USOO841 0129B2

(12) United States Patent (10) Patent No.: US 8,410,129 B2 Brooks-Korn (45) Date of Patent: Apr. 2, 2013

(54) TREATMENT FOR PARESIS/PARALYSIS OTHER PUBLICATIONS Longer et al. (Remington's Pharmaceutical Sciences 18th Edition, (76) Inventor: Howard Brooks-Korn, Millbrae, CA Chapter 91, 1990, p. 1676-1682).* (US) Kahn, S. & Smith, M. “beta-Endorphin and Muscle Contraction.” Muscle & Nerve 18:1250-1256 (1995). (*) Notice: Subject to any disclaimer, the term of this Kahn, S. & Smith, M. “Actions of Endorphin Peptides on Muscle.” patent is extended or adjusted under 35 Peptides, vol. 8, No. 1, 87-92 (1997). U.S.C. 154(b) by 3059 days. Kalman, S. et al., “Morphine and Multiple Sclerosis.” European J. Pain, 6:69-80 (2002). Braund, et al., (1994) “Clinical Syndromes in Veterinary Neurology” (21) Appl. No.: 10/367,386 2d Edition Table of Contents Provided. Gaynor, et al., (1997) “Risk Factors for Acquired Megaesophagus in (22) Filed: Feb. 14, 2003 Dogs”.J. Am. Vet. Med. Assoc. 211 (11): 1406-12. Isozaki, et al., (1996) “Early Diagnosis and Stage Classification of (65) Prior Publication Data Vocal Cord Abductor Paralysis in Patients with Multiple System US 2003/O16667OA1 Sep. 4, 2003 Atrophy” J. Neurol. Neurosurg. Psychiatry 60(4):399-402. Ooi. (1992) “B-Mode Real-Time Ultrasound Assessment of Vocal Cord Function in Recurrent LaryngealNerve Palsy Ann. Acad. Med. Singapore 21(2):214-216. Related U.S. Application Data Osei-Lah, et al., (1999) “Bilateral Abductor Vocal Fold Paralysis Due to Myasthenia Gravis' J. Laryngol. Otol. 113(7):678-679. (60) Provisional application No. 60/357,389, filed on Feb. Reisine, et al., (1996) "Opioid Analgesics and Antagonists' The 15, 2002. Pharmacological Basis of Therapeutics, 9" Edition, pp. 521-555. Remington's Pharmaceutical Sciences 443 (1975) Table of Contents (51) Int. C. Provided. AOIN 43/42 (2006.01) Remington, (1995) “The Science and Practice of Pharmacy.” vol. I, A6 IK3I/44 (2006.01) 19' Edition, Table of Contents Provided. (52) U.S. Cl...... S14/282 Remington, (1995) “The Science and Practice of Pharmacy.” vol. II, Field of Classification Search ...... 514/175, 19' Edition, Table of Contents Provided). (58) Schurig, et al., (1982) Antiemetic Activity of Butorphanol Against 514/169,282 Cisplatin-Induced Emesis in Ferrets and Dogs, Cancer Treatment See application file for complete search history. Rep. 66(10): 1831-1835. International Search Report dated Aug. 8, 2003. (56) References Cited U.S. PATENT DOCUMENTS * cited by examiner 4,803,208 A 2, 1989 Pasternak ...... 514,282 Primary Examiner —Yong Chong 4,816,586 A 3/1989 Portoghese ...... 544,340 5,317,022 A * 5/1994 Borsodi et al...... 514,282 (74) Attorney, Agent, or Firm — David A. Lowin 5,352,680 A 10/1994 Portoghese et al. 514,279 5,393,545 A * 2/1995 Johnson et al...... 426,268 (57) ABSTRACT 5,958.459 A 9, 1999 Chasin et al...... 424/490 6,103,261 A 8/2000 Chasin et al...... 424/459 The present invention relates to a novel use of opioid com 6,136,817 A 10/2000 Schmidhammer .. 514,279 pounds for treatment of a neurologic or neurogenic disorder. 6,150,524 A 11/2000 Hartmann et al...... 546,44 Such neurologic or neurogenic disorders include lingual, 6,162,467 A 12/2000 Miller et al...... 424/468 pharyngeal, laryngeal, esophageal, urinary bladder sphincter, 6,294,195 B1 9, 2001 Oshlack et al. . ... 424/457 lumbar and lumbo-sacral spine, and pelvis and pelvic limb 6,365,742 B1 4/2002 Mudryk et al...... 546,44 6,476,044 B1 11/2002 Winendt et al...... 514,282 paresis/paralysis. The invention provides a unique method of 6,706,704 B2 * 3/2004 Lalley ...... 514,217.02 treating a specified disorder or syndrome by administering to a subject in need of such treatment a therapeutically effective FOREIGN PATENT DOCUMENTS amount of an opioid compound. WO WOO1/O5795 A1 1, 2001 WO WOO1? 12195 A2 2, 2001 25 Claims, No Drawings US 8,410,129 B2 1. 2 TREATMENT FOR PARESS/PARALYSIS to insure an adequate dietary intake of food and water and management of effective oral hygiene. This application claims priority to U.S. Provisional Appli Pharyngeal paresis/paralysis can disrupt the normal gag cation 60/357,389, filed Feb. 15, 2002. and or swallow reflexes resulting in the ineffective swallow ing of food and water, can lead to aspiration pneumonia as the TECHNICAL FIELD opening into the trachea is ineffectively covered during Swal lowing, can allow regurgitation of food or fluid back up into This invention relates generally to methods and pharma the oral and nasal cavities and can impair the normal passage ceutical compositions for treating neurologic and neurogenic of air into the trachea, the resulting disorder is known as disorders of the mammalian nervous system. Specifically, the 10 "Pharyngeal Dysphagia. If an individual's nutritional and invention relates to a novel use of opioid compounds for airway needs are not adequately addressed, death can occuras treatment of centrally and peripherally mediated neuropa the result of complications of starvation and or aspiration thies and neuromyopathies. The list of opioid-treatable neu pneumonia. To date there is no known cure for pharyngeal ropathies and neuromyopathies includes but is not limited to paresis/paralysis. The focus of therapy remains on Strategies lingual, pharyngeal, laryngeal, esophageal, urinary bladder 15 to insure adequate nutritional intake while addressing con sphincter, lumbar and lumbo-sacral spine, pelvis and pelvic tinual problems associated with fluid and food aspiration into limb paresis or paralysis. the lungs. Laryngeal paresis/paralysis can impair one’s ability to BACKGROUND OF THE INVENTION phonate, can cause an upper airway obstructive syndrome severely decreasing airflow into the lungs, and can allow Overview of the Mammalian Nervous System aspiration of food and fluid into the trachea as the arytenoids fail to effectively close over its opening; the resulting disorder The mammalian nervous system is comprised of the Cen is known as “Laryngeal Dysphagia.” If the medical affects of tral and Peripheral Nervous Systems. The Central Nervous laryngeal paresis/paralysis are not effectively dealt with, System (“CNS) is comprised of the brain and its functional 25 death may occur as the result of complications from aspira components. The Peripheral Nervous System (“PNS”) is tion pneumonia, respiratory failure and finally cardiac arrest. comprised of all the cranial and spinal nerves and their func To date there is no known cure for laryngeal paresis/paralysis. tional components. Paired cranial and spinal nerves provide The focus of therapy remains on Strategies to maintain an the means of communication between the brain, the spinal open and adequate airway into the trachea allowing Sufficient cord and the rest of the body. 30 oxygen to reach the lungs and on strategies to deal with In disorders of the nervous system, when the cause origi aspiration pneumonia and its consequences. nates from outside the nervous system the disorder is termed Esophageal paresis/paralysis can result in retention of mas “neurologic, and when the cause originates from within the ticated food and fluid in the esophagus and can lead to reten nervous system it is termed “neurogenic. Such disorders can tion esophagitis, which can result in regurgitation of esoph be identified as a part of a larger neurologic or neurogenic 35 ageal contents into the oral and nasal pharynx, and can allow syndrome, where a “syndrome' is defined as two or more aspiration of the regurgitated esophageal contents into the disorders and their clinical signs occurring together to form a lungs; the resulting disorder is known as "Megaesophagus.” recognized disease state. When the clinical signs associated Death from “Megaesophagus' may ensue from the long-term with a disorder or a syndrome are the result of the dysfunction effects of starvation, as a result of complications of “Reten of a single nerve it is referred to as a “neuropathy,” and when 40 tion Esophagitis, and/or from the secondary complications the clinical signs are the result of the dysfunction of two or of aspiration pneumonia. To date there is no known cure for more individual nerves, it is referred to as a “polyneuropathy.” esophageal paresis/paralysis. The focus of therapy remains The dysfunctioning nerves in a polyneuropathy can be on Strategies to passively allow masticated food and fluid to located in either the CNS, the PNS, or in both nervous sys flow from the oral pharynx to the stomach, and on medical tems simultaneously. 