(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 excitatory properties through nonopioid receptor mechanisms. Morphine-6-glucuronide accumulation has been implicated in increasing levels of nausea and sedation in patients with renal impairment (Babul and Darke, Clin Pharm Ther, 1993;54:286-92). Similarly, the principal metabolite of hydromorphone, hydromorphone-3-glucuronide can accumulate in patients with renal impairment and has been found to be more neurotoxic than morphine-3-glucuronide (Babul and Darke, Pain, 1992;51:260-61; Hagen et al., J Clin Pharmacol, 1995;35:38-45; Babul et al., J Pain Symptom Manage, 1995;10: 184-86; Wright et al., Life Sci, 1998;63:401-ll; Wright et al., Life Sci, 2001;69:409-20.). [0011] There are now many compounds with pharmacological properties similar to those produced by morphine. Although there can be striking variability in response to opioids in an individual patient, none of the commercially available opioids have proven to be clinically superior to morphine in relieving pain when used at equianalgesic doses in carefully controlled clinical trials. Non-limiting examples of morphine-like opioids include alfentanil, carfentanil, diamorphine, dihydrocodeine, fentanyl, hydrocodone, hydromorphone, levorphanol, lofentanil, meperidine, oxycodone, oxymorphone, racemorphan, remifentanil and sufentanil. [0012] Unlike doses of non-opioid analgesics, partial opioid agonists and mixed opioid agonist-antagonists, pure or full opioid agonists such as morphine, hydromorphone, oxycodone, fentanyl, carfentanil. lofentanil, alfentanil and sufentanil do not have a "dose ceiling". In other words, their doses can be increased almost indefinitely, being limited only by the occurrence of side effects. [0013] Among the many side effects of opioids are nausea, vomiting, constipation, sedation, fatigue, pruritus, blurred vision, urinary retention, respiratory depression, convulsions, mood changes and alterations of the endocrine and autonomic nervous systems. Many of these side effects are sufficiently bothersome as to require: i) use of additional medications to treat . the iatrogenic symptoms; ii) more intensive patient management; iii) use of lower doses that leave patients in continued pain; or iv) in other cases, complete discontinuation of analgesic therapy. Opioids can also produce potentially fatal respiratory depression at high doses. (Evidence Based Report of the U.S. Agency for Healthcare Research and Quality (AHRQ) on the Management of Cancer Pain, Report No. 35, AHRQ Publication No. 02-E002, October 2001; Carr et al. J Nat Cancer Inst Monograph 2004;32:23-31; Agency for Health Care Policy and Research Clinical Practice Guidelines for Cancer Pain Management, Guideline No. 9, AHCPR Publication No. 94-0592, March 1994; Guideline for the Management of Cancer Pain in Adults, American Pain Society, 2005). [0014] Fear of opioid side effects and efforts to minimize same often lead to the administration of opioid doses that do not completely relieve pain. In the case of acute postsurgical pain, poorly managed pain has been shown to lengthen hospital stays and increase the number of re-admissions. Severe postsurgical pain can interfere with breathing, digestion, recovery, rehabilitation and discharge. In the case of chronic pain, poorly managed pain adversely affects the patient's quality of life, sleep, psychological state and restoration of physical function. [0015] Undertreatment of pain may also occur when higher doses of opioid analgesics are required to manage the patient's pain due to: 1) prescribing resistance by clinicians and 2) patient and family barriers to dose escalation. Physicians frequently have exaggerated fears about the risk of iatrogenic addiction, respiratory depression and the risk of adverse regulatory sanctions. Similarly, patients and family members have fears about drug addiction and in some cases, equating increased opioid requirement with terminal disease, death and dying. [0016] Opioids exert effects on the neuroendocrine system, including hypothalamic inhibition of the release of gonadotropin releasing hormone and corticotropin-releasing factor, thereby decreasing circulating concentrations of luteinizing hormone, follicle stimulating hormone, adrenocorticotropin and β-endorphin. As a result of the decreased concentrations of pituitary trophic hormones, plasma concentrations of testosterone and Cortisol decline. The administration of opioids increases plasma prolactin concentrations, most likely by reducing the dopaminergic inhibition of prolactin secretion. [0017] Opioid side effects are managed in a variety of ways, including: i) adjusting the dose; ii) adding a non-analgesic drug to manage side effects (e.g., a laxative or antiemetic); iii) switching to another opioid; and iv) using analgesic doses of a non-opioid analgesic. [0018] In some patients, no intervention is effective in attaining an optimal balance between analgesia and acceptable side effects. For this reason, there has been an ongoing but so far unsuccessful effort to develop opioid and non- opioid analgesics with a superior side effect profile than currently available opioids. [0019] An alternative strategy to provide optimal analgesia without intolerable side effects has involved use of lower doses of an opioid analgesic in combination with analgesic doses of one or more non-opioid drugs, thereby reducing the side effects that might otherwise occur from higher opioid doses given alone. [0020] An additional concern with the use of opioids, particularly repeated dose and chronic use is the development of iatrogenic addiction. Unfortunately, it is not possible to fully screen for the risk of iatrogenic addiction before initiating opioid therapy. Furthermore, there is a large population of patients who have uncontrolled pain and who also are at higher risk for iatrogenic addiction. 10021] [0022] As a consequence, opioid abuse continues to be prevalent, i.e., use (i) in quantities or by methods and routes of administration that do not conform to standard medical practice; (ii) outside the scope of specific instructions for use provided by a qualified medical professional; (iii) outside the supervision of a qualified medical professional; (iv) outside the approved instructions on proper use provided by the drug's legal manufacturer; (v) which is not in specifically approved dosage forms for medical use as pharmaceutical agents; (vi) where there is an intense desire for and efforts to procure same; (vii) with evidence of compulsive use; (viii) through acquisition by manipulation of the medical system, including falsification of medical history, symptom intensity, disease severity, patient identity, doctor shopping, prescription forgeries; (ix) where there is impaired control over use; (x) despite harm; (xi) by procurement from non-medical sources; (xii) by others through sale or diversion by the individual into the non-medical supply chain; (xiii) for medically unapproved or unintended mood altering purposes. [0023] Moreover, rapid pharmacologic tolerance to opioids develops in some patients requiring higher doses over time. [0024] The NSAIDs, as a class, are highly effective as analgesics. They are used to treat both acute and chronic pain, usually by the oral route of administration. The main mechanism by which NSAIDs exert an analgesic effect is through the inhibition of the synthesis of certain prostaglandin, or prostanoids. The synthesis of prostanoids utilizes two distinct COX enzymes: COX-I and COX-2. Traditional NSAIDs inhibit both enzymes. NSAIDs may also inhibit other lipogenic enzymes, such as 5-lipooxygenase. Although NSAIDs are not addictive, they are not without significant toxic effects, such as gastrointestinal injury, hepatotoxicity and decrease clotting ability. [0025] NSAIDs in racemic or enantiomeric form, include aceclofenac, acetylsalicylic acid, bufexamac, bumadizone, carprofen, dexketoprofen, diclofenac, diflunisal, droxicam, eltenac, epirizole, etodolac, etofenamate, felbinac, fenbufen, fenoprofen, flufenamic acid, fentiazac, fepradinol, feprazone, floctafenine, flufenamic acid, flunixine, flunoxaprofen, flurbiprofen, flurprofen, glafenine, glucametacin, ibuprofen, indobufen, indomethacin, isonixin, isoxicam, ketorolac, ketoprofen, lomoxicam, loxoprofen, meclofenamic acid, mefenamic acid, meloxicam, mofebutazone, nabumetone, naproxen, nifenazone, niflumic acid, nimesulide, oxaprozin, piketoprofen, piroxicam, piφ rofen, pranoprofen, proquazone, salicylic acid, salsalate, sulindac, suprofen, tenidap, tetridamine, tiaprofenic acid, tenoxicam, tolfenamic acid, tolmetin and zaltoprofen. [0026] NSAIDs use is associated with significant cardiovascular, cerebrovascular, gastrointestinal and other side effects. Although NSAID side effects can occur in any patients, some patient groups are at particular risk. Patients at particular risk include those who: (i) are elderly; (ii) are cachectic' (iii) are immunocompromised; (iv) have a malignancy; (iv) are receiving corticosteroids; (v) with a history of significant alcohol consumption; (vi) are smokers; (vii) are receiving long-term NSAED therapy; (viii) are receiving high doses of NSAID's; (ix) have prior history of peptic ulcer disease, perforations and GI bleeding; (x) have ischemic heart disease; (xi) are undergoing CABG surgery; (xii) have a history of stroke; (xiii) are anticoagulated; (xiv) have a history of renal impairment and renovascular disease; (xv) have hepatic impairment; and (xvi) have a history of hypertension. Additional information on risk factors for NSAID toxicity may be found in the scientific and medical literature. [0027] Furthermore, NSAIDs are not very effective in treating neuropathic pain. [0028] GABA analogs, such as gabapentin and pregabalin are well know antiepileptics that are also effective for the treatment of pain. For example, see Rorarius, et al, Pain 110:175-81 (2004); Caraceni, et al, J. Clin. Oncol. 22:2909-17 (2004); Levendoglu, et al, Spine 29:743-51 (2004); Pandey, et al, Can. J. Anaesth. 51:358-63 (2004); Dierking, et al, Acta Anaesthesiol. Scand. 48:322-7(2004); Gustorff. et al, Anesth. Analg. 98:401-7 (2004); Pandey, et al, Anesth. Analg. 95:1719-23 (2002); Serpell, et al, Pain 99:557-66 (2002); Bone, et al, Reg. Anesth. Pain Med. 27:481-6(2002); Dirks, et al Anesthesiology 97:560-4 (2002); Tai, et al, J. Spinal Cord. Med. 25:100-5 (2002); Werner, et al, Reg. Anesth. Pain Med. 26:322-8 (2001); Morello, et al, Arch. Intern Med. 159:1931-7 (1999); Backonja, M., Epilepsia 40 Suppl 6:S57-9 (1999); Bckonja, et al, JAMA 280:1831-6 (1998); Rice, et al, Pain 94:215-24 (2001); Beydoun, A., Epilepsia Suppl 6:S51-6 (1999); Rowbotham, et al, JAMA 280:1837-42 (1998); Sabatowski, et al, Pain 109:26-35 (2004); Hill, et al, Eur. J. Pain 5:119-24 (2001); Dworkin, et al, Neurology ;60:1274-83 (2003); and Rosenstock, et al, Pain ;1 10:628-38 (2004). [0029] A number of other antiepileptics drugs have also demonstrated efficacy in the prevention and treatment of pain. Nonlimiting examples include carbamazepine, oxcarbazepine, lacosamide, lamotrigine, valproate, phenytoin, and topiramate. For example, see Wilton, T.D., S. Afr. Med. J. 48:869-72 (1974); Eisenberg, et al, Neurol 57:505-9 (2001); Zakrzewska, et al, Pain ;73:223-30 (1997); Chadda, et al, J. Assoc. Physicians India 26:403-6 (1978); Gilron, et al, CHn. Neuropharmacol 24:109-12 (2001); and Vestergarrd, et al, Neurology 56; 184-90 (2001). [0030] Unfortunately, many patients do not achieve adequate pain relief with antiepileptic compounds alone, and frequently, antiepileptic compounds are used in combination with other analgesics to provide optimal analgesia. Although the use of such combination therapy is sometimes effective in overcoming the suboptirnal efficacy of monotherapy with antiepileptic compounds, the use of combination therapy adds to the economic cost of therapy and the adverse effects patients have to deal with. Furthermore, when patients are receiving combination analgesic therapy, it is difficult to attribute causality of side effects to any one drug, making further dose titration and medication management complicated. [0031] Some patients receiving antiepileptic therapy obtain pain relief but have unacceptable side effects. [0032] An additional shortcoming antiepileptic compounds for the treatment of pain is that some of the drugs in this class, e.g., gabapentin, require a prolonged titration period lasting several weeks to months before reaching an optimal dose. For example, a patient may be initiated on gabapentin 300 mg twice a day and require upward dose titration of 300 mg every 3 to 7 days up to doses as high as 6000 mg before achieving optimal analgesia. Similarly, the antiepileptic compound pregabalin is started at a dose of 150 mg per day. Based on individual patient response and tolerability, the dosage may be increased to 300 mg per day after an interval of 3 to 7 days, and if needed, to a maximum dose of 600 mg per day after an additional 7-day interval. [0033] Yet another shortcoming of antiepileptic compounds for the treatment of pain is the occurrence of unacceptable or intolerable side effects that require additional medical management, dose reduction, treatment discontinuation or use of doses that provide only partial relief of pain. For example, in a study of patients with postherpetic neuralgia where the antiepileptic compound gabapentin was initiated on the lowest possible dose of 300 mg/day and gradually titrated to effect over one month, 18.6% of patients discontinued therapy due to side effects (Rowbotham et at, JAMA, 1998). In clinical trials with gabapentin, common side effects include dizziness (28%), sedation (21.4%), peripheral edema (8.3%), asthenia (5.7%). In addition, although nausea only occurs in 3.9% of cases, it is a frequent cause of treatment discontinuation (Physician's Desk Reference, 2005, Thomson). Similarly, for the antiepileptic compound pregabalin, the discontinuation rate due to adverse reactions was 13%. The most common adverse reactions resulting in discontinuation from pregabalin treatment groups were dizziness and somnolence. [0034] Given that significant drawbacks and side effects accompany the use of currently prescribed compounds for the prevention and treatment of pain, there is a need for new therapeutic methods and pharmaceutical compositions that have reduced side effects, enhanced analgesic properties, better therapeutic indices, and/or faster onset of action.

