USOO67871.49B1 (12) United States Patent (10) Patent No.: US 6,787,149 B1 El Khoury et al. (45) Date of Patent: *Sep. 7, 2004 (54) TOPICAL APPLICATION OF OPIOID 5,919,473 A * 7/1999 Elkhoury .................... 424/422 ANALGESC DRUGS SUCH AS MORPHINE 6,011,022 A * 1/2000 EIKhoury .................... 514/78 (75) Inventors: George F. El Khoury, Long Beach, CA FOREIGN PATENT DOCUMENTS (US); Christoph Stein, Baltimore, MD EP O 704 206 A1 9/1995 (US) GB 2 287 404 A 10/1994 WO PCT/US96/19618 12/1996 (73) Assignee: El Khoury and Stein Ltd., Long Beach, CA (US) OTHER PUBLICATIONS European Search Report for Appl. No. EP 9694 4286 (*) Notice: Subject to any disclaimer, the term of this Completed Jul. 11, 2000. patent is extended or adjusted under 35 Tennant et al., “Topical Morphine for Peripheral Pain,” U.S.C. 154(b) by 0 days. Letters to the Editor, The Lancet, vol. 342, 1993, pp. 1047-1048. This patent is Subject to a terminal dis- Khoury, G.F. et al., “Intraarticular Morphine, Bupivacaine, claimer. and Morphine/Bupivacaine for Pain Control After Knee Videoarthroscopy,” Anesthesiology, vol. 77, No. 263, 1992, (21) Appl. No.: 09/319,735 pp. 236-266. (22) PCT Filed: Dec. 12, 1996 C. Stein et al., “Fentanyl Upon Nociception in Inflamed Tissue of the Rat,” Neuroscience Letters, vol. 84, 1988, pp. (86) PCT No.: PCT/US96/19618 225-228. S371 (c)(1), * cited by examiner (2), (4) Date: Jan. 10, 2000 Primary Examiner Thurman K. Page (87) PCT Pub. No.: WO98/25614 ASSistant Examiner-Rachel M. Bennett PCT Pub. Date:Jun. 18, 1998 R. Agent, or Firm Millen, White, Zelano & (51) Int. C.7 - - - - - - - - - - - - - - - - - - - - - - - - - - - A61F 13/00; A61 K 9/00; (57) ABSTRACT A61 K9/06; A61 K9/12 (52) U.S. Cl. ......................... 424/434; 424/45; 424/449; The invention is directed to methods and pharmaceutical 424/401; 514/282; 514/944 compositions for the topical administration of opioid anal (58) Field of Search ................................. 424/401, 434, gesic drugs. Such as morphine. In particular, the invention 424/449, 45; 514/282,944 relates to topical administration of an opioid analgesic agent, e.g., morphine Sulfate, to produce a localized analgesic (56) References Cited effect in inflamed skin or mucosal tissue, and without a transdermal or transmucosal migration of opioid agent, e.g., U.S. PATENT DOCUMENTS into the Systemic circulation. 5,411,738 A 5/1995 Hind 5,866,143 A * 2/1999 Elkhoury .................... 424/401 20 Claims, 1 Drawing Sheet U.S. Patent Sep. 7, 2004 US 6,787,149 B1 F. G. US 6,787,149 B1 1 2 TOPCAL APPLICATION OF OPOD Finally, this intraspinal technique produces a problem of ANALGESC DRUGS SUCH AS MORPHINE itching and the Sequences of continuous itching can be debilitating. This application is a 371 of PCT/US96/19618 filed Dec. In more recent Studies it was discovered that opioid 12, 1996. 5 receptors may also be located in other peripheral tissues. This was reported in Stein, C. et al., Peripheral effect of BACKGROUND OF THE INVENTION fentanyl upon nociception in inflamed tissue of the rat. Morphine is the prototype of the class of opioid analgesic Neurosci. Lett. 84:225-228 (1988), and in Stein, C. et al., drugs which exert their effects by activating opioid receptors Antinociceptive effects of mu- and kappa-agonists in inflam within the brain. When morphine is referred to individually mation are enhanced by a peripheral opioid receptor-specific in this application, this reference is meant to encompass mechanism of action. Eur. J. Pharmacol. 155:255-264 other opioid drugs and is not meant to be morphine exclu (1988). Subsequently, animal experiments were performed sively. Historically, narcotics have been used since the 18th in Dr. Stein's laboratory characterizing peripheral opioid century in the forms of oral or injectable morphine or opium receptors and their activation by morphine and other opioid in order to accomplish pain relief. Morphine is considered to 15 drugs. This was reviewed in Stein, C., Peripheral mecha be unsurpassed as an analgesic for Severe pain. nisms of opioid analgesia. Anesth. Analg. 76:182-191 Unfortunately, morphine and other opioid drugs have a (1993), and in Stein, C., Lehrgerger, K., Yassouridis, A., number of severe side effects which hamper their wide Khoury, G.: Opioids as novel intraarticular agents in arthri Spread use and acceptance by both physicians and patients. tis. In: Progress in Pain Research and Management, Fields, These Side effects include: addiction, nausea, inhibition of H. L., Liebeskind, J. C., eds., 1:289–296, IASP Press, breathing, Somnolence and dysphoria, all of which are Seattle, (1994). A most important determination from these mediated by morphine's action within the brain. It is still the various Studies is that the doses of the drugs required to current belief that narcotics ingested or injected will croSS to produce