45 strategies for treating the resultant esophagitis including neu Disorders involving the CNS, the PNS, or both systems tralizing the affects of differing chemical compositions on together will impact the area(s) of the body normally inner mucosal Surfaces when positional aids fail to prevent move vated by that system or systems. In the disorders treated with ment of foodstuffs passively back out into the oral/nasal phar the methods and uses of the present invention, the area ynX. impacted by nervous system dysfunction is the muscle tissue, 50 Urinary bladder sphincter paresis/paralysis can result in resulting in a partial or total loss of muscular function termed intermittent or continual leaking of urine out of the bladder; a “neuromyopathy.” These disorders are observed individu the resulting disorder is known as “Neurogenic Urinary Blad ally or as part of a larger neurologic and/or neurogenic Syn der Sphincter Incontinence.” The leaking urine's pathway or drome, and can be inherited or acquired. When partial func site of accumulation determines the symptoms associated tion remains in the innervated muscle tissue, it is termed 55 with this incontinence. Urethritis, Cystitis, Nephritis, Vagini “paresis.” When no function remains in the innervated muscle tis, Perivulvar and Vulvar Vaginitis and Urine Scald Derma tissue, it is termed “paralysis.” titis are some of the secondary consequences associated with Lingual paresis/paralysis affects the ability of an individual urinary bladder sphincter paresis/paralysis. To date there is no to prehend food, pass a food bolus to the back of the pharynx known cure for urinary bladder sphincter paresis/paralysis. and interferes with the individual’s ability to swallow food, 60 The focus of therapy remains on strategies to control urine saliva or water; the resulting disorder is known as “Oral or leakage (as in Urinary Bladder Suspension Surgery), or to Lingual Dysphagia. If the individual's nutritional needs are absorb the leaking urine (using absorbent sanitary pads or not effectively addressed, death can occur as the result of the undergarments), to treat primary and secondary areas of body's physical deterioration and eventual organ shutdown inflammation or infection, and to keep the leaking and leaked from the prolonged effects of dehydration, malnutrition and 65 on areas as clean, dry, and sanitary as possible. eventual starvation. To date there is no known cure for lingual Lumbar and lumbo-sacral spine paresis/paralysis can paresis/paralysis. The focus of therapy remains on strategies cause progressive atrophy and weakness of the skeletal US 8,410,129 B2 3 4 muscles over the lumbar and sacral spine. As the disorder derivative, apomorphine, directly stimulates the chemorecep progresses, it becomes increasingly more difficult to use the tor trigger Zone in the brain, triggering an emetic or vomiting back in even the most basic of functions such as in bending, response, which can be helpful in an emergency situation straightening and turning the upper torso. To date there is no where one wants to stimulate a vomiting response. Butorpha known cure for lumbar and lumbo-sacral spine paresis/pa nol, another opioid derivative, has been used as an antiemetic, ralysis. The focus of therapy remains on strategies to assist to help control the vomiting induced by the chemotherapeutic one with ambulation, sitting, standing and reclining Such as agent Cisplatin (Schurig, et al., 1982). Additional gastrointes specially designed walkers, canes, rails, ramps, power tinal effects noted in response to the administration of opioid assisted lifts, etc. compounds include, increase or decrease in the amount of Pelvis and pelvic limb paresis/paralysis causes progressive 10 hydrochloric acid secreted into the stomach, increase in tone atrophy, weakness and eventual paralysis of the muscles in the antral portion of the stomach and upper duodenum, which make up the pelvis and pelvic limbs. Progressive loss resting segmental tone is increased, markedly decreasing the of muscle tone and strength in the pelvis and pelvic limbs propulsive movement of the intestinal contents, which is make even rudimentary functions such as standing, sitting, helpful in treating upper intestinal diarrhea, but can lead to the rising, and ambulating almost impossible without some sort 15 common problem of constipation if diarrhea is not present. of external assistance. To date there is no known cure for pelvis and pelvic limb paresis/paralysis. The focus of therapy SUMMARY OF THE INVENTION remains on strategies for assisted movements when standing, walking or sitting, such as specially designed walkers, canes, The present invention for the first time, establishes the in crutches and carts. Eventually any function requiring muscu Vivo therapeutic (non-analgesic) utility of the opioid class of lar movement or strength below the waist will fail. compounds not for the treatment of pain, but for the treatment These disorders or syndromes of neurologic or neurogenic of a number of specified neurologic or neurogenic disorders. origin are often progressive in nature and can eventually Naturally occurring, endogenous opioid peptides (opiopep result in permanent dysfunction of the particular organ or area tins) have been shown to act as neurotransmitters and appear of the body involved. As only palliative treatment is currently 25 to act as modulators of neurotransmission or as neurohor available to those Suffering from Such debilitating conditions, mones, as have several opium derivatives found in nature there exists a considerable need for better therapeutic choices (morphine, codeine and other related compounds) (Reisine and ultimately a cure for these disorders, as well as disease and Pasternak). It is in this role, i.e., endogenous opioid states seen individually or as part of a larger neurologic or peptide neurotransmitter replacement or neurohormone, that neurogenic disorder or syndrome, and polyneuropathic Syn 30 the opioids are believed to exert their effect on the paretic or dromes that contain some or all of these neurologic or neu paralyzed muscle tissue, partially or completely reversing the rogenic signs and symptoms. paresis/paralysis. The present invention encompasses the novel use of an The Opioids: Mechanism of Action opioid compound to treat a neurologic or neurogenic disorder. 35 Such disorder can be selected from the group: lingual paresis/ Opioids are alkaloid compounds. The prototypic opioid, paralysis, pharyngeal paresis/paralysis, laryngeal paresis/pa morphine, was first isolated from opium in the early nine ralysis, esophageal paresis/paralysis, urinary bladder sphinc teenth century. The opium alkaloids can be broadly divided ter paresis/paralysis, lumbar and lumbo-sacral spine paresis/ into five distinct chemical classes: phenanthrene, benzyliso paralysis, and pelvis and pelvic limb paresis/paralysis. In quinoline, tetrahydroisoquinoline, cryptopine, and miscella 40 another aspect, the invention encompasses the novel use of an neous (Remington's Pharmaceutical Sciences 433, 1975). opioid compound to treat a syndrome including more than Therapeutically useful drugs are primarily isolated from the one of the above-mentioned disorders. phenanthrene and benzylisoquinoline classes. The principal Another aspect of the present invention is the novel use of phenanthrenes are morphine, codeine, and thebaine. The an opioid compound to individually treat disease states or principal benzylisoquinolines are papaverine and noscapine. 45 symptoms identified previously as part of a disorder or Syn The most common use of opioid compounds in today's drome including, but not limited to: Cardiomyopathy, Cen prescription market is for their analgesic properties. The trally Mediated Depression, Congestive Heart Failure and opioids produce their effects by binding to different types of Paralytic Intestinal Ileus. opioid receptors throughout the central and peripheral ner Another aspect of the present invention is the novel use of Vous systems. Opioids act within the central nervous system 50 opioid compounds to treat paresis/paralysis in one or more to elevate the pain threshold and to alter the psychological polyneuropathic syndromes characterized by similar neuro response to pain. The opioids act outside the brain, producing logic or neurogenic signs and symptoms, including, but not their pharmacologic effects by interacting with one or more of limited to: Multiple Autonomic Nervous System Dysfunc four (three major) opioid receptors (mu, sigma, kappa, and tion, Multiple Sclerosis, Muscular Dystrophy, Myasthenia delta) located in the peripheral nervous system. The pharma 55 Gravis and Parkinson's Disease. cologic effects vary among opioid derivatives, depending on The present invention further encompasses a method for the receptor, its location in the body, and the type of interac treating a neurologic or neurogenic disorder comprising tion between the opioid derivative and the receptor. It is administering to a subject in need of Such treatment a thera currently understood that a given opioid derivative