BRIEF SUMMARY OF THE INVENTION

[0035] Surprisingly, antiepileptic compounds can be advantageously used together with alkylxanthine bronchodilators and administered to animals to not only elicit a more potent analgesic response but also to evoke such response with lower doses, fewer side effects, more rapidly and/or for longer duration than possible by administration of the antiepileptic compounds alone. [0036J A first aspect of the present invention is directed to a novel method and pharmaceutical compositions for eliciting a rapid analgesic response, said method comprising administering an effective amount an antiepileptic compound and an analgesic-enhancing amount of an alkylxanthine bronchodilator. [0037] A second aspect of the present invention is directed to a novel method and pharmaceutical compositions for eliciting a robust peak analgesic response, said method comprising administering an effective amount an antiepileptic compound and an analgesic-enhancing amount of an alkylxanthine bronchodilator. [0038] . A third aspect of the present invention is directed to a novel method and pharmaceutical compositions for hastening the analgesic response, said method comprising administering an effective amount an antiepileptic compound and an analgesic-enhancing amount of an alkylxanthine bronchodilator. [0039] A fourth aspect of the present invention is directed to a novel method and pharmaceutical compositions for increasing the duration of the analgesic response, said method comprising administering an effective amount an .antiepileptic compound and an analgesic-enhancing amount of an alkylxanthine bronchodilator. [0040] A fifth aspect of the present invention is directed to a novel method and pharmaceutical compositions for improving the tolerability of antiepileptic therapy, said method comprising administering an effective amount an antiepileptic compound and an analgesic-enhancing amount of an alkylxanthine bronchodilator. [0041] . A sixth aspect of the present invention is directed to a novel method and pharmaceutical compositions for reducing CNS side effects of antiepileptic therapy, said method comprising administering an effective amount an antiepileptic compound and an analgesic-enhancing amount of an alkylxanthine bronchodilator. [0042] A seventh aspect of the present invention is directed to a novel method and pharmaceutical compositions for reducing the frequency of side effects of antiepileptic therapy, said method comprising administering an effective amount an antiepileptic compound and an analgesic-enhancing amount of an alkylxanthine bronchodilator. [0043] An eighth aspect of the present invention is directed to a novel method and pharmaceutical compositions for reducing the severity (i.e., intensity) of side effects of antiepileptic therapy, said method comprising administering an effective amount an antiepileptic compound and an analgesic-enhancing amount of an alkylxanthine bronchodilator. [0044] A ninth aspect of the present invention is directed to a novel method and pharmaceutical compositions for reducing the dosing frequency of antiepileptic therapy (i.e., decreasing the number of doses per day), said method comprising administering an effective amount an antiepileptic compound and an analgesic-enhancing amount of an alkylxanthine bronchodilator. [0045] A tenth aspect of the present invention is directed to a novel pharmaceutical compositions of matter comprising administering an effective amount an antiepileptic compound and an analgesic-enhancing amount of an alkylxanthine bronchodilator. [0046] An eleventh aspect of the present invention is directed to a novel pharmaceutical compositions of matter comprising administering a subanalgesic amount an antiepileptic compound and an analgesic-enhancing amount of an alkylxanthine bronchodilator. [0047] A twelfth aspect of the present invention directed to a novel method for eliciting an analgesic response, said method comprising administering an effective amount of antiepileptic compound and an analgesic-enhancing amount of an alkylxanthine bronchodilator. [0048] A thirteenth aspect of the present invention is directed to a novel method and pharmaceutical compositions for eliciting analgesic response, said method comprising administering a subanalgesic dose of an antiepileptic compound and an analgesic-enhancing amount of an alkylxanthine bronchodil ator.

