neuronal systems by increased inhibitory input to brainstem and associated connections through Stimulation of the afferent system. Affarent stimulation, by fted back through TNC, causes reduction in efferent output from the brainstem, resulting in resolution of clnical symptoms through down-regdation of hyper-active neuronal structures. (00901 Ir the same way the electrical stimulation of VNS accomplishes its effect on the braiistem, topical drug therapy to the posterior cervical region; in clOse proximity to the brainstem and its atTerent inputs, is theorized to provide effec for the conditions mentioned above. Thus, drugs proved of benefit for these disorders, show improved efficacy wi diminished sideeffects if delivered in the manner suggested, Other drugs being developed for these conditions should similarly be considered for such delivery. 25 100911 It is hypothesized that benefits of the present method of topical drug delivery of central nervous system (CNS) active drugs les in the fact that drug concentration gradients and blood flow factors are un-involved in the therapeutic process, in contrast, the proposed delivery operates through direct nerve connections between skin peripheral nerves at the back of the neck at the hairline (BONATh) and brainstem structures, Active drug compounded in an appropriate "dermal penetration enancing" median topically applied to the skin at the back of neck has effect on the free nerve endings of peripheral nerves located immediately below the skin surface,'.Receptors to dopamine, serotonin, norepinephrine, and other neuro transmitters/neuro-chemicals involved with neural transnussion are located on these free nerve endings. Therefore, topically applied drug has near immediate therapeutic effect as direct neural impulses are involved-the concept of brainstem afferent stimulation through topical regional neuro-affective (TRNA) therapy, All prior art and methods of drug delivery to the CNS have involved blood flow and therapeutic drug blood level requirements, The proposed method does not require such, which are the source of undesirable systemic and CNS side-effects. The presently proposed drug delivery process operates on the principle of an electrical capacitor whereas the prior relied on those fluid dynamics and reservoir principles. 100921 The factors which determine the success of TRNA therapy include, the drug being considered, the compounding substance (surfactant deall penetration enhancer), the disease process, and the location of application, For migraine, face and head pain syndrones, Parkinson s disease, and other conditions relying on atTerent input to or through the cervical oord and brainstem, it is believed that the currently proposed method is ideal, The free nerve endings in the skin at the back of the neck are important components of the cervical nerves with rich connectons to the trigeminal, vagal, and sympathetic systems conminmicating with brainstem structures and other components of the central nervous system. These are the areas pat and other symptoms related to neuro& chemical release arc processed and perceived 100931 The skin at the upper part of the back of the neck, at the hairline, is innervated by (supplied by nerves) the cervical nerve roots C 1-3 that are also part of the Trigetinal 26 Nerve system of the hrainsem. These cervical nerves (the wires) have their cell bodies (their generators) within the Nucleus Caudalis (Spinal Nucleus) of the Trigeminal Nerve in the cervical spinal cord and t he brainstem. Accordingly, they have direct neural connections with brainstem processing areas, At the same time, the peripheral nerve receptor sites for these nerves, the free nerve endings, reside under the skin surface at the back of the neck, The nerves in the soft tissues of the back of the neck, representing the C 1, C2, and C3 segments of the cervical spinal cord are unique in that they have ininate connections with pathways directly affecting brainstem and autonomic system function. There are direct connections with the Trigeminal Nerve system of the brainstem which provides for pain and other sensory input and interpretation from the head, face, sinus cavities, the dural covering of the brain, and the back of the neck. There are also connections with the vagus nerve and the sympathetic nervous system through the sympathetic ganglia, Thus, it is through these connections, which are nowhere else in the body as inter-related or at such close proximity to the surface of the human skin, that the potential for the delivery of CNN acting drugs through the skin at the back of the neck (BONATH) is realized. Finally, skin is enbryologically derived from neuro-ectoderrn which is also responsible for the formation of the brain and other aspects of the CNS, Thus, the nerves in the human skin have a particularly direct relationship with these structures, This provides for the efficacy noted with TRN LSONATH therapy, At the same time, systemic and other CNS side-eftects are reduced or avoided, Thus, drugs topically applied to the skin in this region have ready access to brainstem and other CNS stmtures without the requirement of drug in the bloodstream reaching target sites, 100941 In addition to the upper cervical nerves having direct relation to the Trineminal Nerve System, they also contribute to the Cervical Sympathetic Gangia and the Vagal Nerve Systems through direct connections, These latter two systems provide some of the most significant affarent.feedtback to the brainstem and other portions of the CNS from the rest of the body- This allow for additional brainstem afferent stimulation potential through TRNA therapy at the back of the neck. Although skin at other areas of the face and head have eventual neural feed-back to the brainsten, the intimate connections to afferent feed-back systems are lacking. 27 100951 To understand the concept of peripheral afTrent sinuladion (or "de afferentation") as it applies to brainstem afferent sfirnulation and how topic drug delivery to the back of the neck works requires a review of the neuro-anatony and the neuro-physiology of the region. As indicated above, this area of the nervous system is very complicated, compact and highly inter-active and inrarelated. 100961 The Trigeminal Nerve System is a component of the brainstem which coordinates pain inpui rorn the face, head, and the back of the neck. As such, it intimately influences the production of other symptoms assooated with syndromes attributed t. dysfunction within the trigeminal conmplex. These include the photophobia, phonophobia, nausea, anxiety, aliodynia, and other focal sensory symptoms which may accompany migraine attack, Similarly, episodes of trigeinal neuralgia (tic douloreux) frequently involve significant affective (emotional) and visceral components, Because of proximIty and connections to other structures in the brainstem, abnormalities of temperature regulation, thirst, aertess, and mood are common, Some of these symptoms may be as equally disabling as the head and face pain, [00971 In addition to receiving pain and sensory (afferent) input from the face, nasal and para-naal sinuses, the teeth, scalp, the dura of the anterior and middle cranial fossa, the trigeminal system receives similar input from the soft issues of the posterior cervical region. The free nerve endings in the back of the neck are just below the surface oftthe skin, easily accessible to topically delivered drugs formnuated i an appropriate dermat penetration enhancing compounding medium' The free nerve endings, via the small un myelinated and nyelinated "CATibers" (pain fibers) carry pain impulses through afferent sensory nerves back to the Trigeninal Nucleus Caudalis (TNC). TNC is the pain processing center extending from the pons through the entire extent of the brainsten to the upper cervical spinal cord. After synapsing at the thalanms, pain impulses from TNC travel to the somatosensory cortex, where pain is perceived 28 t00981 As providing important afferent input to the brain, the trigeminal system also receives afferent input forL the rest of the body. Afferernt input is defined as neural impulses coming back to the brain from the body, As such, it provides information to the brain for processing and interpretation: of pain, sensation and other perception, motor, and autonomic functions, Efferent output, on the other hand, consists of impulses originating in the central nervous system (brain, brainstem, and spinal cord) flowing to the body for function: movement, response, action, [0099j The nerve' in the soft tisses of the back of the neck, representing the Cl, CZ, and C3 segments of the cervical spinal cord are uique inthat they have inmate connections with pathways directly affecting brainstem and autonomic system function The brainstem represents the primary neural relay and processing center of the body. I the human, it is the size of the thumb and contains the most dense and complicated network of neural connections any w where, It functions to relay all neural impulses fom the brain to the body (efferent output) as well as receive them back from the body to the CNS for processing (atterent input). [001001 There are direct connections between the nerves in the skin at the back of the neck and the Trigeminal Nerve system of the brainstem, which provides pain and sensory input and processing from the head, face, sinus cavities,and the dural covering of the brain There also exist afferent connection with the vagus nerve and the sympathetic nervous system through the sympathetic ganglia, It is through these connections which are nowhere else in the body as inter-related or at such close proximity to the surfaee of the human skin as at the back of the upper neck (BONATH), that tie potential for the delivery of CNS active drugs through TRNA therapy is realized. As providing important afferent input to the brainthe trigeminal system also receives afferents from the rest of the body, [0I011 The vagus nerve includes both efferent and afferent fibers and is attached to the lower brainstem (redula oblongata) via 8 10 radicles, The efferent fibers arise in the jugular and the nodose vagus ganglia. The somatic afferent fibems terminate in the nucleus 29 of the trigernino-spinal tract (TNC), Both the jugular and the nodose ganglia are connected with the superior cervical sympathetic gangion through inter-communicating rami. The superior cervical sympathetic ganglion is located between the intemal carotid artery, and the jugular vein on the ventral aspects of the transverse processes of the 2t 3" and the 4* cervical vertebrae. It is the largest of the syipathetic trunk ganglia., [001021 Sympathetic roots arising from the ganglion join the 1" and the 2 cervical nerves; frequently the 3, and occasionally, the 4 In addition to nerve fibers which extend rostrally from the superior cervical sympathetic ganglion, the sympathetic innervation of the head includes fibers which join the plexi on the common carotid and the vertebrtal arteries, The one on the vertebral artery is coninuous with the plexus on the basilar artery. Rani derived from the internal carotid plexus join he trigeminal nerve and the cavernous pIeXUs in addition to the other structures such as the abducens and deep petrosal nerves. From the cavern ous plexus, located in the middle cranial tossa, sympathetic fibers join the oculomotor, trochlear, and the ophthahnlic nerves. Fibers from the plexus also accompany blood vessels into the hypophysis (pituitary gland), The spheno-paiatine gangion, located in the pterygo-palatine fossa, receives sympathetic fibers from the face with rami distributed to the mucous membranes of the nares, mouth, the pharynx, and some orbital structures. [001031 From the above, itis clear that upper cervical (Cl A) nerve function with peripheral nerve free nerve endings in the skin at the back of the neck (BONATH) is intimately related to vagus nerve afferents and afferents from the face, head, and the dura of cTanial fossae through the trigeminal nerve. These, in turn, provide feedback to the brainstem and other CNS structures for nerve signal processing, 1001041 It has been long reported that vagal nerve stimulation (VNS) in the neck down regulates abnormal discharges from epileptic foci and treats seizures. VNS is now approved as adjunct to medical therapy in certain forms of intractable epilepsy It is also of benefit in severe depression resistant to traditional dtug therapy; Studies with V/NS in 10 migraine anxiety, and fibrmyalgia have been underway and have shown preliminary proraise in benefit [00105 The mechanism of action appears to be the down-regulation of hyper-excitable, dysfunctional neuronalI systems by increased inhibitory input to brainstemr and associated connections through stimulation of the afferent system Affarent stimulation, by feed back through TNC.causes reduction in efferent output from the brainstemresulting in resohion of clinical symptoms through down-reglation of hyper-active neuronal structures. [0010Q6 In the same way the electrical stimulation of'VNS accomplishes its effect on the brainstem, topical drug therapy to the posterior cervical region, in close proximity to the brainstem and its aTet inputs, is theorized to provide effect for the conditions mentioned above, 'Thus, drugs proved of benefit for these disorders, show improved efficacy with diminished s'de-etfects if delivered in the manner suggested. Other drugs being developed for these conditions should similar be considered for such delivery. 