can bind peutically effective amount of a pharmaceutical formulation with one or more types of opioid receptors, and believed 60 comprising an opioid compound. Such pharmaceutical for likely that several subtypes of receptors exist for each of the mulations can be immediate or Sustained release. three major types of receptors (mu, delta, and kappa). The opioid compound useful in practice of the invention Although the primary pharmacologic effects desired from include naturally occurring opium alkaloids, semi-synthetic most all opioids in use today are analgesia, euphoria, and opium alkaloids and synthetic opium alkaloids. One pre sedation without loss of consciousness (Reisine and Paster 65 ferred group of naturally occurring opium alkaloid includes: nak, 1966), the pharmacologic effects of opioids are now morphine, codeine, thebaine, papaverine, and noscapine, or a known to extend beyond the control of pain. One opioid pharmaceutically or veterinarily acceptable salt thereof. A US 8,410,129 B2 5 6 preferred group of semi-synthetic opium alkaloids includes: those compounds or classes of compounds specifically men heroin, hydromorphone, metapon, oxymorphone, levorpha tioned herein or known in the art, which also induce the nol, hydrocodone, oxycodone, tramadol, nalorphine, nalox desired effect. one, or naltrexone, or a pharmaceutically or veterinarily The terms “opioid compound' and “opioids’ refer to sub acceptable salt thereof. A preferred group of synthetic opium stances (natural, semisynthetic or synthetic) that bind to a alkaloids includes: meperidine and congners, methadone and centrally and/or peripherally located opioid receptor to pro congeners, levorphanol and congeners, phenazocine, fenta duce an agonist action, a partial agonistic action (agonist/ nyl, propoxyphene and ethoheptazine, or a pharmaceutically antagonist) or an antagonist action, including the opioid com or veterinarily acceptable salt thereof. Also preferred, indi pounds described below. vidually and collectively, are the opioid compounds/formu 10 “Carriers' or “vehicles' as used herein refer to carrier lations employed in the Examples: oxycodone, morphine, materials suitable for drug administration. Carriers and oxycodone hydrochloride immediate or Sustained release, vehicles useful herein include, but are not limited to any such and morphine Sulphate immediate or Sustained release, espe material known in the art, which is nontoxic and does not cially oxycodone hydrochloride Sustained release. interact with other components of the composition in a del Administration of the pharmaceutical formulation is car 15 ried out within the context of a predetermined dosing regimen eterious manner. such that the agent is effective in the treatment of the specified By a “therapeutically effective' is meant a nontoxic but neurologic/neurogenic disorder. The precise amount of the Sufficient amount of the drug, agent or formulation to provide pharmaceutically effective medication administered will the desired effect, i.e., treatment of a neurologic/neurogenic generally depend on the particular drug selected, the age and disorder that causes paresis/paralysis. general condition, and, or, the pharmacological condition of “Paresis/paralysis” is defined for purposes of the present the Subject being treated, and the judgment of the prescribing invention as partial or total loss of function in innervated physician. In general the Subject is given a daily dose of the muscle tissue resulting from a neurologic or neurogenic dis effective opioid in the range of approximately 0.1 mg to 200 order. mg depending on the amount needed to Sustain a therapeutic 25 “Immediate-release' is defined for purposes of the present blood level, administered preferably, but not limited to, one to invention as the release of the drug (e.g., opioid compound) at eight times in a twenty-four hour period. The drug delivery Such a rate that therapeutic blood (e.g., plasma) levels may be by, but not limited to, oral, intravenous, intramuscular, required by the body are reached, and maintained for a period Subcutaneous, transdermal or another acceptable route. 6 hours or less. 30 “Extended or sustained-release' is defined for purposes of DETAILED DESCRIPTION OF THE INVENTION the present invention as the release of the drug (e.g., opioid compound) at such a rate that therapeutic blood (e.g. plasma) Throughout this disclosure, various publications, patents levels required by the body are reached and maintained for a and published patent specifications are referenced by an iden period lasting over 6 hours and preferably lasting 12-36 hours tifying citation. The disclosures of these publications, patents 35 or longer. and published patent specifications are hereby incorporated The terms “subject,” “individual' or “patient are used by reference into the present disclosure. interchangeably herein, referring to a vertebrate, preferably a mammal. The mammal is either a human or a non-human. DEFINITIONS Non-human mammals include but are not limited to, mice 40 (murines), rats, simians, farm animals, sportanimals, and pets As used in the specifications and claims, the singular form Such as dogs and cats. a”, “an and “the include plural references unless the con text clearly dictates otherwise. For example, the term “an Neurologic/Neurogenic Disorders and Syndromes opioid compound includes a plurality of opioids, including Treated mixtures thereof. 45 Before describing the present invention in detail, it is to be The present invention provides a novel use for an existing understood that this invention is not limited to particular class of compounds, the opioids, to effectively treat neuro drugs or drug delivery systems, and as Such may vary. It is also logic/neurogenic disorders and syndromes. One of the results to be understood that the terminology used herein is for the of such treatment is the cessation and/or reversal of the atro purpose of describing particular embodiments only, and is not 50 phy or wasting of the affected muscle(s). intended to be limiting. One such group of disorders includes (without limitation) The terms “treat”, “treating and “treatment” as used lingual, pharyngeal, laryngeal, esophageal, urinary bladder herein, includes preventing, ameliorating, reducing or curing sphincter, lumbar and lumbo-sacral spine, and pelvis and a disease state, disorder or syndrome; effecting a reduction in pelvic limb paresis/paralysis, whether identified alone or as severity and/or frequency of symptoms, elimination of symp 55 part of a larger neurologic or neurogenic syndrome. toms and/or underlying cause, prevention of the occurrence Examples of disease states seen individually or as part of a of symptoms or their underlying cause, and/or amelioration larger neurologic or neurogenic disorder or syndrome, which of damage caused thereby, e.g., partially or completely respond individually to treatment with one or more opioid reversing paresis/paralysis. The present method of “treating compound(s) according to the present invention include, but a neurologic/neurogenic disorder, as the term is used herein, 60 are not limited to, Cardiomyopathy, Centrally Mediated thus encompasses both predisposed individuals and clinically Depression, Congestive Heart Failure, and Paralytic Intesti symptomatic individuals. nal Ileus. The terms “active agent,” “drug and “pharmacologically Examples of polyneuropathic syndromes that contain active agent” are used interchangeably herein to refer to a Some or all of the neurologic or neurogenic signs and Symp chemical material or compound that induces a desired effect. 