DETAILED DESCRIPTION OF THE INVENTION

[0049] The present invention provides a method of treating or preventing pain comprising administering to a subject in need of pain treatment or pain prevention (a) one or more an antiepileptic compounds and (b) one or more alkylxanthine bronchodilators. In one embodiment, the method comprises administering one antiepileptic compound and one alkylxanthine bronchodilator. The method produces an enhanced analgesic effect of said analgesic. [0050] The present inventor has discovered that that antiepileptic compounds having pain alleviating properties, when co-administered with alkylxanthine bronchodilators result in unexpected improved pain relief. The term "antiepileptic compound" is generally defined to be a pharmaceutically acceptable active ingredient that treats seizure disorders or epilepsy. [0051] The antiepileptic compounds or antiepileptic drugs can be grouped according to their main mechanism of action, although many of them have several actions and others have unknown mechanisms of action. The main groups include sodium channel blockers, calcium current inhibitors, gamma- aminobutyric acid (GABA) enhancers, glutamate blockers, carbonic anhydrase inhibitors, hormones, and drugs with unknown mechanisms of action. [0052] Non-limiting examples of antiepileptic compounds include carbamazepine, felbamate, fosphenytoin, gabapentin, lacosamide, lamotrigine, levetiracetam, mephenytoin, oxcarbazepine, phenytoin, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof. [0053] In some preferred embodiments, the antiepileptic compounds is a compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof. [0054] Without being bound by theory, the term "alkylxanthine bronchodilator" is a compound selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof. [0055] In some preferred embodiments, the alkylxanthine bronchodilator is a compound selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, enprophylline and pentoxifylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof. [0056] In a preferred embodiment of the present invention, antiepileptic compounds having pain alleviating properties include those that have the following Formula I I wherein R is hydrogen or a lower alkyl, n is an integer of from 4 to 6; and the cyclic ring is optionally substituted, and the pharmaceutically acceptable salts thereof. The term lower alkyl includes straight or branched chain alkyl groups of up to eight carbon atoms. An especially preferred embodiment utilizes a compound of Formula I where Ri is hydrogen and n is 5, which compound is l-(aminomethyl)cyclohexane acetic acid, known generically as gabapentin. [0057] Other preferred compounds of Formula I above include, but are not limited to: ethyl 1-aminornethyl-l-cyclohexaneacetate; 1-amino methyl- 1- cycloheptane-acetic acid; 1-aminomethyl-l-cyclopentane-acetic acid; methyl-laminomelhyl-1-cyclohexane-acetate; n-butyl 1-aminomethyl-l- cyclohexaneacetate; methyl 1-aminomethyl-l -cycloheptaneacetate; n- butyl 1-aminomethyl-l-cycloheptane-acetate toluene sulfonate; 1-aminomethyl-l-cyclopentaneacetate benzene-sulfonate; and n-butyl l-aminomethyl-l-cyclopentane-acetate. [0058] Other preferred compounds of Formula I above, wherein the cyclic ring is substituted for example with alkyl such as methyl or ethyl, include, but are not limited to (l-aminomethyl-3-methylcyclo.hexyl)acetic acid, (l-aminomethyl-3 -methyl cyclopentyl)acetic acid, and (1- aminomethyl-3,4-dimethylcyclopentyl)acetic acid. [0059] In another preferred embodiment of the present invention, antiepileptic compounds having pain alleviating properties include those that are included in Formula II:

II «?4

H2NCH C CH2COOH

R2 wherein R2 is a straight or branched alkyl of from 1 to 6 carbon atoms, phenyl, or cycloalkyl having from 3 to 6 carbon atoms, R 3 is hydrogen or methyl, and R_is hydrogen, methyl, or carboxyl, or an individual diastereo- meric or enantiomeric isomer thereof or a pharmaceutically acceptable salt thereof. [0060] The most preferred compound of Formula II is where R 3 and R4 are