00107] The question arises then: does TRNA therapy work with drug application to the forehead face, or other regions of head The answer is prhaps- in some disease states such as migraine and free pain; but, not as effective and efficient as at the back of the neck at the hairline, BONATIA. Free nerve endings are also present at these other locations but the distance back to involved brainstem structures is greater and there is not the added advantage of rich afferent neural connections to the trigemnal vagal, and sympathetic nerve systems whieh are associated with the posterior cervical region. 100108} "TRNA BONATH" delivery diners from traditionatherapy (whether oral, injection nasal spray, inhalation, or rectal) in that it has no reliance on the systemic or cerebral blood flow, Nor does it require therapeutic blood levels of drug, These latter factors are responsible for systemic and CNS side-effects as drug is delivered to areas not intended to be affected in the therapeutic process, Transdermal systemic delivery by patch, although similarly applied to the skin as in TRNA BONATU therapy, differs 31 significantly in its reliance on a drug concentration gradient for absorption into the systemic capillary and venous blood TRNA therapy is unaffected by denial vessels or systeuic blood flow It relies so-ely on the fiction of te free nerve endings )t cutaneous nerves and their connections at the point of appiioation of compounded drug. [00109] "Traditional" transdernal drug delivery by patch and TRNA are both "transdermal" in that in both, drug penetrates the skin (epidermis) for eventual clinical effect The difference lies in the fact that in "traditional" transdermal patch therapy, drug enters the sysremc circulation through a concentration gradient and establishes a therapeutic drug blood level. Although measuring a blood level gives assurance drug is being taken or delivered systemically, allowing fbr checking compliance, it is also the source of undesirable side-effects and drug interactions, Of necessity, with systemic transdermal patch therapy, drug applied to the skin surface must be absorbed through the small vessels in the dermis for eventual presence in the systemic venous blood for measurement of drug level With the proposed TRNA therapy, drug need only be available at the free nerve endings under the epidermis, No concentration gradients or systemic blood levels are necessary. Drug delivery is unaffected by cardiac output or cerebral blo'd flow factors, Of significance, persons afflicted with Parkinson's disease are typically elderly with concomitant cardiac and cerebral vascular disease, [O0l110] Thus, in certain embodiments, the methods and formuldations of the invention deliver an amount of drug (e~g., dopamine agonist) in the TRNA therapy that would provide sub-therapeutic plasma levels if administered orally, but which is therapeutically eff6ctive when administered via TRNA therapy at the BONATH. [001111 It is hypothesized by the inventor that a principal reason TRNA therapy is rapid in the onset of clinica effect (e.g., less than about 10 minutes for migraine with topical sumatriptan and less than tout 15 minutes for Parkinson's disease with topical apomorphine) is that it operates through an "etectro-chemical" process. Active drug compounded in an appropriate dermal penetration enhancing medium acts at free nerve endings, changing the neurochemistry of receptors at the neural synapse: apomorphine (dopamine and norepinephrine agonist), increasing dcpaiine and norepinephrine levels and improving neural transmission, After a point of receptor stimulation, neural (electrical) impulses are generated back to neuronal cell bodies residing in the spinal cord and brainste n: "atTerent feed-back". The nervous system functions through neurons generating electrical impulses and the release of neurochemicals/neuro-transmitters (serotonin, norepinephrine, dopanine, and acetylcholine, being the major ones) at neural receptor sites called "synaptic clefs". Accordingly, the process in TRNA therapy may be considered analogous to an electrical capacitor discharging to perform a fiUction, such as turning on a light switch. Viewed from this perspective, the rapid onset of clinical effect observed in TRNA therapy makes sense (0OU12} Itis further hypothesized that via the use of TRNA therapy, the dopamine stinulation of receptors in the Nigra-stiatal System is physiological and down-stream: fa the cutaneous free nere-endings to the cervical cord, to the brainstem and substantial nigra; then, via ascending nigra-striatal connections to the dopamine receptors within the caudate and putatnen With systemic (oral injection, or patch) the down stream anatomical regions (caudate and putam-en) ny be stimulated in advance of or at the same time as the upstream (brainstem) components. The inventor believes that much of the chronic motor complications of dopamine therapy are the result of tis phenomenon-the resut of "dopanine receptor hypersensitivity" This complication is believed to be avoided, and in fact, alleviated through TRNA dopamnine delivery. in w which it is believed that the dopamine and other neurochemical effects are physiological and flow in the direction and manner in which they were intended---and therefore, most effective. 100131 Altematively, transdenal systemic patch delivery operates on the principles of chemical gradients and fluid dynamics These presses have variability and inherent idiosyncrasies fluctuating heart function as a pump for blood flow being one, Thus, despite the advantage of measurable drug levels, a more circuitous route with slower clinical effect is observed. This makes systemic transdemial patch delivery inappropriate for acute therapy. 33 [00114j Altematively, rapid as well as prolonged clinical efect may be achieved b a sustainedrelease deninal system employing the principles of TRNA therapy through patch application at the skin at the back of the neck at the hairine (BONATHY BONATH refrs to the specific site of topical drug application necessary for cynical effect in TRNA therapy, The location is criticalin TRNA therapyhereas wih the transdermal systemic patch, location is irelevant The uniqueness of this particular area of the human anatomy which allows this delivery method to work is discussed below, jO00 1] Alternatively, SD therapy, the traditional transdermal systemic delivery. operates on the principles of chemical gradients and fluid dynamics. These processes have associated inherent idiosyncrasies and variabilities; heart function as a punp for blood Row being one, Accordingly, despite th advantage of measurable drug levels, traditional rnsderm& systemic delivery involves a more ircuitous route with slower clinical effect. [0011 6, Rapid as well as prolonged clinical effect may be achieved by a sustained release patch placed at the same anatomical site, BONATH. [001171 One skilled in the art having the benefit of the information contained herein will appreciate that there are many classes of drugs which would be useful for topical brainstem de-afferentation therapy These classes of drugs include, but are not limited to: 1 An-Epileptic drugs: Examples irchide Valproic acid (Depacorn@/upakote) Leviteracetem (Keppra@), Lamotrigene (Lamictal@) Topiramate ( Topamna-x), Pregabalin (Lyica@), Gabapentin (Neurontin@), Cataimazepine (Tegretol®), OxCatbazepine (Trileptal@) Phenobarbital and other barbiturates Tiagabine (Gabatril@), Retigabine (Valeant Pharmnaceuticals), Lacosamide@ (Schwarz Biosciences), and Perampanel@ (Fisai) are in development as anti-epileptics and neuromodulators for other associated neurologjcal, pain, and psychiatric conditions, 34 2. Anxiolytic drugs: Benzodiazepines: Examples include lorazepam (Afivan), diazepami (Valiumj clonazepam (Konopin@)® chlordiazepoxide (Lihrium@) and alprazolam (Xanax) 3. NeurolepticAntiPsychotiC drugs: Examples include chlorpromazime (Thorazine®) haloperidol (Haldo ). ri speridone (Risperdal@),olanzapine (Zyprexa@) and quetiapine (Seroque®@) 4, Analgesics/Antiiflammatory drugs Examples include prednisone, solunedrol and other steroids, naproxen, aspirin, acetaminophen, voltaren, ketoprofen, ibuprofen, other 5, Parkinsor's Disease/Similar or Related Syndrome drags: Examples include dopamine agonists such as apomorphine 6, Sexual Dysfunction drugs Examples include dopamirie agonists such as apomorphine 7. Dystonia (cervical and otherwise), hih sometimes occur in conjunction with spasmodic torticollis and spastic conditions: Examples of drugs include dopanine agonists such as apomorphine 8. Eenin essentia1familial tremor, tremr related toMS, chronic encepahalopathies such as from stroke or head injuries, congenital CNS degeneration condiaonscereril palsy, cercellar degeneration syndromes, and spasicity conditions from the above: Examples of drugs include doparine agonists such as apomorphine, 9. NeuropathidNearogenic pain dmgs; Examples include carbamazepine, gabapentin, topiramate, zonisamide, phenytoin, desipramine, amitriptyline, inipramine, doxepin, protriptyline, pentoxifylline, and hydrcxyzine, 3$ 10. Smoking Cessation drugs: Examples include drugs such as varenicline 11, Appetite Suppressant drugs: Examples include drugs such as Sibutramine. 12, Neurodegenerative Diseases: Examples include daigs such as Aricept/donepezil. Exelon/rivasigmine Reminyi/Razadyne/galantamine, and Namendalmemtantiand nd their naturally occurngcounterparts, as well as NMDA antagonists, 13. Multiple Sclerosis (MS Examnples include drugs such as 4-aminpyridine, 14. insomnia: Examples include drugs such as zolpidem 15. Fatigue: Examples include drugs such as pemoline and Modafirill. 16, Vertigo Nasea and/or Dizziness: Exarpas include drugs such as as meciizine. diienhydrinate, prochlorperazine, scopolamine and diphenhydramine, 17. Writer's cramp and restless leg syndrome: Examples include dopamine agonists such as aponorphine, 18. ADD/ADHD: Examples include drugs such as lisdexamnfetamine, methylphenidate. [0011) In general, the formulations and methods described herein am useixl for the treatment of neuronal hyperexcitabil-ity and neurochemical dysfunction syndrromes and the drug may be e.g. an anti-epileptic an anxiolyzic, a neuroleptic, an anti-psychotic, an analgesic, an anti-inflammatory, an anti-Parkinson's disease/syndrome drug, a sexual dysfunction drug, a drug for the treatment of dystonia, a drug for the treatment of spastic conditions, a drug for the treatment of benign essential/familial tremor, a drug for the treatment of tremor related to MS, a drug for the treatment of chronic encepahalopathies, a drug for the treatment of congenital CNS degeneration conditions/cembral palsy, a drag for the treatment of cerebellar degeneration syndromes, a drug for the treatment of 36 neuropathic and/or neurogenic pain, a drug for smoking cessation, a drug for appetite suppression, a drug for neurdegenerative conditions, a drug for the treatment of multiple sclerosis, a drug for the treatment of insomniaa drug for the treatment of fatigue, a drug for the treatment of vertigo, nausea and/or dizziness, a drug for the treatment of writer's cramp and restless leg syndrome, a drug for the treatment of ADD/APHD, and other drugs which can beneficially be administered at the the back of the neck at the hairline in close proximity to and under or on the area of skin above the brain stein to provide regional neuro-affective therapy t.o the patient. [001191 In certain embodiments, the drug is a dopamine agonist such as apomorphine (Apokyn@, APO-go@), pramipexole (Mirapexin@) ropinirole (Requip@), bromocriptine (Parlodel@), cabergoline (Cabaseri, Dostinex@), pergolide (Permax®. Celane) rotigotine (Neupro@) mixtures of any of the foregoing, or other dopamnine agonists known to those skilled inhe ar. One skilled in the art will appreciate that dopamine agonists other than apommphine may be used in the formations and methods of the present invention, and all such agents are meant to he encompassed by the term "dopamine agonists" For example such drugs include, but are not hliited to, carbidopa (Sinemet@), dopam-nine agonists (Requip@, Rotigotine@i), Mirapex@) COMT inhibitors (Entacapone®, Tocapone), rasagiine (Azilect@) (MAO inhibitors) and M-AO-B inhibitors (Selegiline (Etdep@) jo01201 In other embodiments, the drag is opioid such as morphine, codeine, dihydrocodeine, hydrocodone hydromorphone nicomorphine, oxycodone, oxymnorphone , fentanyl, alphamethylfentanyl , alfentanil sufentanil renifentantd carfentanyl , ohmefentanyl, thebaine oripavine, ediacetyimorphine (heroin), phenylpipetridines such as pethidine (meperidine) and ketobemidone, allyiprodine, prodine, propoxyphene, dextropropoxyphene, dextromoramide bezitramide, piritramide, methadone, dipipanone, levomethadyl Acetate (LAAM), loperamide, diphenoxylate, dezocine, pentazociue, phenazocine, buprenorphine , dihydroetorphine, etorphine , butorphanol, nalbuphine levorphanol, levomethorphan, lefetamine, meptazinoi , tilidine, tramadol, tapentadol mixtures thereof, and the like, 37 1001211 in yet other embodimnents, the drug is tarpentadol (a centrally acting oral analgesic having two mechanisms of action combining rn-opioid receptor agonisnm and norepinephrine reuptake inhibition). 