analgesia in the peripheral tissues are extremely the blood stream and from there go to the brain where there Small and therefore devoid of the above mentioned side are morphine receptors. At that time, the narcotics are 25 effects produced by dosages Sufficient to operate on the believed to attach to these morphine receptors and create a brain. dullness of the pain but with all of the side effects described In addition, it was determined that the endogenous ligands above. Of course, the worst potential effect is the addiction of peripheral opioid receptors (endorphins, the body's own that can occur if the morphine is used beyond a few days or pain killers) are located within the inflamed tissue. It was weeks on a continuous basis. also determined that the endorphins can produce intrinsic Because of the fear of addiction, the use of morphine as analgesia within peripheral tissues both in animals and in an analgesic has been restricted. In addition, major research humans (Stein (1993), ibid.). It was further noted that the efforts have been directed toward the development of peripheral opioid effects were more pronounced in inflamed than in non-inflamed tissues. morphine-like drugs that act within the brain but are devoid 35 of the side effects. The market for these other drugs has An anecdotal preliminary Study reported an attempt to never fully materialized because these drugs were not per transdermally locally administer 1-3 mg of morphine to the ceived as having the same analgesic properties of morphine backs of patients who had undergone failed back operations, and because typically these drugs were not produced to be primarily using mechanical methods of enhancing skin both available in oral and injectable formats. 40 penetration and absorption of the morphine (ultrasound, In the past ten years, the intraspinal method of treating massage, heat) as well as by the use of the occlusive topical pain has been developed tremendously but, as more exten vehicle Aquaphor (F. Tennant et al., Topical morphine for Sive use was made of this technique, a number of Serious peripheral pain. Lancet 342:1047-1048 (1993). Some problems developed. The first problem is that the intraspinal improvement in pain relief was noted, and the authors method of treatment requires a spinal tap which of course 45 Speculated that it was due to binding of the morphine to necessitates the use of a needle to the Spinal cord. The peripheral opioid receptors in inflamed (presumably Second problem results from the first in that if it is necessary myofascial) tissue directly under the skin to which the to use the intraspinal method over a period of time, Such as morphine was applied, and absence of morphine in the two or three weeks, medication must be injected into the Systemic circulation was claimed. This result is Scientifically Spine for this period of time and the continuous needle StickS 50 questionable, however, based on the data of the present into the Spine has potential hazards. Further, if it is necessary invention: there had to be Sufficient transdermal transport to to use the intraspinal method over time, even though the carry the morphine completely through the skin and into the dosage is Substantially less compared to oral or intravenous underlying inflamed myofascial tissues, which would almost dosages, there is still a high potential for addiction and with certainly result in a detectible amount of morphine being such addiction the resultant problems of withdrawal and its 55 carried in the Systemic circulation. Alternatively, it is pos asSociated Side effects. sible that the pain relief noted was not reproducible. It is Although intraspinal application of narcotics is still used notable that no further reports of this type of administration to alleviate pain after Surgery, this technique has the limi have been reported Since, either by that group or any others. tations with the potential for addiction as described above. None of these reports discussed the possibility that pain In addition, it has been determined that with frail patients 60 relief could be topically induced in inflamed skin, nor was there is the risk that the patient can Stop breathing and there it even known whether peripheral opioid receptors are have been a number of cases of respiratory arrest after the present in human Skin. administration of narcotics using the intraspinal technique. Severe pain caused or accompanied by inflammation in Further, the intraspinal technique of administering narcotics skin is a particularly intractable problem, because the under creates difficulty with male patients and especially with 65 lying reasons for it tend to be both long-term and yet not elderly male patients in that there can be problems with inherently life-threatening, e.g., Shingles and various kinds urination and with consequent problems of urine retention.