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Wo 2007/120485 A2 (12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (43) International Publication Date PCT (10) International Publication Number 25 October 2007 (25.10.2007) WO 2007/120485 A2 (51) International Patent Classification: IS, JP, KE, KG, KM, KN, KP, KR, KZ, LA, LC, LK, LR, A61K 31/195 (2006.01) LS, LT, LU, LY,MA, MD, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, NO, NZ, OM, PG, PH, PL, PT, RO, RS, (21) International Application Number: RU, SC, SD, SE, SG, SK, SL, SM, SV, SY, TJ, TM, TN, PCT/US2007/0081 14 TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, ZM, ZW (22) International Filing Date: 30 March 2007 (30.03.2007) (84) Designated States (unless otherwise indicated, for every kind of regional protection available): ARIPO (BW, GH, (25) Filing Language: English GM, KE, LS, MW, MZ, NA, SD, SL, SZ, TZ, UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, MD, RU, TJ, TM), (26) Publication Language: English European (AT,BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HU, IE, IS, IT, LT,LU, LV,MC, MT, NL, PL, PT, RO, SE, SI, SK, TR), OAPI (BF, BJ, CF, CG, CI, CM, (30) Priority Data: 60/787,150 30 March 2006 (30.03.2006) US GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). Declarations under Rule 4.17: (71) Applicant (for all designated States except US): CINER- — as to applicant's entitlement to apply for and be granted a GEN, LLC [US/US]; 146 Medinah Drive, Blue Bell, PA patent (Rule 4.17(U)) 19422-3212 (US). — as to the applicant's entitlement to claim the priority of the earlier application (Rule 4.17(Ui)) (71) Applicant and — of inventorship (Rule 4.17 (iv)) (72) Inventor: BABUL, Najib [US/US]; 146 Medinah Drive, Blue Bell, PA 19422-3212 (US). Published: — without international search report and to be republished (81) Designated States (unless otherwise indicated, for every upon receipt of that report kind of national protection available): AE, AG, AL, AM, AT,AU, AZ, BA, BB, BG, BH, BR, BW, BY, BZ, CA, CH, For two-letter codes and other abbreviations, refer to the "G uid CN, CO, CR, CU, CZ, DE, DK, DM, DZ, EC, EE, EG, ES, ance Notes on Codes and Abbreviations" appearing at the beg in FI, GB, GD, GE, GH, GM, GT, HN, HR, HU, ID, IL, IN, ning of each regular issue of the PCT Gazette. (54) Title: METHODS OF TREATING PAIN WITH ALKYLXANTHINES AND ANTIEPILEPTICS AND COMPOSITIONS FOR USE THEREFOR (57) Abstract: The present invention relates to a method of treating or preventing pain and to pharmaceutical compositions useful for carrying out said methods. The present invention is directed to a method of treating or preventing pain comprising adminis tering a selected antiepileptic compound and an alkylxanthine bronchodilator to a subject in need of such treatment, wherein said alkylxanthine bronchodilator produces an enhanced effect of said antiepileptic compound. The present invention is also directed to pharmaceutical compositions comprising an antiepileptic compound and an alkylxanthine bronchodilator useful for carrying out the method of the present invention. METHODS OF TREATING PAIN WITH ALKYLXANTHINES AND ANTIEPILEPTICS AND COMPOSITIONS FOR USE THEREFOR [0001] The application claims the benefit of U.S. Provisional Application No. 60/787,150, filed March 30, 2006, which is herein incorporated by reference in its entirety. FIELD OF THE INVENTION [0002] The present invention is in the field of pharmaceutical compositions and the use thereof for treating and preventing pain. BACKGROUND ART [0003] The medical condition of pain is a complex physiological process that involves a number of sensory and neural mechanisms. Pain can be defined as an unpleasant sensory and emotional experience associated with actual or potential tissue damage, or described in terms of such damage. [0004] Pain is most often classified by time course or mechanism as acute pain, inflammatory pain, visceral pain, breakthrough pain, neuropathic pain, chronic pain, or cancer-related pain. Acute pain is a normal, predictable physiological response to an adverse chemical, thermal, or mechanical stimulus associated with surgery, trauma, or acute illness. It is normally self- limited. When the condition producing the pain resolves, the pain goes away. Acute pain includes post-surgical pain, post-traumatic pain, renal colic, and headache. Acute pain may be experienced as a single event, or it may be episodic. Chronic pain is usually defined as pain persisting longer than the expected time of tissue healing. Injury or a disease process can trigger chronic pain, but other factors besides the triggering event can perpetuate the pain. For example, the nervous system itself may be damaged by the initial injury and be unable to return to normal function despite healing of the injury itself. In some cases, the