1001221 In yet other embodiments, the drug is a selective norepinepbrineteuptake ndibitor, such as Atomoxetine (Strattera@), Mazindol (Mazanor Sanorex@), Nisoxetine (LY 94939), Reboxetine (Edronax®, Vestra) Viloxazine (ialan@) mixtures thereof and the like, 1001231 In yet other embodiments, the drug is a benzodiazepine, such as orazepam (Ativan@), diazepanm (Valium@), clonazepam (K onopin®), chiordiazepoxide (tibrium®), alprazolam (Xanax@), temazeparm (Restoril,), mixtures thereof, and the like, In other embodiments, the drug is a neuroleptic or psychotropic such as chlorpromazine (Thorazine@), haloperidol (Haldol@), risperidone (Risperdal@), olazapine (Zyprexa@) and quetiapine (Seroque@), 1001241 In other embodiments the drug is an agent that treats depression and/or anxiety, for example, seective serotonin reuptake inhibitors (SSRIs) such as fluoxetine (Prozac), sertraline (Zoloft), ven afaxine (Efexor@P), citalopram (Celexa@), parocefine (Paxil) mixtures thereof, and the like (such as trazodone (Desyrel)), and/or serotonin~ norepinephrine reuptake inhibitors (SNRI), such as Desvenlafaxine (Pristiq@), Duloxetine (Cymbalta&), Milnacipran (Ixel@, Savella@), Venlafaxine (Effcxor@t mixtures thereof, and the like, 1001251 in yet other embodiments, the drug isa norepinephrine-dopamine reuptake inhibitor (NDRI), such as Amineptine (Survector®), an aminoketone antidepressant such as Bpropion (Wellbutn®, Zytan4), Dexmethylphenidate (Focalin), Methylphenidate (Ritaiin@, Concerta@) Nomifensine (Merital@), a phenylpiperazine antidepressant such as nefazodone (Serzonc@) a piperazinor-azcpine antidepressant such as mirtazapine (Remeton@), mixtures thereof; and the like, 38 (001261 In yet other embodiments, the dnig may be an NMDA receptor antagonit. Phencycdhine, ketamine, and dextromethorphan ar used as recreational drugs At subanesthetc doses, hoWever, iese drugs have mild stimulant effects, and these agents have shown promise for the treatment of conditions that involve excitotoxicityincuding traumatic brain injury, stroke, and neurodegenerative diseases such as Alzheimer's, Parkinsos, and Huntington's. [0IN 2 Additionally, the drug may be an agent that treats neuropatbicineurogenic pain (pain that arises from nerve dysfunction and not as a result ofinjury, e ugtrigenminal neuralgia), such as carbamazepine, gabapentin, topiranate, zonisanide, phenytoin, desipramine, amitriptylineimipramine, doxepin, protriptyline, penltoxifylline, and hydroxyzine, [001281 in other embodiments, the drug treats insomnia, such as zolpidem (Ambien@) [00129) i other embodiments the drug treats fatigue. Such drugs nclude central nervous system stinulants such as pemoline (Cylett@) and Modafinil (Provigil@k). [001301 In yet other embodiments, the drug treats vertigo, nausea and/or dizziness, such as meclizine (Antivert), dinwuhydrinate (dramamine), prochlorperazine (compazineok) scopolamine (Transderm@) and diphenhydranmine (Benadryl®). In yet other embodiments, the drug is a serotonin-norepinephrine reuptake inhibitor (SNRI), sueh as Desvenlafaxine (Pristiqt), Duloxetine (Cymbalta®) Mdinacipran (Ixel@. Savella@); Venlafaxine (Effexo), mixtures thereof and the like. [001311 n yet oher erbodiments, the drug is a tricyclic antidepressant (TCA) such as Anitriptyline (Elavil@)% Butriptyline (Evadene@, Evadyne) Clomipramine (Anafrnil@), Desipramine (Norpramin, Pertofrane), Dosulepin (Prothiade), Doxepin (Adapin, Sinequan), Imipramine (Toftanil@), Lofepramine (Feprapax@. Gamanil®, 39 Lomont@) Nortriptyline (Aventyl@, Nortrixen@, Pamelor@), Protriptyline (Viv acti®1), Trimipramine (Surronil@). mixtures thereof and the like. 1001321 In yet other embodiments, the drug is a tetracyclic antidepressant, such as Amoxapine (Asendin@) Maprotihne (Ludomil@)t Mianserdo (Thlvon@), mixtures thereof, and the like, 1001331 In yet other embodiments, the drug is an atypical antipsychotic, such as Ziprasidone (GOrdon® Zeldox®) Nefazodone (Serzone@), and the like. 1001341 In yet other embodiments, the drugis an anti-convulsant or anti-epileptic drug such as aryisaffonimide analogues such as Acetazolimide (D~iamox)®, tricyclic imiinostilbene derivatives such as carbamazepine (Tegreto@), benzodiazepines such as clonazepamm (KiMlopin@), clorazepate dipotassiuma (Tranne®) iorazepam (Ativan@) and diazeparn (Valium@) carboxylic acid derivatives such as valproic acid (Depakene@) and divalproex sodium (Depakote@) succininide dervatives such as ethosuximide (Zarontin), carbamate esters of 2~phenyM ,3-propanediol Such as felbiamate (felbatol®>), hydantoins such as phenytoin (Dilantin@) phenytoin sodium (Dilantin@) and fossphenytoin sodium (Cerebyx@), structural analogues of GABA such as gabapentin (Neurontin®) and pregabalin (Lyica@), phenyltriazines such as lamotrigine (Lamictal@0) pyrrolidine derivatives such as levitiracetam (Keppra®), ticyclic iminostilbene derivatives such as oxcarbezepine (Trilepta), barbiturates such as Phenobarbital, desoxybarbiturates such as primidone (Mysobne@), nipecotic acid derivatives such as tiagabine hydrochloride (Cabitril@), sufamated monosaccharides such as topiramate (Topamax@), oxazolidiniedione derivatives such as tnmethadione (Tridione®) and methanesulfonamides such as zonisanide (Zonigran@) Additional drugs such as Reigabine@ (Valeant Pharnaceuticals), Lacosamide@ (Schwanz Biosciences), and Perampanelt@ (E isai) are in development as anti epileptics and neuromodulators for other associated neurological, pain, and psychiatric conditions, and tbus are fther examples of potentially useful drugs in the present invention. 40 [001351 In yet other embodiments, the drug is an analgesidantinhammatory agent such as acetaminophen; prednisone, solumelrol, and other steroids; naproxen, aspirin, votaren, ketoprofen, ibuprofen, nabanetone, and other NSAfIDs, The NSAID may be COX- 1 CCGO2 or mixed COX-I/COX-2 inhibitors; Examples of COX-2 inhibitors include xicam, meloxicae and the more selective celecoxib, rofecoxib vaidecoxib, parecoxib and etoricoxib. Further examples of corticosteroids include methyiprednisIone., prednisolone, dexamethasone, and adrenocortcozrophic hormone(ACTHI), corticotropin, [00136A Additionally, the drug may be an agent that treats neuropathic/neurogenic pain (pain that arises from nerve dysfunction and not as a result of injury, e,g, trigeminal neuralgia), such as carbamazepine, gabapentin, topiramate, zonisamide, phenytoin, desipramine, amitriptyline, imipramine, doxepin, protriptyline, pentoxifyline, and hydroxyzine, mixtures thereof, and the like, 100137J in other embodiments the drug is partial agonist at the a42 nicotinic acetylcholine rceptors, used for smoking cessation The characteristics of varenicline (Chantix@),() having a mole.ular weight (MW) of 261 ard high water solubility, make it ideal for topical delivery. The usul adult dose of varenicline for smoking cessation is: Days 1 - 3: 0 of treatment: I rug orally twice a day, for one or two twelve week cyces of treatment Another agent in thisclass is cytosine (Tabex@), which is a plant alkaloid and is marketed for smoking cessation in Europe, [001381 In other embodiments, the drug is 4-aminopyridine (4-\P; also known as Fampridine@) or a p1armaceutically acceptable derivative thereof This drug has been shown to have the ability to improve the communication between damaged nerves, which may result in increased neurological function in the treatment of conditions such as multiple sclerosis (MS). An example of another such drug is 3,4 diaminopyridine, 41 j(10139J In yet other embodiments, the drug is an appetite suppressant, such as Sibu tramnine (Meridia@, Reductil@), which is a centrally acting serotonin-norepinephrine reuptake inhibitor that is structurally related to amphetamines but having a distinct mechanismn of action. Other poteni ally useful drugs for anti-obesity include Rimonahant (Acompliat), substances related to amphetamine, such as phentermine and/or fenfluramine and/or dexfenfluramine, (the combination popularly referred to phen fen) may also be useful in the treatments of the present invention, It is believed that the present method of treatment would avoid the potential heart value damage found with these combinations when administered orally. [001401 In other embodiments, the drug is useful for the treatment of Dementia/Alzheimer's disease, such as Anicept@/donepezil Exelon®/iivastigmine, Reminy @fRazadyne/galantamnine, and Namenda@lmemantine, their naturally occurring counterparts, and mixtures thereof. [001411 In other embodiments, the drug is useful for the treatment of ADD, ADHD, and sitmiar conditions, and the drug is for example, one or more auphetanine derivatives or isormers thereof, such as lisdexamfetamine (Vyvance@),Adderal(75% d-amphetanine and 25% [amphetamine, methylphenidate (RitalinV, Concerta®), dextroamphetaminc dexmethylphenidate hydrochloride (Focalin®), Ritalin®), atomoxetine (Strattera®) mixtures thereof, and the like, (001421 It has been observed and reported that patients given apomorphine injections regularly developed penile erections, Some of these patients had problems of impotence with erectile dysfunction. These patients reported improvement in sexual function with apomorphine injections Antial studies suggest central dopamnine D2 receptor stimulation may be mediating this effectift is also known that the male sexual response is related to the autonomic nervous system: primarily the parasympathetic component for erection and, the sympathetic for ej aculation, This suggests the possible role of apomophine delivered as TRNA BONATH therapy for the treatment of sexual dysfunction in Parkinson's disease as well as flom other conditions. Thus, the present 42 invention also encompasses the use of apomorphine and other dopamine agonists (e.g, as set forth above), as well as sildenafil (Viagra@)i vardenafli (Levitra@) tadalafil (Cialis@), alprostadil (Prostin@), and imixtums of any of the fibregoing 1001431 All currently approved therapies for the conditions described above reach the central nervous system through the systemic circulation. Cerebral blood flow to brainstem structures is through the posterior circulation, via the vertebra: and basilar arteries and their branches In view of the undesirable side-effects associated with this form of drug delivery to the brain, it makes sense that targeted regional delivery to the brainstern is sought Topical delivery of currently used drugs compounded in an approprate "dermal penetration enhancer" and applied in crean/gel Lomn or as a. sustainedrelease patch at the posterior cervical region (back of the neck) at the hairline is such a method. Lipoderm* is an example of an effective commercially available compounding medium. However, one skilled in the art will recognize that topical Careers meeting the specific chemical requirements of an individual drug can be formulated for maximum efficiency in topical delivery 1001441 The fonnulations of the present invention are prepared such that the drug(s) may be delivered acutely as single dose applications as cream/gel/ointment or as a sustained release topical patch, depending on the condition treated and associated symptom complex in the individual patient. The critical point, again is in the location of the applicadon: at the back of neck at the hair-line for access to posterior cervical afferents with free nerve endings under the surface of the skin, Through feedback connections with vagal and trigeminal afferent systems, this results in ultimate effect on brainstern structures.