both hydrogen and R is -(CH2) ,-iC4H9 as an (R), (S) or (R S) isomer, wherein m is 0 to 2. A more preferred embodiment of the invention utilizes 3- aminomethyl-5-methyl-hexanoic acid, and especially (S)-3-(aminomethyl)- 5-methylhexanoic acid, now known generically as pregabalin. Another pre¬ ferred compound is 3-(l-aminoethyl)-5-methylhexanoic acid. [0061] In the preferred embodiment of the present invention, the combination will comprise a compound of Formula I in combination with one or more alkylxanthine bronchodilators. [0062] In one embodiment, one alkylxanthine bronchodilators and one antiepileptic compound are required to achieve the objects of the invention. In one embodiment, said two or more alkylxanthine bronchodilators and one antiepileptic compound are required to achieve the objects of the invention. In one embodiment, said one alkylxanthine bronchodilators and two or more antiepileptic compound are required to achieve the objects of the invention. In one embodiment, said two or more alkylxanthine bronchodilators and two or more antiepileptic compound are required to achieve the objects of the invention. [0063] In one embodiment, the alkylxanthine bronchodilators of the invention exclude (i.e., do not include) theophylline, or exclude theobromine, or exclude aminophylline, or exclude dyphylline, or exclude oxtriphylline, or exclude etofylline, or exclude enprophylline, or exclude etamiphylline, or exclude pyridophylline, or exclude doxofylline, or exclude bamifylline, or exclude proxyphylline, or exclude diprophylline, or exclude pentoxifylline, or exclude propentofylline, or exclude pentifylline, or exclude lisofylline, or exclude more than one of the forgoing. [0064] In one embodiment, the antiepileptic compounds of the invention exclude (i.e., do not include) carbamazepine, or exclude felbamate, or exclude fosphenytoin, or exclude gabapentin, or exclude lacosamide, or exclude lamotrigine, or exclude levetiracetam, or exclude mephenytoin, or exclude oxcarbazepine, or exclude phenytoin, or exclude pregabalin, or exclude tiagabine, or exclude topiramate, or exclude vigabatrin, or exclude valproate, or exclude zonisamide, or exclude more than one of the forgoing. [0065] In one embodiment, the dosage form of the invention excludes non- oral use. [0066] In one embodiment, the dosage form of the invention excludes parenteral use. [0067] In one embodiment, the dosage form of the invention excludes immediate release oral forms and use. 10068] In one embodiment, the dosage form of the invention excludes controlled release oral forms use. [0069] In one embodiment, the dosage form of the invention application of the dosage form to the skin. [0070] In one embodiment, said one or more alkylxanthine bronchodilators are administered in an amount which enhances the effect of the antiepileptic compound. In one embodiment of the present invention, "enhanced effect" means that, when coadministered with an alkylxanthine bronchodilator, lower doses of the selected antiepileptic compounds are required to achieve the same analgesic effect as when the antiepileptic compound is administered alone or greater analgesic effect is achieved when usual doses of the selected antiepileptic compound are administered with an alkylxanthine bronchodilator. For example, across all doses, a greater analgesic response is achieved with coadministration of an antiepileptic compound with an alkylxanthine bronchodilator when compared with administration of the antiepileptic compound by itself. [0071] In one embodiment, the method of the present invention comprises administering an antiepileptic compound and an alkylxanthine bronchodilator to a patient. The precise amount and ratio of the antiepileptic compound to the alkylxanthine bronchodilator may vary. For instance, in certain embodiments, the method comprises administering an antiepileptic compound and a alkylxanthine bronchodilator in a molar ratio from about 1:1000 to about 1000:1; about 1:500 to about 500:1; about 1:400 to about 400:1; about 1:200 to about 200:1; about 1:100 to about 100:1; about 1:75 to about 75:1; about 1:50 to about 50:1; about 1:40 to about 40:1; about 1:30 to about 30:1; about 1:20 to about 20:1; about 1:15 to about 15:1; about 1:10 to about 10:1; about 1:8 to about 8:1; about 1:5 to about 5:l;about 1:4 to about 4:1; about 1:4 to about 4:1; about 1:3 to about 3:1; about 1:2 to about 2:1; or about 1:1. In specific embodiments, the method of the invention comprises administering an antiepileptic selected from the group comprising carbamazepine, felbamate, fosphenytoin, gabapentin, lacosamide, lamotrigine, levetiracetam, mephenytoin, oxcarbazepine, phenytoiri, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof, and an alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein the antiepileptic compound and the alkylxanthine bronchodilator are preferably present in a molar ratio from about 1:200 to about 200:1; about 1:100 to about 100:1; about 1:75 to about 75:1; about 1:50 to about 50:1; about 1:40 to about 40:1; about 1:30 to about 30:1; about 1:20 to about 20:1; about 1:15 to about 15:1; about 1:10 to about 10:1; about 1:8 to about 8:1; about 1:5 to about 5:l;about 1:4 to about 4:1; about 1:4 to about 4:1; about 1:3 to about 3:1 ; about 1:2 to about 2:1 ; or about 1:1. [0073] In specific embodiments, the method of the invention comprises administering gabapentin and theophylline, or theobromine, or aminophylline, or dyphylline, or oxtriphylline, or etofylline, or enprophylline, or etamiphylline, or pyridophylline, or doxofylline, or bamifylline, or proxyphylline, or diprophylline, or pentoxifylline, or propentofylline, or pentifylline, or lisofylline. [0074] In specific embodiments, the method of the invention comprises administering pregabalin and theophylline, or theobromine, or aminophylline, or dyphylline, or oxtriphylline, or etofylline, or enprophylline, or etamiphylline, or pyridophylline, or doxofylline, or bamifylline, or proxyphylline, or diprophylline, or pentoxifylline, or propentofylline, or pentirylline, or lisofylline. [0075] In specific embodiments, the method of the invention comprises administering lacosamide and theophylline, or theobromine, or aminophylline, or dyphylline, or oxtriphylline, or etofylline, or enprophylline, or etamiphylline, or pyridophylline, or doxofylline, or bamifylline, or proxyphylline, or diprophylline, or pentoxifylline, or propentofylline, or pentirylline, or lisofylline. [0076] In specific embodiments, the method of the invention comprises administering valproate and theophylline, or theobromine, or aminophylline, or dyphylline, or oxtriphylline, or etofylline, or enprophylline, or etamiphylline, or pyridophylline, or doxofylline, or bamifylline, or proxyphylline, or diprophylline, or pentoxifylline, or propentofylline, or pentirylline, or lisofylline. [0077] In specific embodiments, the method of the invention comprises administering zonisamide and theophylline, or theobromine, or aminophylline, or dyphylline, or oxtriphylline, or etofylline, or enprophylline, or etamiphylline, or pyridophylline, or doxofylline, or bamifylline, or proxyphylline, or diprophylline, or pentoxifylline, or propentofylline, or pentifylline, or lisofylline. [0078] In specific embodiments, the method of the invention comprises administering lamotrigine and theophylline, or theobromine, or aminophylline, or dyphylline, or oxtriphylline, or etofylline, or enprophylline, or etamiphylline, or pyridophylline, or doxofylline, or bamifylline, or proxyphylline, or diprophylline, or pentoxifylline, or propentofylline, or pentifylline, or lisofylline. [0079] In specific embodiments, the method of the invention comprises administering oxcarbazepine and theophylline, or theobromine, or aminophylline, or dyphylline, or oxtriphylline, or etofylline, or enprophylline, or etamiphylline, or pyridophylline, or doxofylline, or bamifylline, or proxyphylline, or diprophylline, or pentoxifylline, or propentofylline, or pentifylline, or lisofylline. [0080] In specific embodiments, the method of the invention comprises administering levetiracetam and theophylline, or theobromine, or aminophylline, or dyphylline, or oxtriphylline, or etofylline, or enprophylline, or etamiphylline, or pyridophylline, or doxofylline, or bamifylline, or proxyphylline, or diprophylline, or pentoxifylline, or propentofylline, or pentifylline, or lisofylline. [0081] In specific embodiments, the method of the invention comprises administering tiagabine and theophylline, or theobromine, or aminophylline, or dyphylline, or oxtriphylline, or etofylline, or enprophylline, or etamiphylline, or pyridophylline, or doxofylline, or bamifylline, or proxyphylline, or diprophylline, or pentoxifylline, or propentofylline, or pentifylline, or lisofylline. [0082] In specific embodiments, the method of the invention comprises administering topiramate and theophylline, or theobromine, or aminophylline, or dyphylline, or oxtriphylline, or etofylline, or enprophylline, or etamiphylline, or pyridophylline, or doxofylline, or bamifylline, or proxyphylline, or diprophylline, or pentoxifylline, or propentofylline, or pentifylline, or lisofylline. [0083] In specific embodiments, the method of the invention comprises administering vigabatrin and theophylline, or theobromine, or aminophylline, or dyphylline, or oxtriphylline, or etofylline, or enprophylline, or etamiphylline, or pyridophylline, or doxofylline, or bamifylline, or proxyphylline, or diprophylline. or pentoxirylline, or propentofylline, or pentifylline, or lisofylline. [0084] The invention also provides a method of treating or preventing pain by administering one or more antiepileptic compounds with one or more alkylxanthine bronchodilators wherein the amount of said an alkylxanthine bronchodilator hastens the onset of action of the antiepileptic compound. [0085] The invention also provides a method of treating or preventing pain by administering one or more antiepileptic compounds with one or more alkylxanthine bronchodilators wherein the amount of said alkylxanthine bronchodilators increases the duration of the activity of said antiepileptic compound. [0086] The invention further provides a method of alleviating or preventing pain in a mammal in need of pain treatment or pain prevention by administering one or more antiepileptic compounds with one or more alkylxanthine bronchodilators. In one embodiment, the mammal in need of pain treatment or pain prevention is a human. [0087] The invention further provides a method of alleviating or preventing pain in a mammal in need of pain treatment or pain prevention by administering at least one antiepileptic compound and at least one alkylxanthine bronchodilator as a single pharmaceutical composition. Said antiepileptic compound and said alkylxanthine bronchodilator can also be administered as separate pharmaceutical compositions. In one embodiment, said antiepileptic compound and said alkylxanthine bronchodilator are coadministered as a sustained release dosage form. [0088] Also provided is a composition comprising (a) a pain-alleviating or pain-preventing amount of one or more antiepileptic compounds, wherein said antiepileptic compounds is selected from the group consisting of gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide and (b) one or more alkylxanthine bronchodilators, wherein said alkylxanthine bronchodilators is selected from the group consisting of theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline. In one embodiment, said one or more alkylxanthine bronchodilators are administered in an amount which enhances the activity of said antiepileptic compound. In one embodiment, said one or more alkylxanthine bronchodilators are administered in an amount which hastens the onset of activity of said antiepileptic compound, hi one embodiment, said one or more alkylxanthine bronchodilators are administered in an amount which increases the duration of the activity of said antiepileptic compound. In one embodiment, said one or more alkylxanthine bronchodilators are administered in an amount which decreases the frequency and/or intensity of one or more antiepileptic side effects. In one embodiment, said one or more alkylxanthine bronchodilators are administered in an amount which decreases the frequency and/or intensity of one or more antiepileptic side effects; said side effect reduction achieved through the need for lower (subanalgesic) doses of antiepileptic compounds. [0089] In one embodiment, the compositions of the present invention comprise one or more excipients and one or more inert carriers. [0090] h one embodiment, the method of the present invention is directed to a compositions comprising an antiepileptic compound and a alkylxanthine bronchodilator. The precise amount and ratio of the antiepileptic compound to the alkylxanthine bronchodilator may vary. For instance, in certain embodiments, the composition comprises an antiepileptic compound and an alkylxanthiπe bronchodilator in a molar ratio from about from 1:1000 to about 1000:1; about 1:500 to about 500:1; about 1:400 to about 400:1; about 1:200 to about 200:1; about 1:100 to about 100:1; about 1:75 to about 75:1; about 1:50 to about 50:1; about 1:40 to about 40:1; about 1:30 to about 30:1; about 1:20 to about 20:1; about 1:15 to about 15:1; about 1:10 to about 10:1; about 1:8 to about 8:1; about 1:5 to about 5:l;about 1:4 to about 4:1; about 1:4 to about 4:1; about 1:3 to about 3:1; about 1:2 to about 2:1; or about 1:1. [0091] When a selected antiepileptic compound is combined with an alkylxanthine bronchodilator in accord with the present invention, the alkylxanthine bronchodilator produces an enhanced activity of said antiepileptic compound. The enhanced activity of said analgesic may be one or more of the following: (1) the analgesic effect of the selected antiepileptic compound has a faster onset of action; (2) the analgesic effect of the selected antiepileptic compound has a greater overall effect; (3) a lower dose of the selected antiepileptic compound is required for the same analgesic effect as when the antiepileptic compound is administered alone; (4) across all doses, a greater analgesic response is achieved; (5) the analgesic effect of the selected antiepileptic compound has a longer duration of action; (6) an increase peak analgesic effect; (7) a sub-therapeutic antiepileptic compound produces a therapeutic analgesic effect; and (8) the reduction and/or elimination of one or more side effects caused by the antiepileptic compound. [0092] With respect to the enhanced activity of the antiepileptic compound, it is meant that the method of the present invention will produce an enhanced activity of the antiepileptic compound when compared to administering the antiepileptic compound alone. For example, certain embodiments, the present invention provides an enhanced activity, as described above, of about 2.5, 5, 7.5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 150, 160, 180, 200, 300, 400, or 500%, when compared to the administration of the antiepileptic compound alone. [0093] In specific embodiments, the method of the present invention provides an analgesic that has a faster onset of action by about 2.5, 5, 7.5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 150, 160, 180, 200, 300, 400, or 500%, when compared to the onset of action of the antiepileptic compound alone. [0094] In another specific embodiment of the method, the analgesic effect of the selected antiepileptic compound has a greater overall effect by about 2.5, 5, 7.5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 150, 160, 180, 200, 300, 400, or 500%, when compared to the administration of the antiepileptic compound alone. [0095] In another specific embodiment of the present method, the dose of a the antiepileptic compound required for a given analgesic effect is about 2.5, 5, 7.5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 150, 160, 180, 200, 300, 400, or 500% lower than when the antiepileptic compound is administered alone. [0096] In another specific embodiment of the present method, the analgesic response experienced by the subject from the antiepileptic compound is about 2.5, 5, 7.5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 150, 160, 180, 200, 300, 400, or 500% greater than when the antiepileptic compound is administered alone. [0097] In another specific embodiment of the present method, the duration of action of the antiepileptic compound is about 2.5, 5, 7.5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 150, 160, 180, 200, 300, 400, or 500% longer than when the antiepileptic compound is administered alone. [0098] In another specific embodiment of the present method, the peak analgesic effect of the antiepileptic compound is about 2.5, 5, 7.5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 150, 160, 180, 200, 300, 400, or 500% greater than when the antiepileptic compound is administered alone. [0099] In another specific embodiment of the present method, the amount of the antiepileptic compound that is administered is about 2.5, 5, 7.5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 150, 160, 180, 200, 300, 400, or 500% below the minimal dosage that provides a therapeutic analgesic effect when the antiepileptic compound is administered alone. [00100] In another specific embodiment of the present method, one or more side effects of the antiepileptic compound are eliminated or reduced by about 2.5, 5, 7.5, 10, 15, 20, 30, 40, 50, 60, 70, 80, 90, 100, 120, 140, 150, 160, 180, 200, 300, 400, or 500% compared to the side effects when the antiepileptic compound is administered alone. [00101] In one embodiment of the present invention, administration of an alkylxanthine bronchodilator with a certain antiepileptic compound produces a reduction in one or more side effects of the antiepileptic compound analog. Nonlimiting examples of such side effects include nausea, dizziness, impaired cognition, sedation, peripheral edema, rash and asthenia. [00102] For patients suffering pain, and most especially for patients suffering severe pain, the time from administration of medication to the onset of effective relief is clearly of paramount importance. Accordingly, in one embodiment of the present invention, an alkylxanthine bronchodilator is used to shorten the onset time (i.e., substantially hasten the onset) of pain relief when combined with an antiepileptic compound. [00103] Further, the ability of such alkylxanthine bronchodilators to enhance the effects of antiepileptic compounds, e.g., to substantially reduce the amount of selected antiepileptic compound which is required to elicit a given analgesic response, is also an unexpected and important embodiment of the present invention, and permits the use of the selected antiepileptic compound in quantities substantially less than the dosages presently suggested as a antiepileptic compound in humans. Use of lower doses lowers the incidence and/or severity of undesirable side effects. Moreover, at a given dosage level, a greater analgesic response can be achieved compared to administration of the antiepileptic compound alone. [00104] The disclosed antiepileptic compound/alkylxanthine bronchodilator compositions of the present invention are also advantageous in that the use of an alkylxanthine bronchodilator counteracts the effects of the selected antiepileptic compound such that the patient is more likely to continue therapy with antiepileptic compound, is more alert, has better motor skills, and/or, in certain instances, hosts an improved sense of well-being as compared to when the antiepileptic compound is administered alone. [00105] In adult humans, the dose of antiepileptic compounds required vary considerably, depending on type of pain, pain severity, tolerability of side effects, tolerance to analgesic effects, use of other analgesics and patient response to treatment. For example, the typical effective analgesic amounts of the antiepileptic compounds gabapentin and pregabalin for use with alkylxanthine bronchodilator compositions of the present invention, to be administered every day in single or divided doses are 25 to 4000 mg of gabapentin and 10 to 1200 mg of pregabalin. Table 1 provides usual doses of antiepileptic compounds and alkylxanthine bronchodilators. [00106] The amount of alkylxanthine bronchodilator in the analgesic composition will be an amount sufficient to shorten the onset time and/or to enhance analgesia. For humans, an average dose administered every day, in single or divided doses, is from about 1 mg to about 4000 mg alkylxanthine bronchodilator. [00107] The daily dose for use in the treatment of moderate to severe pain will preferably not exceed 6000 mg of gabapentin, 3000 mg of pregabalin, 2000 mg of lacosamide and 2000 mg of the alkylxanthine bronchodilator, although greater amounts could be employed if tolerated by the patient. [00108] The typical effective analgesic amounts of the antiepileptic compound varies depending on the route of administration and the desired effect. [00109] It is an object of certain embodiments of the present invention to provide dosage forms of the invention in immediate release form. [00110] It is an object of certain embodiments of the present invention to provide dosage forms of the invention in controlled release form. [00111] It is an object of certain embodiments of the present invention to provide dosage forms of the invention with both immediate release and controlled release forms. [00112] It is an object of certain embodiments of the present invention to provide dosage forms of the invention in pulsatile release form. [00113] It is an object of certain embodiments of the present invention to provide dosage forms of the invention wherein the antiepileptic compound and alkylxanthine bronchodilator are dispersed within a matrix. [00114] In certain preferred embodiments the oral dosage form of the present invention comprises a matrix which includes a sustained release material, an antiepileptic compound and alkylxanthine bronchodilator or a pharmaceutically acceptable salt thereof. In certain preferred embodiments, the matrix is compressed into a tablet and may be optionally overcoated with a coating that in addition to the sustained release material of the matrix may control the release of the antiepileptic compound and alkylxanthine bronchodilator or pharmaceutically acceptable salt thereof from the formulation, such that blood levels of active ingredient are maintained within the therapeutic range over an extended period of time. In certain alternate embodiments, the matrix is encapsulated. [00115] In certain preferred embodiments, the sustained release oral dosage form of the present invention comprises a plurality of pharmaceutically acceptable sustained release matrices comprising antiepileptic compound and alkylxanthine bronchodilator or pharmaceutically acceptable salts thereof, the dosage form maintaining the blood plasma levels of the antiepileptic compound and alkylxanthine bronchodilator within the therapeutic range over an extended period of time when administered to patients. [00116] In certain preferred embodiments the sustained release oral dosage form of the present invention is an osmotic dosage form which comprises a single layer or bilayer core comprising antiepileptic compound and alkylxanthine bronchodilator or pharmaceutically acceptable salts thereof; an expandable polymer; a semipermeable membrane surrounding the core; and a passageway disposed in the semipermeable membrane for sustained release of the antiepileptic compound and alkylxanthine bronchodilator or pharmaceutically acceptable salts thereof, such that blood levels of active ingredient are maintained within the therapeutic range over an extended period of time when administered to patients. [00117] In some preferred embodiments of the invention, the antiepileptic compound and alkylxanthine bronchodilator are interdispersed and are not isolated from each other in two distinct layers. In other preferred embodiments of the invention, the antiepileptic compound and alkylxanthine bronchodilator are in the form of multiparticulates, or multiparticulates dispersed in a matrix and contained in a capsule, or multiparticulates dispersed in a matrix and compressed into a tablet. [00118] In some preferred embodiments of the invention, the antiepileptic compound and alkylxanthine bronchodilator are in a matrix that is in the form of pellets or coated beads. [00119] In some preferred embodiments, the dosage form of the invention comprises a compressed tablet, compressed capsule or uncompressed capsule. In other embodiments, the dosage form comprises a liquid fill capsule. [00120] In some preferred embodiments, the dosage form of the invention comprises an oral formulation (e.g., tablet or capsule) which is coated to prevent substantial direct contact of antiepileptic compound and alkylxanthine bronchodilator with oral cavity (e.g. tongue, oral mucosa), oropharyngeal mucosal surface, esophagus or stomach. In some preferred embodiments, the dosage form of the invention comprises an oral formulation which is coated with a film or polymer. In some preferred embodiments, the dosage form of the invention comprises antiepileptic compound and alkylxanthine bronchodilator in an enteric coating. In some preferred embodiments, the dosage form of the invention comprises antiepileptic compound and alkylxanthine bronchodilator formulated with pharmaceutical excipients and auxiliary agents known in the art, such that the antiepileptic compound and alkylxanthine bronchodilator are released after a approximately specific amount of time, or at an approximately specific anatomic location in the gastrointestinal tract, or when the dosage form is in contact with specific gastrointestinal conditions (e.g., pH range, osmolality, electrolyte content, food content.). [00121] In some preferred embodiments, the dosage form of the invention comprises an immediate release suppository or controlled release suppository formulation. [00122] In some preferred embodiments, the dosage form provides an oral pharmaceutical composition for the treatment of pain comprising a therapeutically effective amount of antiepileptic compound and alkylxanthine bronchodilator or pharmaceutically acceptable salts thereof, or mixtures thereof; said therapeutically effective amount in a reservoir comprising: (i) antiepileptic compound and alkylxanthine bronchodilator or pharmaceutically acceptable salt thereof, or mixtures thereof; (ii) a membrane layer, said membrane being substantially permeable to antiepileptic compound and alkylxanthine bronchodilator; wherein the dosage form substantially releases the antiepileptic compound and alkylxanthine bronchodilator from the dosage form to render said dosage form suitable for extended release ' to a human patient. [00123] In some preferred embodiments, the dosage form provides an oral pharmaceutical composition for the treatment of pain comprising a plurality of pharmaceutically acceptable beads coated with a therapeutically effective amount of antiepileptic compound and alkylxanthine bronchodilator or pharmaceutically acceptable salts thereof, or mixtures thereof; and overcoated with controlled release material to render said dosage form suitable for extended release oral administration to a human patient. [00124] In some preferred embodiments, the dosage form provides an oral pharmaceutical composition for the treatment of pain comprising (i) a drug layer comprising a therapeutically effective amount of antiepileptic compound and alkylxanthine bronchodilator or pharmaceutically acceptable salts thereof, or mixtures thereof; and (ii) a displacement layer comprising an osmopolymer; and (b) a semipermeable wall surrounding the bilayer core having a passageway disposed therein for the release of said antiepileptic compound and alkylxanthine bronchodilator or pharmaceutically acceptable salts thereof, or mixtures thereof; said dosage form suitable for extended release oral administration to a human patient. [00125] In some preferred embodiments, the oral dosage from is a controlled release material suitable for extended release oral administration to a human patient of the dosage form comprises a matrix. In some preferred embodiments, the said matrix is a plurality of multiparticulate matrices, hi some preferred embodiments, the multiparticulates are compressed into a tablet. In some preferred embodiments, the multiparticulates are disposed in a pharmaceutically acceptable capsule. [00126] In some preferred embodiments, the controlled release material of the oral dosage form of the invention is selected from the group consisting of hydrophobic polymers, hydrophilic polymers, gums, protein derived materials, waxes, shellac, oils and mixtures thereof. [00127] In some preferred embodiments, the controlled release material of the oral dosage form of the invention is selected from the group consisting of hydrogenated Type I or Type II vegetable oils, polyoxyethylene stearates and distearates, glycerol monostearate, and non-polymeric, non-water soluble liquids carbohydrate-based substances or poorly water soluble, high melting point (mp = 40 to 100° C) waxes and mixtures thereof. [00128] In some preferred embodiments, the oral dosage form comprises a plurality of pharmaceutically acceptable beads coated with drug and overcoated with controlled release material. [00129] In some preferred embodiments, the oral dosage form comprises (i) a drug layer; and (ii) a displacement layer comprising an osmopolymer; and (b) a semipermeable wall surrounding the bilayer core having a passageway disposed therein for the release of said drug. Ϊ00130] In some preferred embodiments, the oral dosage form comprises a compressed tablet, compressed capsule or uncompressed capsule. In some preferred embodiments, the oral dosage form comprises a liquid fill capsule. [00131] The invention is also directed to kits of the dosage forms disclosed herein. [00132] Also disclosed are methods for preventing and treating pain in a human patient suffering comprising a therapeutically effective amount of antiepileptic compound and an analgesic enhancing amount of alkylxanthine bronchodilator, or pharmaceutically acceptable salts thereof or mixtures thereof. [00133] Also disclosed are methods for preventing and treating pain in a human patient suffering comprising a subanalgesic amount of antiepileptic compound and an analgesic enhancing amount of alkylxanthine bronchodilator, or pharmaceutically acceptable salts thereof or mixtures thereof. [00134] AU pain states are contemplated by this invention, regardless of etiology, mechanisms, duration, prior treatment response and anatomic location, including acute pain, inflammatory pain, chronic pain, cancer pain, visceral pain and neuropathic pain. [00135] Also disclosed are methods of providing relief in a human patient suffering from neuropathic and chronic pain comprising administering an antiepileptic compound and an alkylxanthine bronchodilator, or pharmaceutically acceptable salts thereof or mixtures thereof. In some preferred embodiments, the dosage form of .the invention is intended for the treatment of neuropathic pain, peripheral neuropathic pain, central neuropathic pain, chronic pain, osteoarthritis, back pain, cancer pain, fibromyalgia, and chronic inflammatory pain. [00136] Also disclosed are methods of providing relief in a human patient suffering from acute pain comprising administering an antiepileptic compound and an alkylxanthine bronchodilator, or pharmaceutically acceptable salts thereof or mixtures thereof. [00137] All kinds of kits of the present invention are contemplated. In some preferred embodiments, also provided are kits for use in treating or preventing the pain with administering an antiepileptic compound and an alkylxanthine bronchodilator, or pharmaceutically acceptable salts thereof or mixtures thereof for a subject in need of such treatment, comprising: (i) a dosage form of the invention; (ii) a container for the dosage form; and optionally, any of (iii) to (vi): (iii) a container for individual units of the dosage form (e.g., individual tablets or capsules in blisters); (iv) educational instructions in any media about various medical conditions, their etiology, pathophysiology, consequences and treatment, and information on the proper use and disposal of the medication; (v) containers or bags for the safe disposal of any used or remaining unused dosage form, preferably child proof and flushable; (vi) tamper evident and child proof packaging for the kit and its contents. [00138] The amount of antiepileptic compound and alkylxanthine bronchodilator in the dosage form will vary depending on variety of physiologic, pharmacologic, pharmacokinetic, pharmaceutical and physicochemical factors, including: (i) the choice of antiepileptic compound and choice of alkylxanthine bronchodilator; (ii) the nature of the dosage form (e.g, immediate release, extended release, oral, intravenous, topical); (iii) the anatomical location of the pain relieving target; (iv) the intensity and intractability of the pain; (v) the contribution of different mechanism to the initiation, propagation, summation and maintenance of the pain; (vi) the absorption, metabolism, distribution and excretion of the antiepileptic compound and alkylxanthine bronchodilator in patients in good overall health and in patients with renal and hepatic impairment; (vii) the presence of comorbid pathology; (viii) the patient's risk of iatrogenic side effects; (ix) the tolerability of the dose, including the patient's propensity for antiepileptic compound and alkylxanthine bronchodilator associated side effects; (x) use of concurrent analgesics; (xi) the efficiency of the dosage form. [00139] The invention is also directed to methods of preparing the dosage forms disclosed herein. [00140] In certain preferred embodiments, the antiepileptic compound and alkylxanthine bronchodilator in the dosage form is combined with one or more other drugs for the treatment of the same medical condition as the dosage form of the invention or the treatment of a different medical condition. All modes of co-administration are contemplated, including via an oral, subcutaneous, direct intravenous, slow intravenous infusion, continuous intravenous infusion, intravenous or epidural patient controlled analgesia (PCA and PCEA), intramuscular, intrathecal, epidural, intracisternal, intramuscular, intraperitoneal, transdermal, topical, transmucosal, buccal, sublingual, transmucosal, inhalation, intranasal, epidural, intra-atricular, intranasal, rectal or ocular routes. [00141] The treatment of pain is frequently multimodal and involves the use of multiple drugs to provide optimal efficacy and safety. It is contemplated that the present invention may be used alone or co-administered with other drugs to provide additive, superadditive, complementary, or synergistic therapeutic effects. A co-administered drug (in the same or different dosage form, by any route of administration) may include other NSAIDs, NO-NSAIDs, COX-2 selective inhibitors, acetaminophen, nitroparacentamol, tramadol, local anesthetics, antidepressants, beta adrenergic agonists, alpha-2 agonists, selective prostanoid receptor antagonists, cannabinoid agonists, opioid receptor agonists, NO-opioids, NMDA receptor antagonists, gabapentin, pregabalin, gabapentinoids, neuronal nicotinic receptor agonists, calcium channel antagonists, sodium channel blockers, serotonin 5-HT(lB/lD)