65 toms, which respond individually to treatment with one or In the preferred embodiment herein, the terms refer to an more opioid compound(s) according to the present invention opioid compound. Included are derivatives and analogs of include, but are not limited to, Multiple Autonomic Nervous US 8,410,129 B2 7 8 System Dysfunction, Multiple Sclerosis, Muscular Dystro include, but are not limited to, morphine (MS Contin), heroin, phy, Myasthenia Gravis and Parkinson's Disease. hydromorphone (Dilaudid), oxymorphone (Numorphan), Identification of the specific nerve or group of nerves asso codeine (Tylenol 3, 4), hydrocodone (Vicodin, Lorcet), oxy ciated with a neurologic or neurogenic disorder or polyneuro codone, and etorpine (Immobilon). Commercially available pathic syndrome with their attendant clinical signs and Symp oxycodone formulation include: OxyContin, Supeudol, toms, and documenting which of the opioid compound(s) Roxycodone, Endocet, Oxycet, Percocet, Roxicet, Roxilox, used in the present invention effectively treats the associated Tylox, Percodan, Roxiprin, Oxycodan. Examples of phenyl disease signs and symptoms, provides a unique opportunity to heptylamines include, but are not limited to, methadone, apply this knowledge to the treatment of other disease states methadyl acetate, dimeheptanol (methadol), isomethadone, caused by a neuropathic disorder or polyneuropathic Syn 10 dipipanone, dimenoxadol, and propoxyphene (Darvon). drome, which contain some or all of these same effectively Examples of phenylpiperidines include, but are not limited to, treated clinical signs and symptoms as part of their signal meperidine (Demerol), properidine, alphaprodine, beta ment. promedol, alfentanyl (Alfenta), fentanyl (Sublimaze), carfen tanyl, lofentanil, and Sufentanil (Sufenta). Active Agents Employed in the Methods of the 15 Two different opioid compounds can be combined for Invention administration: a first componentanda second component. In one embodiment, the first component is an opioid agonistand In order to carry out the method of the invention, an opioid the second component is an opioid antagonist. Preferably, the compound is administered to an individual prone to or exhib second component blocks at least a portion of the action of the iting one or more neurologic or neurogenic disorders or first component. This blocking results in a reduction of symptoms of paresis/paralysis affecting a Voluntary or invol adverse side-effects, such as one or more of addiction, con untary muscle, or a group of muscles. stipation, and sedation. In a preferred combination, the first In one embodiment, the opioid compound is capable of component is morphine, tramadol or hydrocodone, and the binding to the mu, sigma, kappa or delta opioid receptor, or second component is naltrexone. The first and second com ORL1 receptor. In another embodiment, the opioid com 25 ponents can be administered as a pre-mixed combination, or pound is capable of binding to either: (1) only one of the can be administered separately. above-described receptors or (2) all but one the above-de An opioid antagonist can be a partial agonist-antagonist or scribed receptors. anarcotic antagonist. Examples of partial agonist-antagonists Examples of opioid compounds that can be used in the include, but are not limited to, noscapine, pentazocine (Tal present invention include, but are not limited to: alfentanil, 30 win), butorphanol (Stadol), and nalbuphine (Nubain). allylprodine, alphaprodine, anilleridine, benzylmorphine, Examples of pure narcotic antagonists include, but are not beta-hydroxy 3-methylfentanyl, bezitramide, buprenorphine, limited to, naloxone, nalorphine (Nalline), naltrexone (Re butorphanol, carfentanil, clonitaZene, codeine, cyclazocine, Via), nalmefene and nadide (Enzopride). desomorphine, dextromoramide, dezocine, diacetylmor Thebaine and derivatives and analogues thereof can be phine (heroin), diampromide, dihydrocodeine, dihydroetor 35 synthesized by the methods disclosed by U.S. Pat. Nos. 6,136, phine, dihydromorphine, dimenoxadol, dimepheptanol, dim 817 and 6,365.742. 14-Hydroxydihydro-morphinones, ethylthiambutene, dioxaphetylbutyrate, dipipanone, including oxymorphone, naloxone, naltrexone, oxymorp eptazocine, ethoheptazine, ethylmethylthiambutene, ethyl haZone, naloxazone, naltrexaZone, oxymorphonazine, nalox morphine, etonitaZene, etorphine, fentanyl, hydrocodone, onazine, and naltrexonazine, and analogues thereof can be hydromorphone, hydroxypethidine, isomethadone, ketobe 40 synthesized by the methods disclosed by U.S. Pat. No. 4,803, midone, LAAM, levallorphan, levorphanol, llevophenacyl 208. Morphine derivatives and analogues thereof can be syn morphan, lofentanil, meperidine, meptazinol, metazocine, thesized by the methods disclosed by U.S. Pat. Nos. 6,150, methadone, O-methylmaltrexone, metopon, morphine, myro 524 and 6,476,044. Opioids and opioid antagonists include phine, nalbuphine, nalorphine, naloxone, naltrexone, narce the compounds disclosed by U.S. Pat. Nos. 4,816,586 and ine, nicomorphine, norlevorphanol, normethadone, normor 45 5,352,680, and U.S. Patent Application Publication No. US phine, norpipanone, opium, oxycodone, oxymorphone, 2001 FOO47005. papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, proph Pharmaceutical Formulations and Modes of eptazine, promedol, properidine, propiram, propoxyphene, Administration remifentanil, Sufentanil, tildine, tramadol, salts thereof, mix 50 tures of any of the foregoing, mu-agonists, mixed mu-ago The present invention also encompasses the use of an nists and antagonists, mu-antagonists, combinations of the opioid compound effective to reduce paresis or paralysis in preceding and the like, or any pharmaceutically acceptable the manufacture of a medicament for use in treating a neuro salt(s) thereof, immediate or Sustained release formulations. logic or neurogenic disorder in a Subject in need of Such In one embodiment, the opioid compound is a naturally 55 treatment. The medicament is effective or efficacious in the occurring opium alkaloid, preferably morphine, codeine, the treatment of any of the neurologic or neurogenic disorder baine, papaverine, or noscapine. In another embodiment, the disclosed above. The medicament can further comprise a opioid compound is a semi-synthetic opium alkaloid, prefer mixture of two or more opioid compounds. The medicament ably heroin, hydromorphone, metapon, oxymorphone, levor can be of an immediate or sustained release form. Preferably phanol, hydrocodone, oxycodone, tramadol, nalorphine, 60 the medicament is administered solely or only for treating a naloxone, or naltrexone. In another embodiment, the opioid neurologic or neurogenic disorder, i.e., it is administered to a compound is a synthetic opium alkaloid, preferably meperi subject not in need of pain relief (including relief of moderate dine and congners, methadone and congeners, levorphanol to severe pain in an acute or chronic setting), anesthesia, and congeners, phenazocine, fentanyl, propoxyphene, or emesis or an anticholinergic effect. ethoheptazine. 65 The pharmaceutical compositions can be administered by The opioid compound can be a phenathrene, phenylhepty any Suitable route including but not limited to oral, rectal, lamine or phenylpiperidine. Examples of phenathrenes nasal, topical (including but not limited to transdermal, aero US 8,410,129 B2 10 Sol, buccal, and Sub-lingual), parenteral (including but not profile. Tablets may optionally be provided with an enteric limited to Subcutaneous, intramuscular, intravenous, intrap coating, to provide release in parts of the gut other than the eritoneal, intrathecal, and intracranial), or by inhalation (in stomach. cluding but not limited to nebulization, or by propellantatom The opioid useful herein may be delivered through the skin izer or propellant inhaler). using conventional transdermal drug delivery systems, i.e., The preferred route of administration will depend on many transdermal “patches' wherein the agent is typically con variables (age, condition of the patient, concurrent diseases, tained within a laminated structure that serves as a drug formulations available for delivery). Depending on the spe delivery device to be affixed to the skin. In such a structure, cific mode of administration, the pharmaceutical composi the drug composition is typically contained in a layer, or tions may be in the form of a Solid, semi-solid, or liquid. 10 “reservoir, underlying an upper backing layer. The lami Examples include but are not limited to tablets, Suppositories, nated device may contain a single reservoir, or it may contain powders, liquids, Suspensions, creams, ointments, lotions or multiple reservoirs. In one embodiment, the reservoir com the like, preferably in unit dosage form for single administra prises a polymeric matrix of a pharmaceutically acceptable tion of a precise dosage. The pharmaceutical composition contact adhesive material that serves to affix the system to the comprises a therapeutically effective amount of the opioid 15 skin during drug delivery. Examples of Suitable skin contact compound. The pharmaceutical composition can further adhesive materials include, but are not limited to, polyethyl comprise a pharmaceutically or veterinary acceptable carrier. enes, polysiloxanes, polyisobutylenes, polyacrylates, poly The pharmaceutical composition can further comprise other urethanes, and the like. Alternatively, the drug-containing pharmaceutical agents, adjuvants, diluents, buffers, etc. The reservoir and skin contact adhesive are present as separate and carrier must be “acceptable' in the sense of being compatible distinct layers, with the adhesive underlying the reservoir with the other ingredients of the formulation and not injurious which, in this case, may be either a polymeric matrix as to the patient. described above, or it may be a liquid or hydrogel reservoir, or For Solid compositions, conventional nontoxic Solid carri it may take some other