1001451 By virtue of the method of treatment described herein the disease state/condition to be treated may be treated much faster and more effectively than such prior art modes of administration. 1001461 I certain embodiments of the present invention, the method of treating a human patient comprises applying a topical formulation which comprises a drug suitable for topical administration, which is useft for the treatment of a disease state or condition treatable via the topical brainsteni afferent stimulation (de-afferentation) drug therapy described herein 1001471 The methods of the present invention may also, if desired, involve pre-treatment of the skin with an enhancer to increase the permeability of the skin to the applied drug. The methods of the present invention may include pre-treatment or prepping" of the skin area with a substance that opens up the skin pores. Additional y, the methods of the present invention may includeif desired, pri-treatment or "prepping" oft te skin with an alcohol swab or the like to rid the area ofdirt, make-up, oil, and the like, prior to application of the drug 1001481 In certain embodiments, the topical fornmdation of the present invention comnprises Ahig in an amount which is therapeutically effective when administered topically at the at the back of neck at the hair-line for access to posterior cervical afferents with free nerve endings under the surface of the skin, but which provides a plasma concentration which is subtherapeutie if orally administered 1001491 In certain embodiments, by applying the formulatioa of the present invention comprising a dose of drag at the back of neck at the hair-line for access to posterior cervical afferents with free nerve endings under the surface of the skin, it may be possible for the use of power doses of drug or faster relief of the headache than if applied to the trnk or limbs of a human patient, and the lower plasma levels of drug which result frorn lower doses may thereby reduce unwanted side effects of the drug, 44 I00150H The topical formations of the present intention (e.g, ointment, gel, cream, or the like), must be suitable fbr topical administration of a drag, ie, Mpust contain phannaceutically acceptable excipients compatible with application to the skin tissue, and may optionally contain a sufficient amount of an enhancer composition as described hereinafier. [001511 In certain embodiments, in addition to the drug (e,g., doparnine agonist), the topical fonnulations and/or transdermal therapeutic systems of the present invention may include at least one adjuvant such as a penetration enhancer, anti-oxidant, stabilizer, career, or vehicle, Additionally or alternatively, the present invention may include the application of electric current (iontophoresis) for enhancing permeation of the dpamine agonist, [OCI 521 in certain embodiments; the topical formulations comprising a drug in an ointment, g, cream or the like, wil typicany contain on the order of about 0,001 to about 80% by weight, preferably 0.01 wt % to 0 wt. % drug, and about 0 wt. % to about 50,0 wi. %, preferably from about I wt. % to about 30 wt. % of a permeation enhancer composition, with the remainder of the composition comprising a carter or vehicle hI certain preferred embodiments, the drug is included in a cream or gel or ointment in a concentration of e,g, Img drug/mi of carrier (e,.g, Lipoderm), However, it is to be understood that one skilled in the art can increase the amount of carrier or change the carier and maintain or improve efficacy of the topical fomalaton for TRNA therapy. 1001531 In certain embodiments, the topical formulations comprising a dopamine agonist in an ointment, gel, cream or the like, will typically contain on the order of about 0.001 to about 80% by weight, preferably 0.01 wt, % to 50 wt. % dopamine agonist, and about 0 wt % to about 50.0 wI; %, preferably from about 1 wt % to about 30 wt. % of a permeation enhancer composition with the remainder of the composition comprising a carrier or vehicle in cain preferred eibodiments, the dopamine agonist is apomorphine and is included in a cream or gel or ointment in a concentration of eg I mg drag/ndof carrier (e g, Lpoderm) However, it is to he understood that one skied 45 in the art can increase the amount of carrier or change the carrier and maintain or improve efficacy of the topical formlation for TRNA therapy, in certain preferred embodiments, the drug is applied as a unit dose at the BONATH in immediate release form (e.g., cream, ointment or gel) for acute treatment with a dopamine agonist as would be beneficial to a person suffering from, e,g., Parkinson's disease or impoten6e/male erectile dysfunction, In such instances, it is preferred that the concentration of dopaZine agonist included in the unit dose is from about 0.25 mg to about 4 mg, based on apomorphine, or an therapeutically equivalent amount of another dopamine agonist as described herein. 1001541 Suitable permeation enhancers rnay also be included in the formulations, Such enhancers include, but are not limited to, dimethylsulfoxide (DMSO), N,N dimethyacetamide (DMA), decylmethylsulfoxide (C10 4SO), pclyethylenc glycol monolaurate (PEGML), propylene glycol (Pg), PGML,giycerol monolaurate (GML), lecithin, the 1-substituted azacycloheptan-2-ones, particularly I-n dodecylcyclazacycloheptan~2-one (available under the trademark Azone) from Whitby Research Incorporated, Richmond, Va.), alcohols, and the like, The permeation enhancer may also be a vegetable oil as described in U.S. Pat. No, 5,229,130 to Sharma. Such oils include, for example, safflower oil, cotton seed oil and corn (i. 1001551 Additional enhancers for use in conjunction with the present invention are ipophilic compounds having the formula [RC0 n R, wherein n is I or 2 and R is Ci C16 alkyl optionally substituted with I or 2 hydroxyl groups, and R' is hydrogen or CI C16 alkyl optionally substituted with I or 2 hydroxyl groups. Within this group, a first subset of compounds are represented by the formula (CH3 (CH 2)m COO]ni R' in which m is an integer in the range of 8 to 16, n is 1 or 2, and R' is a lower alkyl (C1 -03) residue that is either unsubstituted or substituted with one or two bydroxyl groups, Preferred enhancers within this group include an ester which is a lower ailky (Cl ~C3) laurate (i.e., m is 10 and n is 1) such as "PGML". It will be appreciated by those skilled in the art that the commercially available material sold as 'PM-L" is typically although not necessarily a mixture of propylene glycol monolaurate itself, propylene glycol dilaurate, and either 46 propylene glycol, meth.y laurate, or both Thus, the terms "GML" or "propylene glycol monolaurate" as used herein are intended to encompass both the pure compound as wel as the mixture that is typically obtained commercially Also within this group is a second subset of compounds, namely esters of fatty alcohols represented by the formula C13 (CH2)m--0-CO-.CHRl R2, in which RI and R2 are independently hydrogen hydroxyl or lower alkyl (CI C3), and m is as above, Particularly preferred enhancers within this group are lauryl acetatee and rnyristyi lactate In addition, a third subset of compounds within this group are analogous fatty acids, Ie, acids having the structural formula CH3 (C-12)m COOH where rn is as above, A particularly preferred acid is laurie acid. (001561 Other enhancer compositions are wherein a Iipophiic compound as just described, particularly PGML is combined with a hydrophilic compound, such as a 02 C6 alkanediol One preferred hydrophilic enhancer within tis group is 1,3-butanediot Such enhancer compositions ate described in detail in POT Publication No, WO 95/05137. published Feb. 23. 1995, herein incorporated by reference. Another hydrophilic enhancer that may be included in these compositions is an ether selected from the group consisting of diethylene glycol ronoethyl ether (Transeutol) and diethylene glycol monomethyl ether. Such enhancer compositions are described in detal in U.S, Pat Nos, 5.053,227 and 5,059,426 to Chiang et aL, the disclosures of which are herein incorporated by reference 1001571 Other enhancer compositions may include mixture or combinations of any of the aforementioned enhancers, and the like. 100M58) In certain embodiments the topical fomulation may include at least one water insoluble, pharmacologically approved, alkyl cellulose or hydroxyatkyl cellulose, and the like, Aikyl cellulose or hydroxyalkyl celulose polymers for use in this invention include ethyl cellulose, propyl cellulose, butyl cellulose, cellulose acetate, hydroxypropyl cellulose, hydroxybutyl cellulose, and ethylhydroxyethyl cellulose, alone or in combination, In addition, a plasticizer or a cross inking agent may be used to modify the 47 polymer's characteristics. For example, esters such as dibutyl or diethyl phthalate, amides such as diethyldiphenyi urea, vegetable oils, fatty acids and alcohols such as acid oleic and myristyl may be used in combination with the cellulose derivatve 1001591 In certain embodiments, the topical formulation may further include hydrocarbons such as liquid paraffin, vaseline, solid paraffin microcrystalline wax, etc.; higher aliphatic alcohols such as cetyl alcohol, hexadecyl, alcohol, stearyl alcohol, oleyl alcohol, etc.; esters of higher fatly acids with higher alcohols such as beeswax, etc,; esters of higher fatty acids wit lower alcohols such as isopropyl myristate, isopropyl palinitate, etc,; vegetable oils, modified vegetable oils, hydrous lanolin and its derivative, squalene, squalane; higher fatty acids such as palmitic acid, stearic acid, etc. and the like. [001601 in certain embodiments, the topical formulation may further include enulsifiers and dispersing agents which include, for example, anionic, cationic and nonionic surfactants, Nonionic surfactants are preferred because of their low levels of irritation to skin. Typical of nonionic surfactants are fatty acid monoglycerides such as glyceryl monostearate, etc.; sorbitan fatty acid esters such as sorbitan monolaurate, etc.; sucrose fatty acid esters; polyoxyethylene fatty acid esters such as polyoxyethylene stearate, etc.; and polyoxyethylene higher alcohol ethers such as polyoxyethylene cetyl ether, polyoxyethylesne oleyl ether, etc. [00161) in certain preferred embodiments, the topical TRNA formuation is aqueous based. 1001621 In certain embodiments of the present invention, the topical formulation may include a gelling agent such as methylcellulose, ethylellulose hydroxyethylcellulose, hydroxypropybcellhdosei hydroxypropylmnethylcellulose, earboxymnethylcellulose, carboier, and the lik Examples of phar-naceitical compositions which rely upon an aqueous gel composition as a vehicle for the application of a drug are US PaL Nos. 4,883,660; 4,767,619; 4,511,563; 4,861,760; ard 5,318,780, the disclosures of which are herein incorporated by reference. 48 1001631 The topical formuation may further include one or more preservatives, stabilizersor anti-oxidants, [001641 Examples of preservatives that may be used in a formulation according to the present invention ineide, but are not limited to, bacteriostatic compounds and other preservatives suitable for topical administration including various alcohols, sorhic acid and saits and derivatives thereof, ethylenediamine, monothioglycerol. and thimerosal. [001651 Examples of stabilizers that may be present in a formulation according to the present invention include p1 butTers suitable for topical administration, complexing agents, chelating agents and the like, [001661 Examples of anti-oxidants that may beused in a formulation according to the present invention include ascorbic acid andis derivatives. eg.. ascorbyl pahnitate, as well as butylated hydroxyanisole, butylated hydroxytohuene sodiup bisulfite, sodium muotabisdfite and others, [001671 Other adjuvants that may be included in the drug fomralation includecarriers, tackifiers, pigments, dyes, and other additives that do not adversely affect the mechanical or adhesive properties of the formulation. 10016$]: "Carrirs" or "~Vehicles"~ as used herein refer to cab er mnaterials suitable for transdermal drug administration, and include any such materials known in the at, g any liquid, gel, emulsion, solvent, liquid diktent. soiubihzer. or the like, which is nontoxic and which does not interact with other components of the composition in a deieterioUs manner. The term "earrier"or "vehicle" as used herein may also refer to stabilizers crystallization inhibitors, dispersing agents or other types of additives useful for facilitating transdermal drug delivery. It will be appreciated that compounds classified as "vehicles" or "carriers" nmay sometimes act as perneation enhancers, and vice versa, 49 and, accordingly, these two classes of chemical compounds or compositions may sometimes overlap. 1001691 Carrier materials suitable for use in the instant compositions include those well known for use in the cosmetic and medical arts as bases for ointments, lotions, salves, aerosols, suppositories and the like. Suitable carriers include, for example, water, liquid alcohols, liquid glycols, liquid polyalkylene glycols, liquid esters, liquid aides, liquid protein hydrolysates, liquid akylated protein hydrolysates, liquid lanolin and lmolin derivatives, and like materials cominorly employed in cosmetic and medicinal compositions. Other suitable carriers herein include for example alcohols, including both monohydric and polyhydric alcohols, e ethanol, isopropanol, glycerol, sorbitol, 2 methoxyethanol, diethyleneglycol, ethylene glycol, hexyleneglycol, mannitol, and propylene glycol; ethers such as diethyl or dipropyl ether; polyethylene glycols and methoxypolyoxyethylenes (carbowaxes having molecular weight ranging from 200 to 20,000); polyoxyethylene glycerots polyoxyethylene sorbitols, stearoyl diacetin, and the like. [001701 In certain preferred embodiments ofthe present invention where it is desired that the drug (.ego, dopamine agonist) is administered chronically, the formulations of the present invention may be formuated as a transdermal delivery systein (also referred to herein as a transdermal therapeutic system) such as a transdermal patch, a trnsdennal plaster, a transdermal disciontophoretic transdermal device, or the like, Such formulations are recognized by those skilled in the art as providing a release of drug and absorption into the skin of the patient in a sustained manner over an extended period of time (eg., 1 -7 days). In such embodiments of the present invention, the transdermal delivery system comprises, eg.,a dopansine agonist contained in a reservoir or a matrix, and an adhesive which allows the transdennal patch to adhere to the skin, allowing the passage of the active agent from the transdermal patch through the skin of the patient. in preferred embodiments, the transdermal patch is applied topically at the back of the neck at the hairline ("BONATW) so as to achieve topical regional neuro-affective therapy (fTRNA THERAY*) as described herein. bi embodiments i which the drug is 50 contained in a transdermal patch, it is contemplated that the drug will be absorbed more slowly and the transdermal patch will provide a sustained release and prolonged therapeutic effect as compared, e.g, to a cream or ointment intended to provide an immediate release of the drug and rapid onset of the TRNA therapy. 100171J In certain embodiments, the transdermal delivery devices as well as other transdermal delivery systems in accordance with the invention can be made in the form of an article such as a tape, a patch, a sheet, a dressing or any other fon known to those skilled in the art. Generally the device will be in the form of a patch of a size suitable to deliver a unit dose of serotonin agonist through the skin. The drug may be introduced into a transdermal therapeutic system in different forms (solid, in solution in dispersion); it may also be nicroencapsulated. [001721 in certain embodiments the present invention provides a cransdennmal therapeutic system comprising a drug (e.g.. serotonin agonist) in an amount that would provide sub therapeutic plasma levels if administered orally, but is therapeutically effective when administered via transdermal delivery at the headache region [001731 A transdermal delivery system. for use in accordance with the present invention can also be constructed with an enhancer composition and other ingredients described hereinahove with respect to the topical fornadation. Preferably, the transdermal delivery system is formulated for the prolonged delivery of a drug (e.g., dopamine agonist) as would be benecfiial to a person suffering from e~g,, Parkinson's disease or impotence/male erectile dysfimetion. The targeted skin flux for delivery of a particular drg can be achieved by adjusting vehicle composition and vehicle loading, as well as by. adjusting the surface area through which the compositions are administered to skin, 1001741 In certain preferred embodiments, the transdenmal delivery system (e g., patch) is formulated to deliver from about 4 mg to about 50 mg of the dopamine agonist per each 24 hours through the skin of the patient based on apomophine or a therapeutically equivalent amount of a suitable atermative dopamine agonist as described herein, In