receptor agonists superoxide dismutase mimetics, p38. MAP kinase inhibitors, triptans, TRPVl agonists, dextromethorphan, dextrorphan, ketamine, glycine receptor antagonists, antiepileptics, and any other drugs that can be shown by a person proficient in the art to prevent or treat pain. [00142] Other therapeutically active agents from various therapeutic classes may also be used in combination with the present invention. They include, but are not limited to decongestants, analgesics, analgesic adjuvants, antidepressants, antipsychotics, anxiolytics, hypnotics, sedatives, drugs to treat urinary incontinence, antihistamines, expectorants, antitussives, diuretics, anti inflammatory agents, antipyretics, antirheumatics, antioxidants, laxatives, local anesthetics, proton pump inhibitors, motility modifying agents, vasodilators, inotropes, beta blockers, beta adrenergic agonists, drugs to treat asthma and COPD, antiinfectives, anti-migraine agents, antihypertensives, antianginal agents, gastric acid reducing agents, anti-ulcer agents, anticoagulants, lipid and cholesterol lowering drugs, anti-diabetic drugs, anti- epileptics, hormones, smooth muscle relaxants, skeletal muscle relaxants, bronchodilators, vitamins, trace minerals, amino acids, biological peptides and drugs to treat various infectious, immunologic disorders, cardiovascular, pulmonary, gastrointestinal, hepatic, biliary, nutritional, metabolic, endocrine, hematologic, oncologic, musculoskeletal, neurologic, psychiatric, genitourinary, gynecologic, obstetric, pediatric, otolaryngogologic, ophthalmic, dermatologic, dental, oral, and genetic disorders, diseases and maladies. The drug being used in combination therapy with the present invention can be administered by any route, including parenterally, orally, topically, transdermally, sublingually, and the like. [001431 All oral pharmaceutical dosage forms of the invention are contemplated, including oral suspensions, tablets, capsules, lozenges, effervescent tablets, effervescent powders, powders, solutions, powders for reconstitution, transmucosal films, buccal products, oral mucoretentive products, oral gastroretentive tablets and capsules, orally disintegrating tablets, fast dissolving tablets, fast dispersing tablets, fast disintegrating dosage forms, administered as immediate release, modified release, enteric coated, sustained release, controlled release, pulsatile release and extended release dosage form. [00144] AU rectal pharmaceutical dosage forms of the invention are contemplated, including suppositories, suspensions, solutions, capsules and tablets, administered as immediate release, modified release, sustained release, controlled release, pulsatile release and extended release dosage forms. [00145] As used herein, "controlled release" is interchangeable with "extended release", "sustained release", "modified release", "delayed release" and the like. [00146] In some embodiments, the dosage form of the invention comprises the antiepileptic compound in controlled release form and the alkylxanthine bronchodilator in controlled release form. In some embodiments, the dosage form of the invention comprises the antiepileptic compound in immediate release form and the alkylxanthine bronchodilator in immediate release form, hi some embodiments, the dosage form of the invention comprises the antiepileptic compound in controlled release form and the alkylxanthine bronchodilator in immediate release form. In some embodiments, the dosage form of the invention comprises the antiepileptic compound in immediate release form and the alkylxanthine bronchodilator in controlled release form. In some embodiments, the dosage form of the invention comprises the antiepileptic compound in controlled release .form and the alkylxanthine bronchodilator in controlled release form, and additionally, the antiepileptic compound or the alkylxanthine bronchodilator or both in immediate release form. [00147] Controlled release dosage forms of the present invention release the antiepileptic compound and/or the alkylxanthine bronchodilator from the dosage form at slower rate than immediate release formulations. In some preferred embodiments, controlled release dosage forms the antiepileptic compound and/or the alkylxanthine bronchodilator at such a rate that blood (e.g., plasma) concentrations (levels) .or therapeutic effects are maintained within the therapeutic range (above the minimum effective therapeutic concentration) but below toxic levels for intended duration (e.g., over a period of 1 to 24 hours, preferably over a period of time indicative of a Q8, Ql 2 or Q24H administration). Notwithstanding the foregoing, in some preferred embodiments, the controlled release formulations of the present invention provide therapeutic effects for a duration that is longer or substantially longer than the duration of meaningful or detectable plasma concentrations of the antiepileptic compound and/or the alkylxanthine bronchodilator. Controlled release dosage forms can also involve PRN administration, e.g., Q3 PRN, Q4 PRN, Q6 PRN, Q8 PRN, Q12 PRN or Q24H PRN administration. [00148] The term "immediate release" in reference to antiepileptic compounds of the invention and alkylxanthine bronchodilators of the invention refers to a dosage form which is formulated to release the active drug from the dosage form immediately (i.e., without an attempt to delay or prolong the release of the active drug from the dosage form as is the case for extended release dosage forms). [00149] hi certain preferred embodiments of the present invention, an effective amount of antiepileptic compound and/or alkylxanthine bronchodilator in immediate release form is included in the controlled release unit dose. The immediate release form of the antiepileptic compound and/or the alkylxanthine bronchodilator is preferably included in an amount which is