form. ers include, for example, but are not limited to pharmaceutical 25 Pharmaceutical compositions for topical administration grades of mannitol, lactose, starch, magnesium Stearate, according to the present invention may also be formulated as, Sodium saccharin, talc, cellulose, glucose, Sucrose, magne but not limited to an ointment, cream, Suspension, lotion, sium carbonate, and the like. Liquid pharmaceutically admin powder, Solution, paste, gel, spray, aerosol or oil. istratable compositions can, for example, be prepared by Formulations for rectal administration may be presented as dissolving, dispersing, etc., an active compound as described 30 a Suppository with a suitable base comprising, for example, herein and an optional pharmaceutical adjuvant in an excipi cocoa butter, or a salicylate. Formulations suitable for nasal administration, wherein ent, such as (without limitation) water, saline, aqueous dex the carrier is a solid, include a coarse powder having a particle trose, glycerol, ethanol and the like, to thereby form a solution size, for example, in the range of about 20 to about 500 or Suspension. If desired, the pharmaceutical composition to 35 microns, which is administered in the manner in which Snuff be administered may also contain minor amounts of non is taken, i.e., by rapid inhalation through the nasal passage toxic auxiliary Substances such as (without limitation) wet from a container of the powder held close up to the nose. ting or emulsifying agents, pH buffering agents and the like, Suitable formulations wherein the carrier is a liquid for for example, Sodium acetate, triethanolamine oleate, etc. administration as, for example, nasal spray, nasal drops, or by Actual methods of preparing Such dosage forms are known, 40 aerosol administration by nebulizer, include aqueous or oily or will be apparent, to those skilled in this art; for example, see Solutions of the agent. Remington: The Science and Practice of Pharmacy, Nine Formulations suitable for parenteral administration teenth Ed. (Easton, Pa.; Mack Publishing Company, 1995). include aqueous and non-aqueous isotonic sterile injection Formulations of the present invention suitable for oral Solutions that may contain anti-oxidants, buffers, bacteri administration may be presented as discrete units such as, but 45 ostats and solutes which render the formulation isotonic with not limited to capsules, cachets or tablets, each containing a the blood of the intended recipient; Suspending agents and predetermined amount of the active ingredient; as, but not thickening agents, and liposome's or other microparticulate limited to a powder or granules; as a solution or Suspension in systems which are designed to target the compound to blood an aqueous or non-aqueous liquid; or as an oil-in-water liquid components or one or more organs. The formulations may be emulsion or a water-in-oil emulsion. The active ingredient 50 presented in unit-dose or multi-dose sealed containers, for may also be presented as a bolus, electuary or paste. example, ampules and vials, and may be stored in a freeze A tablet may be made by compression or molding, option dried (lyophilized) condition requiring only the addition of ally with one or more accessory ingredients. Compressed the sterile liquid carrier, for example, water for injection, tablets may be prepared by compressing in a Suitable immediately prior to use. Extemporaneous injection solu machine, the active ingredient in a free-flowing form Such as, 55 tions and Suspensions may be prepared from sterile powders, but not limited to a powder or granules, optionally mixed with granules or tablets of the kind previously described. but not limited to a binder (e.g., povidone, gelatin, hydrox The pharmaceutical formulation can deliver the opioid ypropylmethyl cellulose), lubricant, inert diluent, preserva compound prepared in an immediate or Sustained-release tive, disintegrant (e.g., Sodium starch glycolate, cross-linked form. A variety of Sustained-release forms of opioids are poVidone, cross-linked sodium carboxymethylcellulose) Sur 60 known in the art (e.g., U.S. Pat. Nos. 5,958,459; 6,103.261; face-active or dispersing agent. Molded tablets may be made 6.294, 195; 6,162.467). To prepare the sustained-release by molding in a suitable machine a mixture of the powdered forms, the selected opioids are typically (without limitation) compound moistened with an inert liquid diluent. The tablets incorporated into a Sustained release matrix; incorporated may optionally be coated or scored and may be formulated so into a Sustained-release coating; incorporated as a separated as to provide slow or controlled release of the active ingredi 65 Sustained-release layer with an immediate release layer, or ent therein using, for example, hydroxypropylmethyl cellu are incorporated as a powder, granulation, etc., in a gelatin lose in varying proportions to provide the desired release capsule. US 8,410,129 B2 11 12 The coatings are typically capable of producing a strong, cal formulation effective for treating a neurologic or neuro continuous film that is Smooth and elegant, non-toxic, inert genic disorder or syndrome, including the steps: (a) evaluat and tack-free, capable of Supporting other pigments and other ing the function of an organ of a Subject, wherein said subject coating additives. A variety of hydrophobic Substances are Suffers from a neurologic or neurogenic disorder or Syn Suitable for preparing the coating including (without limita drome, (b) administering an opioid compound or pharmaceu tion) hydrophobic polymers such as acrylic polymer, meth tical formulation to said Subject, (c) evaluating the function of ylcellulose, or a mixture thereof. said organ of said Subject, and (d) determining whether said Preferred Sustained-release matrices comprise a polymer including (without limitation) pharmaceutically acceptable opioid compound or pharmaceutical formulation provided gum, an alkylcellulose, a cellulose ether, an acrylic resin, effective treatment. In one embodiment, the method involves protein-derived materials, and mixtures thereof. 10 repeating steps (a)-(d) for testing oridentifying more than one It should be understood that in addition to the ingredients opioid compound or pharmaceutical formulation. When nec particularly mentioned above, the formulations of this inven essary, the method can further involve repeating steps (b) and tion can further comprise other agents conventional in the art (c) one or more times for each opioid compound or pharma having regard to the type of formulation in question; for ceutical formulation tested. Preferably, the function evaluated example, those Suitable for oral administration may include 15 is lingual, pharyngeal, laryngeal, esophageal, urinary bladder Such further agents as Sweeteners, thickeners and flavoring sphincter, lumbar and lumbo-sacral spine, or pelvis and pel agents. It also is intended that the agents, compositions and vic limb control or function. Preferably, the step of evaluating methods of this invention be combined with other suitable the function of an organ involves grading the function using a compositions and therapies. grading system. The compound tested can be either presently known or unknown to be an opioid compound. Dosage In order to evaluate the effectiveness of a dose of an opioid formulation, over time, when being used to treat the Symp The amount of active agent administered and the dosing toms of a neurologic/neurogenic disorder or syndrome, the regimen used, is dependent on the particular drug selected, following grading protocol is a means to quantify and docu the age and general condition of the Subject being treated, the 25 ment the neurologic/neurogenic function of the target organ severity of the subjects condition, and the judgment of the prescribing physician. Preferably, the daily drug dosage will or organs affected by the neuropathy or polyneuropathy at the be administered one to eight times, preferably one to four start and conclusion of a time interval. times daily or over a 48-hour period. Preferably, a daily dose In this regard, an organ is considered to be neurologically of an active agent when administered ranges from 0.1 mg to normal when there is no neuropathology affecting its func 200 mg. depending on the half-life of the drug in the treated 30 tion. Any partial loss of function in that organ that is neuro subject, the availability of the active compound via the chosen logic/neurogenic in origin is termed paresis. Total loss of route of administration, and the ability of the drug to Sustain function in that organ that is neurologic/neurogenic in origin a therapeutic level in the patient. The dosing regimen can be is termed paralysis. Because in most cases an organ can be modulated in order to achieve the