precise cause of chronic pain may be unknown (idiopathic pain), but the pain may still respond to the treatment. Chronic pain includes such syndromes as low back pain, myofascial pain, osteoarthitis, neuropathic pain, fibromyalgia and inflammatory pain states such as rheumatoid arthritis. Cancer-related pain is due to the primary tumor itself, metastatic disease, paraneoplastic syndromes, or effects of cancer treatment. Cancer-related pain can include elements of both chronic pain and acute pain. Neuropathic pain is secondary to injury to the peripheral and central nervous system and includes postherpetic neuralgia, diabetic neuropathy, postamputation pain, mono- and polyneuropathies, radiculopathy, and central pain. [0005] Management of pain, and particularly chronic pain, is complex and frequently unsuccessful or only partially successful. However, rarely do physicians engage in aggressive pain management. Undertreatment for pain frequently leads to conditions where patients are forced to suffer pain up to the point of tolerability before receiving medication, and the medication is usually only partially effective. Ineffective pain management is a consequence of lack of training, and of fear of narcotics on the part of patients, the medical personnel, and society in general. Children, because of their natural reticence and budding communication skills combined with a greater fear of over- administering "dangerous" narcotics, particularly suffer from under treatment for pain. [0006] Frequently, a patient suffering from chronic pain will require medication to control stomach and other gastric problems as a result of oral administration of drugs. Alternatives to oral self-administration for most of the analgesic and sedative medications for the treatment of chronic pain are not common, can be cumbersome (e.g., i.v. or s.c. administration requires use of a cannula or needle), and generally require medical training. [0007] Currently, medical practitioners may choose from several well- accepted classes of pharmaceutical agents in their attempts to alleviate pain. Acute pain is managed with a variety of drugs, frequently in combination, including opioid analgesics, e.g., morphine, hydromorphone, hydrocodone, oxycodone, tramadol, and codeine; acetaminophen; non-steroidal anti¬ inflammatory drugs (NSAIDs) e.g., ketoprofen, ibuprofen, naproxen, tiaprofenic acid, aceclofenac, diclofenac, piroxicam, loxaprofen, fenoprofen, flurbiprofen, tenoxicam, lornoxicam, acetylsalicylic acid, flufenamic acid, mefenamic acid, niflumic acid, tolfenamic acid, diflunisal, etodolac, feribufen, isoxicam, piφ rofen, sulindac, tolmetin, and piketoprofen and more recently, cyclo-oxygenase isoform 2 (COX-2) selective NSAIDs, e.g., celecoxib, valdecoxib, piketoprofen, etoricoxib, rofecoxib, and lumiracoxib; tricyclic antidepressants, e.g., amitriptyline and despiramine; and antiepileptics, e.g., gabapentin, pregabalin, carbamazepine, oxcarbazepine, and lamotrigine. [0008] Additionally, a number of other drugs with analgesic properties are being investigated, including neuro-active steroids; beta adrenergic agonists, e.g., albuterol; selective prostanoid receptor antagonists; NMDA antagonists; neuronal nicotinic receptor agonists; calcium channel antagonists; serotonin 5- HT(1B/1D) receptor agonists sodium channel blockers; cannabinoid agonists; superoxide dismutase mimetics; p38 MAP kinase inhibitors; triptans, TRPVl agonists; ketamine; NKl receptor antagonists; gabapentinoids; and glycine receptor antagonists. [0009] Of the many challenges that occur when pharmacologically treating any disease or pathological condition, including pain, alleviating the symptoms without causing counterproductive side effects is often the greatest. This challenge presents itself when medical practitioners use medicinal agents to treat pain. Although the aforementioned pharmacological classes are frequently effective for the treatment of certain types of pain, the chronic and acute use of these analgesic agents produces a number of significant, undesirable side effects. [0010] Morphine is extensively utilized for the management of severe pain due to its global availability, extensive clinical experience, significant pharmacokinetic and pharmacodynamic data, low cost and the availability of various extended release formulations (Babul et. al, J Clin Pharmacol, 1998;38:74-81). However, the incidence and severity of side effects limits the use of morphine in some patients (Hagen and Babul, Cancer 1997;79:1428- 37). In patients with renal impairment, morphine's principal metabolites, morphine-3-glucvιronide and morphine-6-glucuronide can accumulate. Morphine-3-glucuronide accumulation has been implicated in hyperalgesia, respiratory stimulation, and behavioral
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