SI

embodiments in wich the transdermal delivery system is intended to be applied to the skin at the BONATH for multiple days, the transdermal delivery system (eg., patch) is formulated to provide a flux rate over the useful life of the system such that a similar amount (e., mean dos) is delivered on a daily basis until he system is removed and replaced with a fresh system. [00175] The transdermal delivery system used in the present invention may be prepared, for example in accordance with U.S Patent Nos. 5,069,909; 4,806534; 5A26,556; 4,58580; 5,16,652; 3,598122; 4,144,3174,201,211; 4,262,003; and 4,379,4S4; all of which are incorporated herein by reference. [00176J Additionally, the transdermal delivery system used in the present invention may be in accordance with US. Patent No. 6,689,379, hereby incorporated by reference, which system is a matrix or reservoir system which comprises: at least one pharmaceutical active agent selected from the group consisting of basic pharmaceutical active agents and neutral phatnaceutical active agents ( such as rivastignine); and a pressure-sensitive adhesive comprising a polyacrylate polymer, wherein said polyacrylate polymer has a polyacrylate backbone containing monomer units selected from the group consisting of acrylic acid, methacrylic acid and ester derivatives of acrylic or methacrylic acid, and said rnonomer units comprise at least 50% (w/w) relative to a mean polymer mass of said polyacrylate polymer; a total amount of monomers selected frm the group consisting of non-esteriftied acrylic acid and non-esterified methacrylic acid is 0,5 to 10.0% (w) relative to the mean polymer mass of said polyacrylate polymer, and the carboxyl groups of said non-esterified acrylic and methacrylic acid monomers are present stoichiometrically at 5 to 100% in the form of alkali salts or alkaline-earth saltsaid salts being reaction products of a neutralization reaction of an alcoholic solution of ai alkaline hydroxide or an alkaline-earth hydroxide with said acrylate polymer(s), or of a neutraization reaction of an alkali alcoholate or an alkaline-earth alcoholate with said acrylate polymerss. 52 [001771 In certain embodiments, the dosage fonm can be a transdemal patch comprising a laminated composite for administering the drug (e.g, dopamrnine agonist) to an individual transdermnally comprising: (a) a plymer backing layer that is substantially impermeable to the dopamine agonist; and (b) a reservoir layer compnsing a water-base acrylte pressure-sensitive adhesive, I to 12% by weight serotonin agonist and 2 to 25% by weight of a permeation enhancer comprising propylene glycol monolaurate in combination with caprice acid or oleic acid, wherein the skin contact area of the composite is lato 100 m2. f00178] The dosage form can be a transdermal patch comprising (a) a polar solvent material selected from the group consisting of C3 -C4 diols, C3 -C6 trials, and mixtures thereof; and (b) a polar lipid material selected from the group consisting of fatty alcohol esters, fatty acid esters, and mixtures ther f wherein said polar solvent material and said polar lipid material are present in a weight ra tio of solvent material: lpid material of from about 60:40 to about 99.1 100179j In certain embodiments, the dosage form also comprises a transdermal plaster comprising (1) a film layer which comprises a polyester film of 0,5 to 4,9 microns thickness, 8 to 85 g/nn strength, rspectively in the two directions intersecting substantially at right angles, 30 to 150% elongation, in the two directions intersecting substantially at right angles and an elongation ratio of A to B of LO to 50, wherein A and B represent data in two directions intersecting at right angles, and A is greater than B, and wherein said.polyester film comprises 0,01 to L0% by weight, based on the total weight of said polyester filrn, of solid fine particles in which (a) the average particle size is Ut001 to 310 microns, and (b) the average particle size is substantially not more than L5 tines the thickness of said polyester film; and (2) an adhesive layer (a) which is composed of an adhesive containing said serotonin agonist and further wherein said adhesive layer (a) is laminated on said film layer over the surface in a 2 to 60 micmns thickness. [00180 SInla certain embodiments, the dosage form can be a transdermal disc comprising: (a) a backing layer which is substantially ipervious to the dopamine agonist; and (b) a 53 polymer matrix disc layer which is adhered to said backing layer and which has microdispersed therein said serotonin agonist, said polymer being bioacceptable and pernitting said serotonin agonist to be transmitted for tramsdermnal absorption, the dopanine agonist being stable in said polymer matrix. [00181) In certain embodimentshe topical formulation or transdernal therapeutic system may further comprise another active ingredient in combination with the first drug (eg, dopamine agonist), e.g., analgesics, antinimetics, psychophamacologic agents, or sedatives. [OO1821 The present invention is contemplated to encompass all transdemnal formgulations, e.g, the technologies described above, with the inclusion of a drug (e.g., dopanine agonist(s)), such that the administration of a drug useful for treatment of disease state or condition in humans via topical brainstem afferent stimulation (de afferentation) therapy via topical administration. Therefore, nodiications of the invention via, esg, the choice and/or amount of drug are considered to be obvious variations of this disclosure and within the scope of the appended claims. 1001831 The present invention also contemplates the administration of the drag (e.g, dopamine agonist) directly below the skin to affect direct brainstem afferent stimulation to the free nerve endings under the epidermis. Such administration may be effected as an injection (eg, subcutaneous injection) or implantation of the drug in immediate release or sustained release form. It will be appreciated by those skilled in the art that providing the dumg in sustained release form and administering it in a suitable form below the skin may provide benefits, including less frequent administration (e.g., in chronic therapy). 1001841 In certain embodiments of the invention, the drug (e,g., dopamine agonist) can be formulated for controlled or sustained delivery at the BONATH via incorporation into a bioconpatible and implantable polyner which can be in the form of microparticles or an implantable insert, or a liquid that fbrns a gel or colloid or a sen-solid after injection (thereby encapsU rating the drug and allowing it to be released in a prolonged and 54 controlled manner at the desired site), For chronic conditions (e g, Parkinson's) or desired prolonged effect, it is contemplated that a drug depot or reservoir may be created under the skin at the BONATH which then provides a sustained release of the drug in proximity to the desired nerve endings and which may be replenished or replaced at the end of the dosing interval. It is contemplated that such administrations of the drug (e.g, dopamine agonist) may provide a prolonged therapeutic effect for at least about 3 days, preferably at least about 7 days, or longer. Such formulations may be administered in certain embodiments as, for example, a subcutaneous depot, 1018561 Implants are placed subcutaneously by making an incision in the skin and forcing the implants between the skin and the muscle, At the end of their use, if not dissolved, these implants are surgically removed. U.S, Patent No, 4,244,949, hereby incorporated by reference, describes an implant which has an outer rmatrix of an inert plastic such as polytetrafluoeroethylene resin. Examples of this type of implantable therapeutic system are Progestasert IUD and Ocusert system. It is contemplated that suc systems can be appropriately modified by one skilled in the art for use in conjunction with the present invention. A conmmercially available product, Norplant@, which is an implant having a core containing levonorgestrel as the active substance, and where the core it surrounded by a membrane of a silicone elastomer of poly(dimethylsiloxatne) (PDMS), Another preparation of this kind is Jadelle@&, in which the core is a poly(dimethy.siloxane) based matrix with levonorgestrel dispersed therein. The membrane is an elastomer made from PDMS and silica filler, which, besides giving necessary strength properties to the membrane, also retards the permeation of the active agent through the membrane. U.S Patent 3,854,480, hereby incorporated by reference describes a drug delivery device, eg, an implant, for releasing a drug at a controlled rate for a prolonged period of tine, The device has a core of a matrix in which the drug is dispersed. The core is surrounded by a membrane that is insoluble in body fluids. The core matrix as well as the membrane are peneable to the drug by diffusion. The materials of the core and the membrane are chosen so that the drug diffuses through the membrane at a lesser rate than through the core matrix. Thus, the membrane controls the release rate of the drug, As a suitable polymer for the core matrix is mentioned 55 poly(dimethylsiloxane) (PDMS), and as suitable polymers for the membrane are mentioned polyethylenec and a copolymer of ethylene and vinyl acetate (EVA), It is contemplated that the above systems may be adapted by one skilled in the art to deliver the drug (eg, dopamine agonists) in accordance with the present invention 1006] One device which may be adapted by one skilled in the art for use in the present invention is described in U.S, Patent No 5,968,542 (Tipton), hereby incorporated by reference, which describes a high viscosity liquid controlled delivery system as a medical or surgical device is provided that includes: (i) a non-polymeric, non-water soluble liquid carrier material (HVLCM) of viscosity of at least 5000 cP at 37.degree, C that does not crystallize neat under ambient or physiological conditions; and, optionally,i) ai substance to be delivered j001871 The ph.armaceutical compositions suitable for injectable use in accordance with this invention include sterile aqueous solutions or dispersions and sterile powders or lyopholysates for the extemporaneous preparation of steride inetable solutions or dispersions. 'The dosage forms must be sterile and it mst be stable under the conditions of manufacture and storage. The carier for injectable fomulations is typically water but can also include ethanol, a polyol (for example, glycerol, propylene glycol and liquid polyethylene glycol), mixtures thereof, and vegetable oil. 1001881 Injectable formulations used in the present invention can also be formulated as itjectable prolonged release fornuations in which the active compound is combined wth one or more natural or synthetic biodegradable or biodispersible polymers such as carbohydrates, including starches, gums and etherified or esterified cellulosic derivatives, polyethers, polyesters, polyvinyl alcohols, gelatins, or alginates. Such dosage fformulations can be prepared for example in the fonn of microsphere suspensions, gels, or shaped polymer matrix implants that are well-known in the art for their function as "depot-type" drug delivery systems that provide prolonged release of the biologically active components. Such compositions can be prepared using artrecognized formulation techniques and designed for any of a wide variety of drug release profiles, 56 1001 89J One example of a useful formulation which may be used in the methods of the present invention for providing a prolonged duration of action is described in US. Patent No. 7,332.,503 (Wikstron, et at), hereby incorporated by reference, Therein, apoiorphine derivatives and the physiologically acceptable salts thereof as wel as formulations thereof are described which provide a prolonged duration of action, The apomorphine pro-drugs can be suspended (as a neat oil or as crystals, or dissolved in a suitable and pharmaceutically acceptable solvent (e.g. water, ethanol, DMSO, i-PraHO or benzylbenzoate)) in a pharmaceutically acceptable depot oil (e,g, viscolco, sesame oil or olive oil) and injected subcutaneously or intramuscularly with a syringe or a "pen injector". Alternatively, these drugs may, in a suitable composition and with a suitable vehicle (penetration enhancer), be applied to a patch for transdennal administration, The composition could include also a local anesthetic (e.g. lidocaine) to avoid injection pain, in particulas at intramuscular injections, In one embodiment, the composition is in the form of a patch or an ointment for trandermoal administration, The patch or ointment preferably also comprises stabilizers, solubilizers and permeation activators to facilitate the passage of the active principle through the skin hi another preferred embodiment, the composition is in the forn of a depot preparation for subcutaneous or intanuscular administration comprising an aponorphine derivative or the physiologically acceptable sal thereof apornorphine derivative, the formulation further contains a local anesthetic, The fonmulations described in the $03 patent can be modified as understood by one skilled in the art to contain other active drugs as described herein fir use at the BONATE. [001901 An injectable depot formuhttion is a dosage form, which is generally intended to have a therapeutic activity for 2 to 4 weeks afler administration (e.g. neuroleptics like Fluphenazine decanoate in sesame oil). In order to maintain effective drug plasma levels the dosage frm should relese the drug at a more or less constant rate during the desired dosinginterval. The difference between such prior art depots and depots used in the present invention is that the in accordance with the present invention, the drug is not needed to be absorbed into the systemic circulation, 57 [001911 A suitable form of depot preparation is the subcutaneous or intramuscular administration of an oil solution and/or oil suspension of a lipophilic drug. This gives a slow transport over the oil-biofluid interface and a slow dissolution in the biophase, Thus, when the drug is dissolved in a polar solvent (e.g., oils), which is non-miscible with the aqueous biological fluids, the drug has to be transported over the oil/water interface, When the oil/water partition coefficient is high, thie transport will be slow, For very lipophilio drugs, the release from the oil phase may last for up to several weeks., The use of depot preparations such as those described herein may be used to deliver the drugs described herein at the BONATI{ [001921 The miaximam volune of an oil solution/suspension to be injected intramuscularly or subcutaneously is 2-4 mL. This is fesile for the preparations of the aporphine derivatives of the present invention, The accumulated daily dose used in apomorphine s.c. therapy in Parkinson's disease is, e.g, 4-10 times about 1-4 rmg (4-40 mg/day). For example, 2 mg Apomorphine HO (or equivalent molar amount of another dopanine agonist(s), as the base or as a suitable salt or ion-pair) may be dissolved in I mL of an oil (sesame oil, Viscoleo or another approved oil) and the mixture gently heated (max 50*C) shaken in a test tube shaker and ultrasonicated for a short time (minutes) until the mixture becomes a homogeneous solution or suspension If necessary, the dopamine agonist may first be dissolved in 50-300 -mul DMSO, water, t-BuOf, PEG, benzzyibenzoate, or another suitable and approved solvent or mixtures thereof, before adding the oil to a total volume of I mL 100193j Another example of a polymeric drg delivery system which may he adapted ftr use in the present invention by one skilled in the art is described in US Patent No. 5,601,835 (Sabel, et al), hereby incorporated by reference, which describes a polymeric drug delivery system for delivery of any substance to the central nervous system. The delivery system is preferably implanted in the central nervous system for delivery of the drug directly to the central nervous system. These implantable devices can be used, for example, to achieve continuous delivery of dopamine, which cannot pass the blood brain 58 barrier, directly into the brain for an extended time period, The inplantable devices display controlled, zero-orde" release kinetics, a life time of a minimum of several weeks or months even when the devices contain water sobe, low mo ecular weight compounds, biocompatibiity and relative non-invasiveness. The polymeric devices are said to be applicable in the treatment of a variety of central nervous system disorders including Parkinson's disease, Alzheinier's dementiaHuntington's disease, epilepsy, trauma, stroke, depression and other types of neurological and psychiatric illnesses, and one skilled in the art can adapt that drug delivery system for delivering the drugs contemplated herein at the BONATh. (001941 Yet another example ofa system that may be adapted for use in the present invention is described in US. Patent No. 5601,S35 (Sabel, et at) , hereby incorporated by reference, wherein a compound such as dopairine is encapsulated within a polymer to form a polymeric device, the device forned of a biocompatible polymer that is plastically defonable selected from the group consisting of ethylene vinyl acetate, polyurethanes, polystyrenes, polyaride, polyacrylamide, and combinations thereof having a non-porous polymer coating thereon with one or more openings, with united water sorptivity and slight perieability to the passage of small, aqueous-soluble molecules, wherein said compound is linearly released (e.g, zero order release) front said polymeric device over a sustained period of time of at least 65 days at a predetermined level and rate when implant ed in a patient at a specific site within the central nervous system where the compound is released directly into the central nervous system and the device remains essentially intact throughout the release period The delivery device is a two-phiase system which is manufactured using standard techniques such as blending, mixing or the equivalent thereof, following selection of the biologically active material to be delivered and an appropriate polymer for formation of the matrix,'The general method of solvent casting as disclosed by Siegel and Langer, "Controlled release of polypeptides and other macromolecules", Phanaceutical Research 1,410 (1984), is modified so that drug is dispersed within the devices to create channels and pores to the surface