desired effect. In increasing clearly identified as having normal neurologic function, order of preference, a daily dose can range from 0.1 mg to 100 35 decreased neurologic function (paresis), or no neurologic mg, from 0.1 mg to 80 mg, from 1 mg to 80 mg, and from 3 mg function (paralysis), the documenting of the degree of to 40 mg. Preferably, when an animal Subject is in the range of remaining neurologic function of an organ lends itself to a 60 to 80 pounds, a starting dose of OxyContin R, is 5-10 mg simple grading system. An organ that functions normally and given every 12 hours; if the Subject starts to show the Symp is considered to be neurologically normal receives the highest toms of drug tolerance, the dose is elevated by 5 mg every 12 40 grade of (4). An organ that has no function as a result of a hours. A starting dose of morphine Sulfate extended release neurologic/neurogenic disorder or syndrome and is para for such a subject is 7.5 to 15 mg given every 12 hours; if the lyzed, receives the lowest grade of (0). An organ that has lost Subject starts to show the symptoms of drug tolerance, the partial function (paresis) as a result of a neurologic/neuro dose is elevated by 7.5 mg every 12 hours. genic disorder or syndrome receives a grade of (1), (2) or (3) The lowest effective dosage is the least amount of the 45 depending on the degree of neurologic function remaining. pharmaceutical formulation sufficient to effect treatment of a neurologic or neurogenic disorder or syndrome. The lowest An increase of the grading of a function in a Subject, after effective dose of an opioid formulation used to control the administration of an opioid formulation, indicates that the presenting symptoms in the studies underlying the present formulation is effective in treating a symptom of the neuro invention was, oxycodone immediate release, in Suspension, logic or neurogenic disorder affecting the function. A greater 3 mg administered every 12 hours, to a 47 lb subject. 50 increase in the grade of neurologic or neurogenic function The highest tolerated dosage is the maximum amount of received while on a medication corresponds to greater effec the pharmaceutical formulation to effect treatment without tiveness in providing treatment. the occurrence of adverse side effect(s) outweighing the ben Application of this grading system to the individual disor efit received. The highest tolerated dose of an opioid formu ders described previously proceeds as follows: lation used in the studies underlying the present invention was 55 Lingual (Paresis/Paralysis): Grade (4) observation of nor OxyContin R, 120 mg. More preferably, this is administered mal lingual musculature, normal lingual movement while as 2 (40 mg) tabs given every a.m., and 1 (40 mg) tab given Swallowing and normal lingual withdrawal in response to every p.m. pinching with a hemostat. Grade (O) atrophy of lingual mus The dose of medication is adjusted according to the weight culature, inability to swallow abolus of food, audible choking and need of a Subject, to ameliorate the presenting symptoms. 60 and gagging and no lingual withdrawal in response to pinch One of ordinary skill in the art has the means to determine the ing with a hemostat. Grade (1), (2) or (3) depending on the adjustment needed. degree of lingual musculature remaining, the amount lingual movement during attempted Swallowing and degree of with Evaluating Opioid Dosage and Effectiveness drawal remaining in response to pinching with a hemostat. 65 Pharyngeal (Paresis/Paralysis): Grade (4) normal swal The present invention further encompasses a method for lowing of a bolus of food or liquid. No audible obstructive testing or identifying an opioid compound or a pharmaceuti airway sounds. No choking, or gagging Sounds audible. US 8,410,129 B2 13 14 Grade (0)=no ability to swallow a bolus of food of liquid, (1) Pharmaceutical formulations from the group of drugs audible obstructive airway Sounds with choking and gagging known as “opioids are effective as a treatment for the audible. Grade (1), (2) or (3)-depending on the degree of neurologic/neurogenic symptoms associated with the swallow reflex remaining the amount of audible obstructive disorders including lingual, pharyngeal, laryngeal, airway sounds present and the degree of choking and gagging esophageal, urinary bladder sphincter, lumbar and present. lumbo-sacral spine, and pelvis and pelvic limb paresis/ Laryngeal (Paresis/Paralysis): Grade (4)-normal unob paralysis. structed flow of air into and out of the larynx with normal (2) When a subject’s neurologic/neurogenic symptoms vocalization. Grade (O) obstructed flow of air into the larynx have been ameliorated by the use of a specific pharma with obstructed upper airway sounds, choking and gagging 10 ceutical formulation of opioid, substitution of a differ ent, but equivalent pharmaceutical formulation of opioid noted, and loss of vocalization. Grade (1), (2) or (3)-depend does not guarantee continued successful treatment of the ing on the amount of unobstructed airflow remaining, the same symptoms (as in Example 3, where resuming amount of choking and gagging noted and the degree of administration of the initial agent Successfully re-estab Vocalization remaining. An exemplar of a grading system for 15 lished treatment). In other subjects (as in Examples 6 laryngeal function, further divided into breathing, Swallow and 7) continued Successful treatment has been demon ing, laryngospasm, jaw tone, and overall exposure of the strated after substitutions between sustained and imme larynx for examination, is described in Gross et al. (J. Am. diate release formulations and between naturally occur Animal Hosp. Assoc. 38:503-62002). ring and semi-synthetic opioids. Esophageal (Paresis/Paralysis): Grade (4) normal passage (3) Different subjects with similar presenting neurologic/ of a bolus of food or fluid, after swallowing, from the back of neurogenic disorders do not respond the same when the throat into the stomach. Grade (O)-delayed or impaired treated with the same pharmaceutical formulations of passage of abolus of food or fluid, after Swallowing, from the opioids, in the same manner (as in Examples 1 and 2). As back of the throat into the stomach, due to a lack of peristaltic further illustrated in Example 2, successful treatment contractions within the esophagus, with possible secondary 25 can be accomplished by consideration of the particular symptoms of regurgitation, esophageal pain and halitosis. Subject and symptoms, and adjusting the active agent, Grade (1), (2) or (3)-depending on the degree of peristaltic the dose and/or the formulation employed. muscular contraction remaining in the esophagus and the The examples are provided as a guide to a practitioner of extent of the impairment to the passage of a bolus of food or ordinary skill in the art, and are not meant to be limiting in any fluid from the back of the throat, after swallowing, into the 30 way. stomach, and the secondary symptoms associated with the impairment. EXAMPLES Urinary Bladder Sphincter (Paresis/Paralysis): Grade (4)-normal urinary bladder sphincter function, normal ability Example 1 to store and pass urine. Grade (0)=no urinary bladder sphinc 35 ter function with continual leaking of urine out of the bladder The following case study establishes the efficacy of a sus and Subsequently out of the urethra, with secondary conse tained release formulation of a semi-synthetic opioid agonist, quences including urine scald, moist dermatitis, urethritis, oxycodone hydrochloride (OxyContin R, Purdue Pharma LP, cystitis, nephritis. Grade (1), (2) or (3)-depending on the Stamford, Conn.) in particular, in the treatment of pharyngeal degree of urinary bladder sphincter function remaining and 40 paresis/paralysis, laryngeal paresis/paralysis, urinary bladder the amount of urine leaking with its secondary side effects. sphincter paresis/paralysis, lumbar and lumbo-sacral spine Lumbar and Lumbo-Sacral Spine (Paresis/Paralysis): paresis/paralysis, and pelvis and pelvic limb paresis/paraly Grade (4) normal amount and function of muscles that are S1S. responsible for moving the lumbar and lumbo-sacral spine “SR. an 8/2 year old spayed, female, Rhodesian Ridge while bending, moving the back, and Supporting the lower 45 back (dog), Suffered from a neurologic/neurogenic syndrome torso. Grade (0)=atrophy and loss of all tone of the muscles consisting of the following disorders: pharyngeal paresis/ that are responsible for movement of the lumbar and lumbo paralysis, laryngeal paresis/paralysis, urinary bladder sphinc sacral spine rendering the body incapable of Supporting the ter paresis/paralysis, lumbar and lumbo-sacral spine paresis/ back and lower torso and thus preventing any Voluntary paralysis, and pelvis and