effective to shorten the time to Cma or increase the magnitude of the Cmax of the antiepileptic compound and/or the alkylxanthine bronchodilator in the blood (e.g., plasma). In such embodiments, an effective amount of the antiepileptic compound and/or the alkylxanthine bronchodilator in immediate release form may be coated onto the substrates of the present invention. For example, where the extended release the antiepileptic compound and/or the alkylxanthine bronchodilator from the formulation is due to a controlled release coating, the immediate release layer would be overcoated on top of the controlled release coating. On the other hand, the immediate release layer maybe coated onto the surface of substrates wherein the antiepileptic compound and/or the alkylxanthine bronchodilator is incorporated in a controlled release matrix. Where a plurality of the sustained release substrates comprising an effective unit dose of the antiepileptic compound and/or the alkylxanthine bronchodilator (e.g., multiparticulate systems including pellets, spheres, beads and the like) are incorporated into a hard gelatin capsule, the immediate release portion of the antiepileptic compound and/or the alkylxanthine bronchodilator dose may be incorporated into the gelatin capsule via inclusion of the sufficient amount of immediate release the antiepileptic compound and/or the alkylxanthine bronchodilator as a powder, granulate, bead or even tablet within the capsule. Alternatively, the gelatin capsule itself may be coated with an immediate release layer of the the antiepileptic compound and/or the alkylxanthine bronchodilator. In some other embodiments, the immediate release the antiepileptic compound and/or the alkylxanthine bronchodilator is in liquid form, for example as a capsule within a capsule or as a liquid in contact with an extended release dosage form within a capsule. One skilled in the art would recognize still other alternative manners of incorporating the immediate release the antiepileptic compound and/or the alkylxanthine bronchodilator into the unit dose. Such alternatives are deemed to be encompassed by the appended claims. By including such an effective amount of immediate release the antiepileptic compound and/or the alkylxanthine bronchodilator in the unit dose, the experience of relatively higher levels of pain in patients may be significantly reduced. [00150] It is understood that each of the various embodiments of methods and pharmaceutical compositions described herein may be used alone or in conjunction with one or more or all of the various embodiments described herein. [00151] Additionally, it is understood that each of the various embodiments of the pharmaceutical compositions described herein may be used with each of the various embodiments of the described method of the present invention as described herein.