flbr release of the dr'ug at the desired rate Where appropriate, a coating impermeable to the drug is placed over a portion of the drug containing polymer matrix to further regulate the rate of 59 release. One skilled in the art can adapt ihat drug delivery system fr deliveiag the dregs contemplated herein at the B{ONATH. jOU951 Yet another foemulation which may used to deliver the drug (e.godopamine agonists) as set forth in the present invention at the BONATH is described in U.S. Patent No. 7,3 4)636 (Caseres, et aQ, hereby incorporated by reference, which describes injectable implants comprising glycolic acid and biocompatible/bio-absorbable polymeric particles containing a polymer of lactic acid. The particles are small enough to be injected through a needle but large enough to avoid engulfment by macrophages, The injectables of this invention may be in a pre-activated solid fonn or an activated fomI (eg.) injectable suspension or emulsion). [)01961 t is further contemplated that the system described in US Patent No. 6,86,006 (Roser, et ai hereby incorporated by reference can be adapted by one skilled in the art for use in the present invention for delivery of drugs at the BONATH, Therein. are described delivery systems suitable for delivery of bioactive materials to subcutaneous and nradermal, intramuscular, intravenous tissue, the dehvery system being sized and shaped for penetrating the epidermis. The delivery systems conpfses a vitreous vehicle loaded with the guest substance and capable of releasing the guest substance in situ at various controlled rates, Subdermal implantable therapeutic systems have also been formulated for slow release of certain pharmaceutical agents &r extended periods of time such as months or years: A well-known example is Norplant@ for delivery of steroid hormones. [001971 In membrane peineation-type controlled drug delivery, the drug is encapsulated within a compatment that is enclosed by a ratelimiting polymeric membrane. The drug reservoir may contain either drug particles or a dispersion (or solution) of solid drug in a liquid or a matrix type dispersing medium. The polymeric membrane may be fabricated f&m a homogeneous or a heterogeneous nonporous polymeric material or a microporous or semipernneable membrane. The encapsulation of the drug reservoir inside the polymeric membrane may be accomplished by molding) encapsulation, 60 microencapalation, or other techniques, The imphmts release drugs by dissolution of the drug in the inner core and slow diffusion across the outer tnarix. The dug release from this type of implantable therapeutic system should be relatively constant and is largely dependent on the dissolution rate of the drug in the polymeric membrane or the diffusion rate across or a microporous or semipermeable membrane The inner core may substantially dissolve over time; however, in devices currently in use, the outer matrix does not dissolve, [001981 Other implantable therapeutic systems involve matrix diffusion-type controlled drug delivery, The drug reservoir is formed by the homogeneous dispersion of drug particles throughout a lipophilic or hydrophilic polymer matrix, The dispersion of drug particles in the polymer matrix may be accomplished by blending the drug with a viscous liquid polymer or a semisolid polymer at room temperature, followed by cross-linking of the polymer, or by mixing the drug particles with a meIted polymer at an elevated temperature. It can also be fabricated by dissolving the drg particles and/or the polymer in an organic sol'veIt followed by mixing and evaporation of the solvent in a mold at an elevated temperature or under vacuum, The rate of drug release from this type of delivery device is not constant, Examples of this type of implantable therapeutic system are the contraceptive vaginal ring and Compudose implant. PCT/03B 90/00497 describes slow release glassy systems for formation of implantable devices. The described implants re bioabsorhable and need not be surgically removed One skilled in the art can adapt these drug delivery systems or delivering the dmugs contemplated herein at the BONATH> [001 99) in microreservoit dissolution-controlled drug delivery, the drug reservoir, which is a suspension of drug particles in ant aqueous solution of a water-miscible polymer, forms a homogeneous dispersion of a multitude of discrete, unreachable, microscopic dug reservoirs in a polymer matrix, The microdispersion may be generated by using a high-energy-dispersing technique Release of the drug from this type of drug delivery device follows either an interfacial partition or a matrix diffusion-controlled process An example of this type of drog delivery device is the Syncro-Mate-C Implant 61 (O02lOI Yet another fornulation which may be adapted by one skilled in the art for use in the present invention is described in U& Patent No. 6,576;263 (Truong , et at hereby incorporated by referencewhich describes a prefrrmied object for delivering an active agent for a subject, the preformed object including crosslinked protein and methods of making and using [00201 Yet another formulation which. may be adapted by one skilled in the art for use in the present invention Is described in U.S, Patent No. 6,287,5 8 (Shih , et a,), hereby incorporated by reference which describes a composition and method for releasing a bio~ active agent or a drug within a biological environment in a controlled manner The composition is a dual phase polymeric agent-delivery compositions comprising a continuous biocompatible gel phase, a discontinuous particulate phase comprising defined microparticles and an agent to be delivered, A microparticle containing a bio active agent is releasably entrained within a bioconpatible polymeric gel matrix The biotactive agent release may be contained in the microparticle phase alone or in both the microparticles and the gel matrix, The release of the agent is prolonged over a period of time, and the delivery may be modulated and/or controlled, In addition, a second agent may be loaded in some of the microparticles and/or the gel matrix. 100202 Yet another formulation which may be adapted by one skilled in the art for use in the present invention is described in U.S Patent No. 7,364,568 (Angel , et al), hereby incorporated by reference, which describes a transdermai transport device includes a reservoir for holding a formulation of an active principle, and a needle with a bore extending along the length of the needle from a first end of the needle to a second end of the needle the second end is substantially aligned to a plane parallel to a body stuface of a biological body when the device is placed on the body surface, The device also includes an actuator which pumps the formulation through the bore of the needed between a target area of the body and the reservoir, [002031 In yet other embodinents of the invention, the dopamine agonist is infused into the patient at the BONATH using technology known to be usefu for infutsing other 62 drugs, such as an insulin pump. One such system, U.S. Patent No, 7,354,420 (Steil et al, hereby incorporated by reference, describes a closed loop infusion system contros the rate that fluid is infised into the body of a user, The closed loop infusion system includes a sensor system, a controller, and a delivery systemThe sensor system includes a sensor for monitoring a condition of the user. The sensor produces a sensor signal, which s representative of the condition of the user, The sensor signal is used to generate a controller input. The controller uses the controller input to generate conunands to operate the delivery system The delivery system inifses a liquid into the user at a rate dictated by the commands from the controller, Preferably, the sensor system monitors the glucose concentration in the body of the user, and the liquid inkhsed by the delivery system into the body of the user includes insulin, {002041 The present invention is contemplated to encompass all inplantable or injectable formulations, e,g, the technologies described above, with the inclusion of a drug(s) (eg. dopamine agonist(s)), such that the administration of a drug useful for treatment of disease state or condition in humans via topical brainstem afferent stimulation (de-afferentation) therapy, Therefore, modi fications of the invention via, e.g the choice and/or amount of drug are considered to be obvious variations of this disclosure and within th e scope of the appended claims, 63 DETAILED DESCRIPTION OF PREFERRED EMBODMMENTS [00205] The present inventipn will. now be more fully described with reference to the accompanying examples, it should he mderstood, however, that the following description is illustrative only and should not be taken in any way as a restriction on the generality of the invention specified above. EXAMPLE I TOPICAL FORMULATION [002061 An aqueous based apomorphine cream was proAuced using Lipoderm" as the career, Lipodermi/LP is a commercially marketed compounding agent (from PCCA, Pharmaceutical Compounding Centers of America) having the following ingredients: Ethoxydiglycol, Water (Aqua), Glycerin, C>sAlkyl Benzoate, Glyceryl Stearate, Dimethcone, Cetearyl Alcohol, Cetearyl Gluoside, Polyacrylamide, Cetyl Alcohol, Magnesium Aluminum Silicate, Xanthan Gum, Aloe Vera (Aloe Barbadensis), Tocopheryl Acetite (Vitamin E Acetate), Prunus Amygadalus Amara (Bitter Almond) Kemel Oil, Vitis Vinifera (Grape) Seed Extract, Triticum Vulgare (Wheat) Germ Oil, Retinyl Palmitate (Vitamin A Palmitate), Ascorbyl Palmitate (Vitamin C Pahnitate), Pro Lipo Multi-emulsio Liposomic System. Tetasodium EDT A, Phenoyethanol, and Sodium Hydroxymethylglycinate. The concentration was lmg of apomorphine in Iml of Lipoderm, The concentration of apomorphine in the Lipoderm is 1mg in 0.5 ml, Lipoderm is a whitish cream with no smell 64 EXAMPLE 2 DRUG STUDV USING FORMULATION OF EXAMPLE I 1001 The efficacy of a topical apomorphine formulation was studied in six human patients suffering from Parkinson's disease who presented to the author's neurologic clinic at a certain stage of "off state" in their functioning For each of these patients, an amount of the compounded cream prepared in accordance with Example I containing approximately 1 mg apoinorphine (except 0.5mg in one patient, E-K) in 0.5 mi of compounding mediuma, was applied at the back of the neck at the hairline (BONATH) of the patient, so as to deliver the drug though topical regional neuro-affctive (TRNA) therapy, (002081 The patients, who were all on other routine Parkinson's medications, were evaluated using the UPDRS Motor Scale pre and posttreatment with te topical apomorphine. All patients had not had their respective Parkinson's medications for 4-6 hours and thus were in Lheir "oftstates't The UPDRS is an Objectified observer-rated scale for evaluating Parkinsowns disease that is used extensively in research. The scale looks at 27 tems with 0 to 4 ratings for each: 0 for normal and 4 for the most extreme dysfunction. Accordingly, for a given patient, a UPDRS Motor Scale of 0 is normal and worse case scenario, 108 (27x4). A. representative UPDS form is presented as Table I 65 TAKEF . U . .O ED PARKNSONS DISEASE RARLNC SCALE (UP j PAR I MaS r Eaaae (13h =c to be ampleltd inceet t 00,31.0. k$40) - -- Nan 2i shloss ofxpressndetie, adoru 2. MAen aslsnred bhaander'stadr; saodera ely imp' ssd 3. Marked imnpaiss1'cs lt to un~devtand 0. a snrai I. Miainim hypasrfr'a could be har poakcsr &c 2. Susightat dcenniiay *1'nat d 4sm a affacW axpscon 3. Maeah ypamimoa; lips pasnome sac 4 e tre 4, Maske o tixed heses wssh severe o mpletes of a fal ssptsskn lps pasted M~ inch, or sae 20. reesr st sat: 2Oa) Fae. ips.n ae 0 Abent 201) Fight ad 1. Slight ad intmquensdy presseni 24t)Lef lad 2s Mild is amphnde ss per s, as ma.derm: in aspliude~at tniy interdimemly preset 20di) 11k ibuo3 Modeate ina amlitude and pssetmast of the St 2 a) La. ibs4 Maked its amph..ssl ansd pesenti mass sfithe tham 1,Aetlan 'r poatsa frerroflszsdst 21a) IRght . Abst 216') it)I Shght p stuwstl rations 2. Maderase as arpsdg prset twas action tod a e ampun ee; present w paauehald s as weH s action 4. Mated amphude: tsro %int Sedin 2 ig dity 5gesdg pqs samv ement amajer joists WISh pallena rsed s an ttig patitiasss gweeleg" to bhe dgno 22a) Nek 0. leans 221' Rsghpoet 1, Sght or detetabkey whii en acsivaald by nsror at other mslt 22, ) iupp tosst 2 wMi a 22D) Rs t at. Ma&rd rssangeo oymaon ead;y vano 224 Left lowes 4. Seyee; rantg of sdess acMmed wsth difly 66 TAaL.E Odue UNIFAE EiMLRKINSON'S DISEASE ATI$UO SCALE WO (UERS)(Ceno 25 Finger ap*s4 ip et tapa Ttthumb hn indea 1l3 i npid ssu esn wath vide-t dsitode poasibe ohh srpar1yp~ 23*) R3h ght Ntsnna 233>) La. Mihslowig andr sedundeii p i sd 2. d4tosky imapainid; derinite and endy fatin may Pave oecaos S anrests in nemar 3. Semey impaired; fregunt tesitaiarmin iraa moverasuts es arresi in ngoing meet 4. Can barely pedim the tak 24, Hand: rnovementas (padent operas and coes hmnttu rapid sucevsaen with msidit ampiWden possible, ebah tran separd ly 24a1) Righi Med 241>) Lef I Ml Wsawng atter adacoen iratspltut 2. Modedy impaired;dfinie and eay faiguing; may havecsona areat in rnov~enot S Serey mpai fre un eira n in iniztiang n me ns or at in *ngnir rumewt 4. Can barely p INfrmhe ask 5 Epid afternadag movements OMad lot i los new s of dpandtavericaly or hsruti ms ae kn A ptlirtde as possible, both amds wsftal y4 tSa Itght Nonrml 214 Len3 Mud shaingi nr eduston m nwplitue 2 Mdeeiy paired; denite andi ady fag; y have a caniosal asnsan VSeeely imspaired; freo t ?esmaton n i iag nwemrtatsr arrest inrongoing nasvemnent xIb L1f 'Oc r anry prot A taste 24 Eet agity (atnt s heel on groudn rap seerso pic;Ing up enNore We anpldde should be about incks 26ay Rigin 0 Normars 26/s tea I. Mislong and/r metideon in amgud 2. Moderately i md;delw ard early fatiguing;imy have occaional aresta ma moemrerr 3. Severely im'paerieddegethesitadan in iaiv oen or arrens in ongrorng momnt 4 ra barey perform fi task 21 MAig fromt thai tadleis terripta te arise fron a stralglm4aekeed wond er metal hr'. with ain fola across chet) 27a) Righti, Normal 270) Left Sow or arsay need more than oe attempt 3. Pusms sef tsp from sme or sat 3. Tends to fall back ar nay hm to try more than on dmne b'stagetu.p eamisi hebp 4. Unable in ase wnhrt help 67 TABLE (Cwnmled} VNWE1 PAtKiNSON'S DISEASE RATING SCALE (UfDit) COIntMed 3'AS ItU Motor Examan (We seeto b ,emphd nrmem A9 0.5 3.3. O) 25 Pottura Nomd eff*dt Not qnite erei hd y stooped3 pusa eo c s .e.orrna P- olde persn 2 Modeertety stooped sre~ ttely ahnord can sieAly le s owne side Swevely s t p yrie with kypheisa eshem:node y caning tn one side 4. barked niaon with eaee a~snstmaly of po'ete 29, Gzaz Norm Z. aks skddy; may shdle with sho te as tnoeheatnion popit n 2 Wlls wos ifficuly ot reires titde or so es'ataco ary have some testin tioe. skot stoe, or propsssion 'verI dishbance of gait; rtquins aswstzzme Cannot wlk at a<,even with assaner 30, fstuat atbity (response to suddo postrior di4Ptsnwst preduted by pult on shaoidirs white patie 0ree.tshT ees open and foot Aghty apartpaents prerdp O Nomea 2 Retruune hoateesoOS onaded Absence of postuaegsponn tvdft if otesgh by antier 3. Veg unskytb, tend tolose atas e spon usly 4. 3s Iate ta tand ithnuaasasisane 31. ndy bdylesia and lypoWdeaa ombing swua. tameydwerised arm sigenl aenpil ant poverty of msovemsent in generaW 0. None 3 Miorsrill siownoss, gin aoeent a 'dlihmta ehastr ossl be nomalforsome pesns;possie reduced amplitude 2. ilddegreofsowns nd poae of novemeni thatis d iely abnoesral akemrnidyV some reduced amnputadt 3. Moderate sleoess; poveity or -mlansmphtdek of iovonene mared stow nspverty or ssoiol mplitude ofmos'wne 68 [002091 The results of the study of Example 2 are set forth in Table 2 below: TABLE 2 CLINICAL RESPONSE OF PARKINSON'S PATIENTS IN THE "OFF-STATE" TO TOPICAL APOMORPITINE THERAPY CHANGE IN UPDRS MOTOR SCORES* patient sex Age Ouration Parkinsmts corrrent Paklu) nes UPDRS Motor Mediations Pre POA Diff EB F 86 8 years Stalevo (Siwemet & 51 32 19 Comntan) GV N 87 12 Stalevo 38 i8 20 EK F 75 6 Sinetnet and Mirapex 36 19 17 NWIV M 88 Sinelmet and Mirapex 51 31 20 SK F 89 5 Sinemet 66 52 14 IR M 64 1 Sinenmet, Mirapex and 57 34 23 Amantatine *L) mg of apornorphine in05ml Lipodrm except 0.Smg in patient (K,) Patients were re-examined within M$ hour after topical application., 1002101 As can be appreciated from Table 2, these 6 patients were fairly significantly affected by their disease, Within 15-30 minutes after application of the compounded apomorphine cream, they were all improved significantly. The average UPDRS score post-treatment was 31, indicating an average improvement of 19 points, The duration of improved functional sate was observed to be frotn 2% to 26 hours, representing the time period patients felt they were able to fiunction otT their usual Parkinsons medications due to the positive therapeutic effect of the topical apomorphine, Alter this period, all patients returned to their Previous drug region, which consistdof taking Parkinson's 69 medications 3-4 times per day, By their own accounts and those of their care-takers, their current therapy was considered suboptima This was evident on fmial clinical exar and documented by the UPDRS, as noted in Table 2, The only significant side-effects expressed were transient fatigue and dizziness, in patients EK. and S.K [002111 Video-tape of pre and post--treatment states with topical apomopltine was performed on several patients additionally documenting clinical improvement. EXAMPLE 3 ADDITIONAL CLINICAL EXPERIENCE-. PARKINSON'S DISEASE [002121 In the inventor's out-patient neurology practice, in excess of 60 PD patients have been treated with topical apomorphine emnploying the princip es of topical regional neuroafkctive (TRNA) therapy in similar fashion as in Exampe 2 That experience suggests topical apomorphine alleviates clinical symptoms of PD in a measurable way over 85% of the tine when patients are treated in the "off-state" and exhibiting such symptoms: tremor, rigidity, postural instabilityand reduced spontaneity among others Symptom improvement was o nically evident to both the patient and the treating physician within 15 minutes of topical drug applications No appreciable side-efTects were noted; Clinical benefit lasted, on the average, 4 hours, with some patients reporting over I0 hours. Formal double blind, placebo-controllede cross-over long-term studies are contemplated.