pelvic limb paresis/paralysis. movement of this part of the body. Grade (1), (2) or (3)-de 50 Historically, SR's owner reported a progressive exercise pending on the amount of muscle and muscle tone remaining intolerance attributed to an increasing difficulty in breathing and the extent to which Voluntary Support and movement of and a progressive weakness and incoordination of the rear the lower back and torso remain. legs resulting from the loss of muscle mass over the lumbar Pelvis and Pelvic Limb (Paresis/Paralysis): Grade (4)-nor and lumbo-sacral spine, pelvis and pelvic limbs. Excessive mal amount and function of muscles that are responsible for 55 panting, choking and gagging were noted throughout the day extending and flexing the joints of the pelvis and pelvic limbs. even if the temperature is cool and the body is at rest. Leaking Grade (0)=atrophy and loss of all tone of the muscles that are of urine was noted as a continual problemand a stagnanturine responsible for extending and flexing the joints of the pelvis odor is detectable from the area of the Vulva. and pelvic limbs, rendering them incapable of Supporting the On physical examination the mouth was open, and panting body and unable to ambulate. Grade (1), (2) or (3)-depending 60 with increased airway resistance is audibly noted. The tongue on the amount of muscle and muscle tone remaining and the was visibly drier thanusual. There was visible muscle atrophy extent to which voluntary support and movement of the pelvis over the lumbar and lumbo-sacral spine, pelvis and pelvic and pelvic limbs is possible. limbs, as evidenced by visible and palpable bony promi The use of opioid formulations for the treatment of speci nences in each of these affected areas. There was a stagnant fied neurologic/neurogenic disorders are illustrated in the 65 urine Smell coming from the area of the Vulva. example section below. These examples support the follow The mouth was opened and the tongue extended to allow 1ng: visualization of the throat. A small but ineffective Swallow US 8,410,129 B2 15 16 reflex was noted. The ineffective swallow reflex allowed a tial dose (/8 of a 10 mg tablet every 12 hours), many of the Small pool of Sticky saliva to collect at the opening of the neuropathic symptoms began to Subside. arytenoids, which additionally had lost their paradoxical out Initially, she appeared more alert and interested in her ward movement during inspiration. The inspiration of pooled, surroundings. Shortly thereafter, the volume and strength of Sticky saliva into the tracheal opening caused a continual her respiration began to improve; as it did, most if not all of cough response, which in turn caused chronic inflammation the obstructed laryngeal sounds seemed to subside. When of the arytenoids. Chronic inflammation of the arytenoids asked to go outside for a walk, this dog who previously was caused Swelling of the mucosal tissues, increasing resistance too weak to stand, stood up, shook herself as if shaking water to air movement through the swollen and therefore smaller from her coat, and walked briskly towards the clinic’s front arytenoid opening. More effort was therefore used to inspire. 10 door. When outside, she squatted, Supporting her weight eas ily, urinated, stood back up and trotted back to the clinic door. The initial medication selected to treat the symptoms of She was sent home with the same medication, dose and dos this polyneuropathy was the Sustained release, semi-syn ing interval and her owners instructed to call daily with thetic, opioid agonist oxycodone hydrochloride, 20 mg/tab progress reports. let, dosed at /2 tablet every 12 hours. 15 The following day, JS's owners reported that her condition After 1 week of administration, no further symptoms of had deteriorated almost as quickly, overnight, as it had pharyngeal or laryngeal paresis/paralysis were reported by improved the day before. On examination she was in fact very the owner. Panting was no longer observed at inappropriate tired and reluctant to move or obey even simple commands times and the Sounds of restrictive air movement were no Such as heal or stand. Her head was hanging and her newly longer audible. Additionally, it was reported that the leaking found interest in life had all but receded. Her heart rate, which of urine had completely stopped. had been between 120-140 bpm only yesterday, was now only After 2 weeks of administration SR’s body movement 60-80 bpm at rest. Her respiratory rate, which had been mark during ambulation, were reported to show an almost complete edly elevated, the prior day, was now very depressed. While return to normal. The previously described symptoms of these findings were disheartening, one significant difference weakness and incoordination were gone. The previously vis 25 did remain from SR's condition upon initial presentation. ible bony prominences of the vertebrae, pelvis and pelvic Although her body, heart and respiratory rates were limbs were now almost completely covered with visible and depressed, she was still breathing without any of the obstruc palpable muscle tissue. Further, the owner reported that the tive Sounds symptomatic of her presenting pharyngeal or urinary incontinence had stopped. laryngeal neuromyopathy. 30 Medication was discontinued and the owners kept SR Example 2 stable and reported her vital signs daily. After 48 hours her cardiac and respiratory rates began to rise and other symp The following case study establishes the efficacy of an toms began to resolve. The symptoms that initially appeared immediate release formulation of a semi-synthetic opioid to indicate a relapse turned out to be those of drug-induced agonist, oxycodone hydrochloride (Roxicodone(R), for the 35 depression and were in fact symptoms of an opioid overdose. treatment of lingual paresis/paralysis, pharyngeal paresis/pa After several attempts to adjust SR’s medication, it was ralysis, laryngeal paresis/paralysis, esophageal paresis/pa finally determined that an immediate release formulation of ralysis, urinary bladder sphincter paresis/paralysis, lumbar oxycodone hydrochloride (Roxycodone(R) effectively con and lumbo-sacral spine paresis/paralysis, and pelvis and pel trolled the symptoms of her polyneuropathic syndrome. The vic limb paresis/paralysis. This case also establishes the util 40 effective dose and frequency of medication was established to ity of an immediate (i.e., not Sustained) release formulation of be (2 drops of Roxycodone in syrup, 20 mg/ml, every 12 oxycodone hydrochloride to maintain an effective level of hours). With this formulation she no longer suffers from the medication to effectively treat and resolve this dog's poly symptoms of general body weakness, lingual, pharyngeal, neuropathy. laryngeal, esophageal, urinary bladder sphincter, lumbar and “JS. an 11 year old spayed, female, Standard Poodle 45 lumbo-sacral, pelvis and pelvic limb paresis/paralysis. (dog), presented with a neurologic/neurogenic syndrome consisting of the following disorders: lingual paresis/paraly Example 3 sis, pharyngeal paresis/paralysis, laryngeal paresis/paralysis, esophageal paresis/paralysis, urinary bladder sphincter pare The following case study establishes the effectiveness of a sis/paralysis, lumbar and lumbo-sacral spine paresis/paraly 50 Sustained release formulation of a semi-synthetic opioidago sis, and pelvis and pelvic limb paresis/paralysis. nist, oxycodone hydrochloride (OxyContin R) for the treat Historically, “JS's symptoms included, general body ment of a polyneuropathic syndrome, and the return of the weakness, difficulty Swallowing, difficult, noisy breathing, ameliorated symptoms when a Sustained release formulation reflux of gastric acid into her esophagus, regurgitation of of a naturally occurring opioid agonist, Morphine Sulfate gastric acid from the esophagus into her oral and nasal cavi 55 E.R., with an equivalent amount of opioid, was substituted in ties, with accompanying oral and nasal discharges. Visible its place. The disorders in the syndrome included lingual wasting of the muscles over her lumbar and lumbo-sacral paresis/paralysis, pharyngeal paresis/paralysis, laryngeal spine, and pelvis and pelvic limbs made it difficult to rise from paresis/paralysis, urinary bladder sphincter paresis/paralysis, a sitting position or walk without stumbling. She also exhib lumbar and lumbo-sacral spine paresis/paralysis, and pelvis ited an uncontrolled leaking of urine. 