DEFINITIONS

[00152] "Drug," "pharmacological agent," "pharmaceutical agent," "active agent," and "agent" are used interchangeably and are intended to have their broadest interpretation as to any therapeutically active substance which is delivered to a living organism to produce a desired, usually beneficial effect. In general, this includes therapeutic agents in all of the major therapeutic areas, also including proteins, peptides, oligonucleotides, and carbohydrates as well as inorganic ions, such as calcium ion, lanthanum ion, potassium ion, magnesium ion, phosphate ion, and chloride ion. [00153] "Pharmaceutically or therapeutically acceptable excipient or carrier" refers to a substance which does not interfere with the effectiveness or the biological activity of the active ingredients and which is not toxic to the hosts, which may be either humans or animals, to which it is administered. Pharmaceutically or therapeutically acceptable excipients or carriers are well known in the art. [00154] "Therapeutically effective amount" refers to the amount of an active agent sufficient to induce a desired biological result. That result may be alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system. [00155] The phrase "therapeutically-effective" is intended to qualify the amount of each agent which will achieve the goal of improvement in disease severity and the frequency of incidence over treatment of each agent by itself, while avoiding adverse side effects typically associated with alternative therapies. [00156] The term "effective amount" means the quantity of a compound according to the invention necessary to prevent, to cure, or at least partially arrest a symptom of local pain or discomfort in a subject. A subject is any animal, preferably any mammal, more preferably a human. Amounts effective for creating a substantially local therapeutic effect will, of course, depend on the severity of the disease causing the painful condition, and the weight and general state of the subject. Typically, animal models, such as those described in the Background and Examples herein, may be used to determine suitable dosages to be used. A recent pain scale developed by Galer et al, Neurology 48:332-338 (1997), which uses terminology specific for neuropathic pain, should be better able to delineate the symptoms within the syndrome. Ia addition, various general considerations taken into account in determining the "therapeutically effective amount" are known to those of skill in the art and are described, e.g., in Gilman et al, eds., Goodman And Gilman's The Pharmacological Basis of Therapeutics, 10th Ed., McGraw Hill (2001); Remington: The Science and Practice of Pharmacy, 21st Ed, Lippincott Williams & Wilkins (2005); and Martindale: The Complete Drug Reference, 34th Ed., Pharmaceutical Press (2004), each of which is herein incorporated by reference. [00157] The term "alkylxanthine bronchodilator", as used herein, refers to a pharmaceutically acceptable active ingredient or drug from among the following: theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, their pharmaceutically acceptable salts, solvates, polymorphs, hydrates, in racemic or enantiomeric form, or mixture thereof. To qualify as an alkylxanthine bronchodilator, a pharmaceutically acceptable active ingredient or drug need not be a bronchodilator, an alkyxanthine or both, provided it is selected from the group comprising theophylline, theobromine, arninophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, their pharmaceutically acceptable salts, solvates, polymorphs, hydrates, in racemic or enantiomeric form, or mixture thereof. [00158] The term "antiepileptic compound", as used herein, refers to a . pharmaceutically acceptable active ingredient or drug which is: (i) used to treat at least one type or form of epilepsy; and/or (ii) has efficacy in treating at least one type of epilepsy; and/or (iii) approved for the treatment of at least one type or form of epilepsy. The term "subject" for purposes of treatment includes any animal subject who has any one of the known forms of pain. The subject is preferably a mammal and more preferably is a human. [00159] As used herein, "tolerance" refers to: 1) the need to increase the dose of antiepileptic over time in order to achieve the amount of analgesia or euphoria, or 2) the observation that chronic administration of the same dose results in reduced analgesia, euphoria, or other effects. It has been found that a remarkable degree of tolerance develops to the pharmacologic effects of antiepileptic compounds. However, the rate at which this attenuation of effect (tolerance) may develop in either a patient with pain depends on the pattern of use. If the antiepileptic compound is used frequently, it may be necessary to increase the dose. Tolerance does not develop equally or at the same rate to all the effects of antiepileptic compounds. [00160] As used herein, "equianalgesic doses," also referred to as "analgesic equivalence," is a term used by practitioners of the art to refer to approximately comparable doses of analgesics required to provide a similar magnitude of analgesia. There are established standards to allow practitioners of the art to convert the dose of one analgesic, given by any route of administration, to an approximately equivalent dose of another analgesic, given by any route of administration. These analgesic conversion tables provide what in the art is called "analgesic equivalence" or "equianalgesic doses" (Principles of Analgesic Use in the Treatment of Acute Pain and Cancer Pain, Fourth Ed., American, Pain Society (2003); Gutstein H.B. & AMI H. Opioid Analgesics. In: Goodman and Gilman 's The Pharmacologic Basis of Therapeutics, 10th Ed., Hardman J.G. & Limbird L.E., Eds., p 569- 619, McGraw-Hill, New York, NY). The availability of analgesic equivalence tables allows practitioners of the art to convert patients from one analgesic to another without a protracted titration period on the new analgesic. [00161] In another embodiment, the alkylxanthine bronchodilator is used as a racemic mixture. In another embodiment, the alkylxanthine bronchodilators is used as a single stereoisomer. In another embodiment, the alkylxanthine bronchodilator is used as a mixture of stereo isomers containing unequal amounts of stereoisomers. [00162] Generally, the alkylxanthine bronchodilator is administered in an amount of about 0.1 mg to about 4000 mg per day in single or divided doses. In another embodiment, the alkylxanthine bronchodilator is administered in an amount from about 1 to about 2000 mg per day in single or divided doses. In another embodiment, the alkylxanthine bronchodilator is administered in an amount from about 10 to about 1800 mg per day, or 10 to about 1500 mg per day, or 10 to about 1200 mg per day, or 10 to about 1000 mg per day, or about 10 mg to about 800 mg per day, or 10 to about 600 mg per day, or 10 to about 400 mg per day, or 10 to about 300 mg per day, or 10 to about 200 mg per day, or 10 to about 100 mg per day, or 10 to about 75 mg per day, or 10 to about 50 mg per day in single or divided doses. In another embodiment, the alkylxanthine bronchodilator is administered in an amount from about 10 mg to about 600 mg, per day in single or divided doses. In another embodiment, the alkylxanthine bronchodilator is administered in an amount from about 10 mg to about 400 mg, per day in single or divided doses. [00163] The alkylxanthine bronchodilator may be administered on a weight basis as well. In one embodiment, the alkylxanthine bronchodilators is administered in an amount of about 0.001 mg/kg/day to about 60 mg/kg/day. In another embodiment, the alkylxanthine bronchodilator is administered in an amount of about 0.01 mg/kg/day to about 15 mg/kg/day. In one embodiment, the alkylxanthine bronchodilator is administered in an amount of about 0.1 mg/kg/day to about 10 mg/kg/day.