EXAMPLE 4 TRNA THERAPY IN TREMOR oo02l3 In the inventor's out-patient neurology practice, approximately 20 patients with tremor have been treated with topical apomorphine in sini lar fashion as in Example 2. Improvement in tremor not attributed to Parkinson's disease has also been noted with TRNA apomorphine therapy. This has consisted of patients with benign essential/familial tremor as well as tremor associated with Multiple Sclerosis, stroke disease, and degenerative CNS conditions such as cerebellar degeneration, 1002141 The inventor treated 5 patients with benign essential tremor. They were either all on their tremor medications at the time or had given up on drg therapy because of side-effects One 74 yr. old lady (on video)-with tremor since age 19, was on 4 meds when the inventor treated her on 3 occasions, She responded dramatically tremor improved over 70%) each time and is now using the topical apomorphine (1 mg/05 ml) 2xiday on a regular basis. All the other patients also responded to I mg of apomorphine to varying degrees---anywkrhere from 30-80% reduction in tremor. 1002151 The inventor also treated 3 patents with MS related tremor, They also all responded with 50-80% reduction 100216) The inventor also treated 2 patients with stroke related tremor. One had been severely affected by tremor and incoordination for over 10 year's and she responded dramatically. As of filing, this patient is using it on a regular basis: I mg once to twice a day. The other patient also improved but the cost of drug from the compounding p harmacy was prohibitive. [002171 The inventor has treated 2 patients with CNS degeneration related tremor (cerebelar degeneration); one is 46 yr. old female the other a 20 yr old male (video taped). As of filing, both responded and are using the cream 2x/day. Both these patients had either failed other drugs or could not tolerate them.

71i 10021,81 The balance of the tremor patients, 6 patients, were of uncertain etiology Some of them had components suggestive of early Parkinsons Disease (PD) or tremor predoninant PD, In these, the response was present but not as dramatic, 30-50% reduction, [002191 The duration of improvement of tremor in all these patients was on average 4 hours. EXAMPLE 5 DYSTONIA AND TORTIOLULIS [002201 in the inventots outpatient neurology practiceseveral patients with cervical dystonia and torticollis have .e observed to improve wit topicalapomorphine administered in similar fashion as in Example 2. Some of these patients also exhibited improvement in the spasticity that involved aspects of their bodies when present. in patients with significant rigidity and dystonia, the reduction i muscle tone was noticeably accompanied by an overall improved affect and spontaneity, This may be attributed to diminished pain and disability associated with the dystonia bat other mechanisms associated with TRNA aponiorphine therapy need also to be considered. This phenomenon was also observed in Parkinson's Disease (PD) patients with significant rgidity and motor complications Improved cognitive abilities and speech was also observed in some of these patients, These observations require further detailed study [00221] The inventor has treated 3 patients with cervical dystonia and torticollis, One patient was treated three times and she continues to use I mg apomorphine twice a day on her own for relief ofsymptoms. A video exists on this patient. The other two patients also responded to varying degrees that was noted by family embers, [O(2221 When PD was associated with significant rigidity, speech difficulty, and distress (both physically ad emotionally), the response appeared to be the most dramatic All 72 patients reported a "calming and relaxing" effect which was obvious in their facial exprmssions. Speech was also significantly improved, 1i the 15 patients the inventor treated in an uncompleted trial (discontinued for reasons other than the treatment), speech, swallow (by video), and cognition were documented as improved, In these IS patients, active and placebo were given in 5 patients twice and once each for the remaining 10 patients, EXAMPLE 6 OTHER APPLICATIONS OF TRNA THERAPY IN CLINICAL PRACTICE [002231 The inventor has also used topical clonidine and rivastignine in the form of currently comnercialiy available transdermal patches (Catapress TTS and Exelon patch, respectively) applied to the posterior cervical region (back of the neck at the hairline, 4 BTONA'ITH") to capitalize on the principles of TRNA delivery, These transdenal patches were used in patients clinically unresponsive to the usual methods of treatment with these patches----placement at the usual ites of placement on the body. In placing the transdermal patches at the BONATHmore efficient and effective therapeutic action of these 2 dogs is elicited. 100,2241 The inventor administered Catapres TTS@ 11 mg patch at the BONATH ona female patient 52 yr, old whd had sutfered an intracranial hemorrhage from a ruptured aneurysm. She had uncontrolled central hypertension despite 4 ieds and had also failed traditional placement therapy with Catapres, The patch was placed at the BONATE and after 1045 minutes, the patient's B? topped from 240/80 to I80. 110, still unacceptable but better than what it had been for years. The patient discontinued application of the patch at the BONATH after a period of time due to apparent headaches and remains with severe hypertension which has been deemed incurable by cardiologists and renal physicians. 73 f002251 Wih respect to the Exelkn@ patch, the inventor is administering this patch at a dose of 4.6 mg/24 hr patch diiy at the BONATH, in 6 patients at the time of filing. The patients are tolerating this treatment, but it is still too early to determine the effect on their dementia [002261 One of the problems with systemic choflnesterase therapy (whether the treatment is with Aricept), FxelonV, or Reminyl@), is that of G1 side-effects (especially nausea and upset stomach). TRNA therapy appears not to have this, But, still the patch was designed for absorption into the bloodstream and may get into the systemic circidation when administered at the BONATH. It is hypothesized that when made specifically fbr BONATH application, the dose (particularly tissue penetration) from a patch could be much lower and for a more prolonged delivery, eg.. from about 3 days to about I week, CONCLUSIONS REGARDING EXAMPLES 2-6 (00227 These preliminary open-label findings in an outpatient office setting suggest potential Utilty for apomorphine TRNA therapy in the management of Parkinson's Disease (PD) and other conditions This form of apornorphine has also been used in benign essential tremor and tremo r associated with multiple sclerosis (MS), stroke, and CNS degenerative processes, such as cerebellar degeneration, with similar results. No formal blinded, placebo-controlled studies have been performed at this time; however, preliminary trials using placebo (oompounding medi untalone) and active drug suggest the validity of the reported findings. A double-blind, placebo-controlled, crossover study is deemed necessary to establish "proof of concept" and confirm these preliminarvy results. .74 (002281 The examples provided above are not meant to be exclusive. Many other variaions of the present invention would be obvious to those skilled in the art, and are i~mtcntenatec to be Within the scope of the appended &hims. [00229] The hypotheses of the inventor provided throughout the specificadon are for possible explanation purposes only, and are not meant to be limiting iany way 75