60 and pelvic limb paresis/paralysis. Her condition was so unstable at presentation that it took 72 “ML, a 13/2 year old, spayed, female, large breed canine hours to sort out and address all of her secondary medical cross (dog), Suffered with a neurologic/neurogenic syndrome problems. At this point only the above-described underlying, consisting of the following disorders: lingual paresis/paraly polyneuropathic syndrome remained. The initial medication sis, pharyngeal paresis/paralysis, laryngeal paresis/paralysis, selected to treat her polyneuropathy was the Sustained-re 65 urinary bladder sphincter paresis/paralysis, lumbar and lease, semi-synthetic opioid agonist, oxycodone hydrochlo lumbo-sacral spine paresis/paralysis, and pelvis and pelvic ride (OxyContin). Within 2-3 hours of administering the ini limb paresis/paralysis. US 8,410,129 B2 17 18 Historically her symptoms included, continual panting, R. (15 mg, 72 tab every 12 hours), which was replaced by dryness of the tongue and mouth, difficulty Swallowing, OxyContin R (10 mg every 12 hours) to treat the symptoms choking, gagging and coughing, inspiratory difficulty accom associated with a polyneuropathy which included: lingual, panied by moist obstructive airway sounds, Snoring, and pro pharyngeal, laryngeal, and pelvis and pelvic limb paresis/ gressive rear leg weakness especially noticeable because of 5 paralysis. The replacement with OxyContin R has also effec the muscle atrophy seen over her lumbar and lumbo-sacral tively reduced the neuromyopathic symptoms. spine, pelvis and pelvic limbs. ML’s owners had also noticed a problem with leaking of urine over the previous few years. Example 7 The medication selected to treat her polyneuropathy is the Sustained release, semisynthetic opioid agonist, oxycodone 10 “LG, a fourteen year old, spayed, female, Golden hydrochloride (OxyContinR), one 10 mg tablet, given orally Retriever (dog), was initially treated with Morphine Sulfate, every 12 hours. Within the first six hours after starting the Immediate Release, Suspension (20 mg/ml, 5-10 drops every medication, the lingual, pharyngeal and laryngeal symptoms 12 hours), which was replaced with oxycodone Extended had all but abated. After the first week on medication all the Release (15 mg, 72 tab every 12 hours) to treat the symptoms symptoms of her urinary tract incontinence began to recede. 15 associated with a polyneuropathy which included: lingual, By the 3rd week after starting the medication, most of the pharyngeal, laryngeal, and pelvis and pelvic limb paresis/ muscle mass had returned to the lumbar and lumbo-sacral paralysis. The replacement treatment has also been effective spine, pelvis and pelvic limbs. For the next several months she in reducing the neuromyopathic symptoms. stayed on the same dose and frequency of (OxyContinR), 10 Although the invention has been described with reference mg administered every 12 hours. This provided a stable thera to the presently preferred embodiments, it should be under peutic blood level, which ameliorated all the symptoms of the stood that various modifications can be made without depart aforementioned polyneuropathic syndrome. ing from the spirit of the invention. All publications, patents, Because of cost issues, the owner elected to change the patent applications, and web sites are herein incorporated by medication to an equivalent amount of the Sustained release reference in their entirety to the same extent as if each indi opioid agonist, Morphine Sulfate E.R., one 15 mg/tab, given 25 vidual publication, patent or patent application was specifi every 12 hours. After one week on the new medication, all of cally and individually indicated to be incorporated by refer the previous symptoms of her polyneuropathic syndrome had ence in its entirety. The disclosure of each individual returned. She was again choking, gagging and coughing, publication, patent or patent application is not an admission having trouble Swallowing, and showing symptoms of respi that each is a prior art reference. ratory distress, especially when stressed or when exercising 30 and urine staining was noted in areas where she had been What is claimed is: resting or sleeping. The most Surprising finding, however, 1. A method for treating paresis/paralysis resulting from a was an almost complete loss of muscle mass over her lumbar neurologic or neurogenic disorder comprising administering and lumbo-sacral spine, and down her pelvis and pelvic to a subject in need thereof an effective amount of an opioid limbs, which accompanied the return of weakness and inco 35 compound, wherein said neurologic or neurogenic disorder ordination in these areas. is: lingual, pharyngeal, laryngeal, or esophageal paresis/pa The owner was instructed to discontinue the Morphine ralysis. Sulfate E.R. and to immediately resume administration of the 2. The method of claim 1, wherein said subject suffers from previously prescribed dose of OxyContin R; 24 hours after a syndrome comprising more than one of the disorders: lin resumption, the owner reported complete return of the laryn 40 gual, pharyngeal, laryngeal and esophageal paresis/paralysis. geal, pharyngeal, and lingual function. Over the next two 3. The method of claim 1, wherein said opioid compound is weeks the function and muscling of the lumbar and lumbo a naturally occurring opium alkaloid. sacral spine, pelvis and pelvic limbs returned, as did the 4. The method of claim3, wherein said naturally occurring patency of the urinary bladder sphincter. opium alkaloid is morphine, codeine, thebaine, papaverine, 45 or noscapine, or a pharmaceutically or veterinarily acceptable Example 4 salt thereof. 5. The method of claim 1, wherein said opioid compound is “KP, a three year old, neutered, male, Siberian Husky a semi-synthetic opium alkaloid. (dog), was medicated with high dose (OxyContin R 40 mg 6. The method of claim 5, wherein said semi-synthetic am, and 60 mg pm) for the treatment of an inherited form of 50 opium alkaloid is hydromorphone, metapon, oxymorphone, laryngeal paresis/paralysis. The treatment has been effective levorphanol, hydrocodone, oxycodone, tramadol, nalor in ameliorating the laryngeal paresis/paralysis. phine, naloxone, or naltrexone, or a pharmaceutically or vet erinarily acceptable salt thereof. Example 5 7. The method of claim 1, wherein said opioid compound is 55 a synthetic opium alkaloid. “PJ, a seventeen year old, neutered, male, Belgium Shep 8. The method of claim 7 wherein said synthetic opium ard (dog), was treated with (OxyContinR) 10 mg every 12 alkaloid is meperidine, methadone, levorphanol, phenaZo hours) for the treatment of lingual, pharyngeal, laryngeal, cine, fentanyl, propoxyphene, or ethoheptazine, or a pharma urinary bladder sphincter, lumbar and lumbo-sacral, pelvis ceutically or veterinarily acceptable salt thereof. and pelvic limb paresis/paralysis. The treatment has been 60 9. The method of claim 1, wherein said opioid compound is effective in eliminating or reducing these neuromyopathic in an immediate or Sustained release pharmaceutical formu symptoms. lation. 10. The method of claim 9, wherein said pharmaceutical Example 6 formulation is a Sustained release formulation. 65 11. The method of claim 1, wherein said pharmaceutical “MG. a thirteen year old, neutered, male, mid-sized, Ter formulation is administered about no more than eight times rier cross (dog), was initially treated with Morphine Sulfate E. within a twenty-four hour period. US 8,410,129 B2 19 20 12. The method of claim 1, wherein said compound is 19. The method of claim 17 where said opioid antagonist is administered to the subject in a daily dose range of about 0.1 maltrexone. mg to 200 mg. 20. The method of claim 1 where said compound is oxyc 13. The method of claim 12, wherein said compound is odone or morphine or a pharmaceutically or veterinarily administered to the Subject in a daily dose range of about 1 mg acceptable salt thereof. to 100 mg. 21. The method of claim 1 where said compound is oxyc 14. The method of claim 1, wherein said compound is odone or a pharmaceutically or veterinarily acceptable salt administered orally, intravenously, intramuscularly, Subcuta thereof. neously, or transdermally. 22. The method of claim 1 where said compound is sus 15. The method of claim 1, wherein the subject is a mam 10 tained release oxycodone or a pharmaceutically or veteri mal. narily acceptable salt thereof. 16. The method of claim 1, comprising administering two 23. The method of claim 1 where said subject suffers from different opioid compounds wherein the first opioid com a syndrome that is neuropathic or polyneuropathic in origin. pound is an opioid agonist and the second opioid compound 24. The method of claim 1 where said treatment at least is an opioid antagonist. 15 partially reverses paresis/paralysis associated with said dis 17. The method of claim 16 where said opioid agonist is order. morphine, oxycodone, tramadol or hydrocodone or a phar maceutically or veterinarily acceptable salt thereof. 25. The method of claim 15 wherein the mammal is a dog. 18. The method of claim 16 where said opioid antagonist is maltrexone.