Claims (22)

1. A method of Itreating a disease state or condition in hinans with a drug comprising administering a drug selected from the group consisting of anti epileptican anxiolytc, a neuroleptic, an antipsychotic, an analgesic, an anti inflammatory, an anti4'arkison'stdseaselsyndrome drug, a sexual dysfunction dnig, a drug for the treatment of dystonia, a drug for the treatment of spasie conditions, a drug for the treatment of benign essential/famifal tremor, a drug for the treatment of tremor, a dog for the treatment of chronic encepahalopathies, a drug for the treatment of congenital CNS degeneration conditions/cerebral palsy, a drug for the treatment of cerebellar degeneration syndromes a drug for the treatment of neuropathic and/or neurogenic pain, a drug for smoking cessation, a drug for appetite suppression, a drg for neurodegenerative conditions, a drug for the treatment of multiple sclerosis, a drug for the treatment of insomnia, a drag for the treatment of fatigue, a drug for the treatment of vertigo, nausea and/or dizziness, a dug for the treatment of writer's cramp and restless leg syndrome, a drug for the treatment of ADD/ADHD, in a therapeutically effective amount to treat the disease state or condition, to the back of the neck at the haidine in close proximity to and under or on the area of skin above the brain stem to provide regional neuro-affeetive therapy to the patient. 2, The method of claim 1, wherein the drug is a dopamine agonist;

3. The method of claim 2, wherein the dopamine agonist is selected from the group consisting of apomnorphine, pramipexole, ropinrale, bromocriptine, cabergoline, pergolide, rotigotine. entacapone, tocapone seligiline, and mixtures of any of the foregoing

4. The method of claim 2, wherein the drug is apomorphine. 76

5. The method of claim 2, wherein the disease state or condition is Parkison's disease and/or related syndrones/diseases 6, Tlhe method of caim 1, wherein the drug is selected from the group consisting of the drug is a dopamine agonist, COMT inhibitors, MAO-B inhibitors, aid mixtures of any of the foregoing. 7, The method of laim 2, wherein the condition is male ereetle dysfunction

8- The method of claim ', wherein the drug is an anti-epileptic drug selected from the group consisting of Valproic acid, Leviteracetem, Lamotri gene, Topiramate, Pregabalin, Gabapentin, Carbamazepine, Oxcarbazepine, Phenobarbital and other barbiturates, Tiagabine, Retigabine, Lacosamide, Perampanel, and mixtures of any of the foregoT ng The method ofcaim 1, wherein the drug is an anxiolytic 10, The method of claim , wherein the drug is a neuroleptic and/or an antipsyotic, 1. The method of claim 1, wherein the drug is an analgesio and/or an anti inflammatory. 12, The method of claim 1, wherein the drug is used in the treatment ofneuropathic and/or neurogenic pain. 13, The method of claim 1, wherein the drug is for smoking cessation,

14. The method of claim 1, wherein the drag is for multiple sclerosis. 15, The method of claim 1, wherein the drug is for insomnia. 77 16, The method of claim 1 -wherein the drug is for fatigue.

17. The method of claim 1, wherein the drug is for verfigo, nausea and/or dizziness. 1 The method of claim , wherein the drug is fbr writer's cramp and restless leg syndrwme,

19. The method of claim I, wherein the drug is an appetite suppressant; 20, The method of clain 1, wherein the drug is for ADD/ADD-I.

21. The method of claim , wherein the drug is a tricyelic antidepressant (TCA). 22 The method of claim wherein the drug is a tetracyclic antidepressant 23 The method of claim , wherein the drug is an atypical antipsychotic,

24. The method ofe claim 1, wherein the drug is an appetite suppressant.

25. The method of claim 1, wherein the drug is formulated in a pharmaceutically acceptable immediate release topical carrier 26 Th method of claim 25, wherein the carter is aqueous-based 27 The method of any of claims 2-5, further comprising formaating the dopamine agonist in a pharmaceutically acceptable immediate release aqueous-based carrier, and applying a sufficient amount to the BONATR of the human patient such that the onset of clinical effect occurs i less than about 30 minutes, 28, The method of claim 1, wherein the therapeutically effective amount of dopanmino agonist is applied as a unit dose comprising from about 0.25 mg to about 4 mg dopamine agonist based on apomorphine, or an therapeutically equivalent amount of another dopamine agonist. 78

29. The method of any of Claims 25 or 26, wherein the carrier is a gei or cream 30, The method of any of claims 25, 26 and 29, further comprising adding at least one adjuvant selected fom the group consisting of a penetration enhancer, anti oxidamt, stabilizer, and mixtures thereof the earner.

31. The method of any of claims 2-5, wherein the dopamine agonist is incorporated into a sustained release transdermal delivery system which is capable of delivering from about 4 mg to about 50 mg of the dopaxrine agonist through the skin of a human patient over a 24 hour period, the transdermal delivery system being capable of delivering the dopamine agonist in such amounts for a time period from about I to-about 7 days,

32. The method of claim 31, wherein the transdermal delivery system is selected from the group consistingof a transdemai patch, a transderrnai plaster, a transdermal disc, and an iontophoretic transdermal device.

33. The method of claim 1, father comprising formulating the drug in a pharmaceutically acceptable immediate release agnueous-based carrier, and applying a sufficient amount to the BONATHI of the human patient such that the nset of clinical effect occurs in less than about 15 minutes. 34, The method of claim wherein the drug is administered via implantation or injection at the BONATRi 35 The method of claim 1, wherein the drug is administered via injection in an immediate release phanaceuticaly acceptable carrier for injection 79

36. The method of clam1 wherein the drug is administered via injection or implantation in a controlled release carrier to provide a prolonged effect of the dopamine agonist. 3 The method of claim i.wherein the dg is incorporated into a delivery system selected from the group consisting of a gel, a matrix, micropartices, a pelet, an insert, a c,, cida material, and mixtures of any of the foregoing

38.Jhe method of claim L" wherein the drug is administered to create a depot under the skin at the BONATH

39. The method of any of claims 2-5, wherein the administration provides from about 4 nig t o about 50 mg of the dopamine agonist per 24 hour period, based on apomorphine, or an therapeutically equivalent amount of another dopamine agonist. 40 The method of claim 1, wherein the administration provides an effective administration of drug at the back of the neck at the hairline in close proximity to and under or on the area of skin above the brain stern to provide a therapeutic effect for at least about 3 days. 4L The method of claim 40, wherein the administration provides an effective release of drug at the site for at least about 7 days, 42, A topical formulation, comprising a dopamine agonist in a pharmaceutically acceptable aqucousbased cancer, the dopamine agonist being incorporated t into the carter in at least one init dose comprising from about 4 mg to about 50 mg dopamine agonist, based on apomorphine, or an therapeutically equivalent amount of another dop amine agonist. 80 43, The topical formulation of claim 42, which when applied in a unit dose to the BONHAT- of the human patient provides an onset of clinical effect occurs in less than about 30 ininutes.

44. The topical formulation of claim 43, wherein the dopamine agonist is apomorphine,

45. The topical fonnulation of claim 44, comprising 0.001 to about 80% by weight dopamine agonist and frorn about 0 wt, % to about $01) wt. % of a permeation enhancer composition, with the remainder of the composition comprising a carrier or vehicle, 46 The topical formulation of claim 45 wherein the dopamine agonist is included in a concentration of about I mg drug/mi of carrier 47 A topical fonnulation, comprising a drug selected from an anti-epileptic, an anxiolytic, a neuroleptic, an antipsychotic, an analgesic, an anti infianmatory, an antn-Parkinson's disease/syndrome drug, a sexual dysfunction drug, a drug for the treatment of dystonia, a drug for the treatment of spastic conditions, a drg for the treatment of benign essential/familial tremor, a drug for the treatment of tremor related to MS, a drug for the treatment of chronic en-cepahalopathies, a drug for the treatment of congenital CNS degeneration condtions/cerebrai palsy, a drug for the treatment of cerebeflar degeneration syndromes. a drug for the treatment of neuropathic and/or neurogenic pain, a drug for smoking cessation, a drug for appetite suppression, a drug for neurodegenerative conditions, a drug fir the treatment of multiple sclerosis, a drug for the treatment of insomnia, a drug for the treatment of fatigue, a drug for the treatment of vertigo, nausea and/or dizziness, a drug for the treatment of writer's cramp and restless leg syndrorne, a drug for the treatment of ADD/ADHID, and conibinations of any of the foregoing, in a formulation suitable for administration at the the back of the neck at the hairline 8 in close proximity to and under or on the area of skin above the brain stem of a human patient to provide regionalneurowaffectve therapy to the patient

48. The formulation of claim 47, which is in a fonn selected from a topical crean, ointment or gel; a transdennal device; or an implantable or injectable formulation,

49. A sustained release transdennal deliverysystem comprising a therapeutically effective amount of a dopamine agonist in a reservoir or in a matrix, the transdermal delivery system being capable of delivering from about 4 mg to about 50 Mg of the dopamine agonist through the skin of a human patient over a 24 hour period after being applied to the skin, the transdernnal delivery system being capable of delivering the dopamine agonist in such amounts for a time period from about I to about 7 days, 50, An injectable or implantable sustained release formulation of a dopamine agonist incorporated with a sustained release carrier which is capable of deliveing from about 4 rg to about 50 mg of the dopamine agonist to the trigeniinal nerve system of the brainstem on a daily basis for at least about 3 days, $1. The use of a dAug selected from, the group consisting of anthepieptic, an anxiolytic a neuroleptic an anti-psychotic, an analgesic, an anti inflammatory, an ann-Parkinson's diseesyndrome drug, a sexual dysfinction drug, a drug for the treatment of dystonia, a drug for the treatment of spastic conditions, a drug for the treatment of benign essential/familial tremor, a drug for the treatment of tremor related to MS, a drug for the treatment of chrnic encepahalopathies, a drug for the treatment of congenital CNS degeneration conditions/cerebral palsy, a drug for the treatment of cerebellar degeneration syndromes, a drug for the treatment of newropathic and/or neurogenic pain, a drug for smoking cessation, a drug for appetite suppression, a drug for neurodegenerative conditions, a drug for the treatment of multiple sclerosis a drug for the treatment of insomnia, a drug for the treatment of fatigues a drug for the treatment of vertigo, nausea and/or dizziness, a 82 drug for the treatment of writer's cramp and recess leg syndronie a drug for the treatment of ADD/ADHD, in the preparation of a medi'ament for providing regional neuro-affective therapy to a human patient, wherein the drug is administers at the back of the neck at the hairline in close proximity to and under or on the area of skin above the brain stem to provide regional neir-affective therapy to the patient. 83