TYPES OF PAIN

[00164] The methods and compositions of the present invention are useful in preventing or treating all types of pain. Preferred types of pain to be treated by the present invention are acute pain, chronic pain, neuropathic pain, visceral pain and idiopathic pain. [00165] As used herein, the term "pain" includes: (i) peripheral neuropathic pain, e.g., acute and chronic inflammatory demeyelinating polyradiculopathy, alcoholic polyneuropathy, chemotherapy-induced polyneuropathy, complex regional pain syndrome (CRPS) Type I and Type II, entrapment neuropathies (e,g., carpal tunnel syndrome), HIV sensory neuropathy, iatrogenic neuralgias (e.g., postthoracotomy pain, postmastectomy pain), idiopathic sensory neuropathy, painful diabetic neuropathy, phantom limb pain, postherpetic neuralgia, trigeminal neuralgia, radiculopathy (e.g., cervical thoracic, lumbosacral), sciatica, acute herpes zoster pain, temporomandibular joint disorder pain and postradiation plexopathy; and (ii) central neuropathic pain, e.g., compressive myelopathy from spinal stenosis, HIV myelopathy, multiple sclerosis pain, Parkinson's disease pain, postischemic myelopathy, post postradiation myelopathy, poststroke pain, posttraumatic spinal cord injury and syringomyelia; and (iii) cancer associated neuropathic pain, e.g., chemotherapy induced polyneuropathy, neuropathy secondary to tumor infiltration or nerve compression, phantom breast pain, postmastectomy pain, postradiation plexopathy and myelopathy; (iv) chronic pain, e.g., back pain, rheumatoid arthritis, osteoarthritis, inflammatory pain, non-inflammatory pain, myofascial pain, fibromyalgia, cancer pain, visceral pain, somatic pain, pelvic pain, musculoskeletal pain, post-traumatic pain, bone pain and idiopathic pain; (v) acute pain, e.g, acute postsurgical pain (including laparoscopic, laparatomy, gynecologic, urologic, cardiothoracic, arthroscopic, gastrointestinal, neurologic, orthopedic, oncologic, maxillofacial, ophthalmic, otolaryngologic, soft tissue, plastic, cosmetic, vascular and podiatric surgery, including abdominal surgery, abdominoplasty, adenoidectomy, amputation, angioplasty, appendectomy, arthrodesis, arthroplasty, arthroscopy, bilateral cingulotomy, biopsy, brain surgery, breast biopsy, cauterization, cesarean section, cholecystectomy, circumcision, commissurotomy, cordotomy, corneal transplantation, cricothoracotomy, discectomy, diverticulectomy, episiotomy, endarterectomy, endoscopic thoracic sympathectomy, foreskin restoration, fistulotomy, frenectomy, frontalis lift, fundectomy, gastrectomy, grafting, heart transplantation, hemicorporectomy, hemorrhoidectomy, hepatectomy, hernia repair, hypnosurgery, hysterectomy, kidney transplantation, laminectomy, laparoscopy, laparotomy, laryngectomy, lithotripsy, lobotomy, lumpectomy, lung transplantation, mammectomy, mammoplasty, mastectomy, mastoidectomy, mentoplasty, myotomy, mryingotomy, nephrectomy, nissen fundoplication, oophorectomy, orchidectomy, parathyroidectomy, penectomy, phalloplasty, pneumotomy, pneumonectomy, prostatectomy, psychosurgery, radiosurgery, ritidoplasty, rotationplasty, sigmoidostomy, sphincterotomy, splenectomy, stapedectomy, thoracotomy, thrombectomy, thymectomy, thyroidectomy, tonsillectomy, tracheotomy, tracheostomy, tubal ligation, ulnar collateral ligament reconstruction, ureterosigmoidostomy, vaginectomy, vasectomy, vulvectomy; renal colic; incisional pain; inflammatory incisional pain; nociceptive incisional pain; acute neuropathic incisional pain following surgery), renal colic, trauma, acute back pain, burn pain, burn dressing change pain, migraine pain, tension headache pain, acute musculoskeletal pain, acute exacerbation or flare of chronic back pain, acute exacerbation or flare of osteoarthritis, acute exacerbation or flare of chrome pain, breakthrough chronic non-cancer pain, breakthrough cancer pain, acute exacerbation or flare of fibromylagia, acute exacerbation or flare of rheumatoid arthritis, acute exacerbation or flare of myofacsial pain, acute exacerbation or flare of chronic idiopathic pain, acute exacerbation or flare of neuropathic pain, procedure related pain (e.g., arthroscopy, laparoscopy, endoscopy, intubation, bone marrow biopsy, soft tissue biopsy, catheterization), and other self-limiting pain states. [00166] As used herein, the term "acute pain" refers to self-limiting pain that subsides over time and usually lasting less that about 30 days and more preferably lasting less than about 2 1 days. Acute pain does not include chronic conditions such as chronic neuropathy, chronic neuropathic pain and chronic cancer and non-cancer pain. [00167] As used herein, "neuropathic pain" is pain initiated or caused by a primary lesion or dysfunction of the nervous system and includes (i) peripheral neuropathic pain and (ii) central neuropathic pain. [00168] As used herein, the term "chronic pain" includes all non-neuropathic pain lasting more than 30 days, including inflammatory pain, non inflammatory pain, muscle pain, joint pain, fascia pain, visceral pain, bone pain and idiopathic pain. ADMINISTRATION

[00169] Administration of the antiepileptic compound and alkylxanthine bronchodilator can be via oral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, transmucosal, buccal, inhalation, intranasal, epidural, intrathecal, intra-atricular, rectal or ocular routes for systemic or local analgesic effects. [00170] The antiepileptic compound and the alkylxanthine bronchodilator may be administered as a single pharmaceutical composition. That is, the antiepileptic compound and the alkylxanthine bronchodilator may be formulated together so that both active agents are contained in one pharmaceutical compositions. For example, the antiepileptic compound and the alkylxanthine bronchodilator may be formulated together in a unit dosage form. Suitable unit dosage forms include tablets, pills, capsules, caplets, hard gelatin capsule in powder or granular form, trochet, soft gelatin capsule. [00171] While the antiepileptic compound and alkylxanthine bronchodilator need not be administered together, they must both be present in the patient at effective levels at the same time. While it is within the scope of the invention to separately administer the antiepileptic compound and the alkylxanthine bronchodilator, as a matter of convenience, in one embodiment, these drugs are coadministered in a single dosage form. All modes of co-administration are contemplated, e.g., orally, rectally, parenterally, topically, transdermally or by intravenous, intramuscular, intrathecal, epidural, intracisternal or subcutaneous injection or in a form suitable by inhalation. The formulations can, where appropriate, be conveniently presented in discrete dosage units and can be prepared by any of the methods well known in the art of pharmacy. [00172] The methods of the present invention comprise administering an antiepileptic compound and administering an alkylxanthine bronchodilator. Accordingly, the antiepileptic compound and the alkylxanthine bronchodilator may be administered concurrently. When administered concurrently, the antiepileptic compound and the alkylxanthine bronchodilator are administered to the subject at the same time. Concurrent administration may comprise administration of a single pharmaceutical composition comprising the antiepileptic compound and alkylxanthine bronchodilator. For example, a tablet comprising an antiepileptic compound and the alkylxanthine bronchodilator is administered to a subject in need of analgesic treatment. Alternatively, concurrent administration may comprise administering of a first pharmaceutical composition comprising an antiepileptic compound and administering a second pharmaceutical composition comprising an alkylxanthine bronchodilator. [00173] Administration of the antiepileptic compound and alkylxanthine bronchodilator can be via oral, subcutaneous, intravenous, intramuscular, intraperitoneal, transdermal, topical, transmucosal, buccal, inhalation, intranasal, epidural, intrathecal, intra-atricular, rectal or ocular routes for systemic or local analgesic effects. [00174] AU oral pharmaceutical dosage forms of the invention are contemplated, including oral suspensions, tablets, capsules, lozenges, effervescent tablets, effervescent powders, powders, solutions, powders for reconstitution, transmucosal films, buccal products, oral mucoretentive products, oral gastroretentive tablets and capsules, orally disintegrating tablets, fast dissolving tablets, fast dispersing tablets, fast disintegrating dosage forms, administered as immediate release, modified release, enteric coated, sustained release, controlled release, pulsatile release and extended release dosage form. [00175] All rectal pharmaceutical dosage forms of the invention are contemplated, including suppositories, suspensions, solutions, capsules and tablets, administered as immediate release, modified release, sustained release, controlled release, pulsatile release and extended release dosage forms. [00176] All parenteral routes of administration are contemplated by the invention, including subcutaneous, direct intravenous, slow intravenous infusion, continuous intravenous infusion, intravenous or epidural patient controlled analgesia (PCA and PCEA), intramuscular, intrathecal, epidural, intracisternal, intramuscular, intraperitoneal, and intra-atricular. [00177] All routes of administration for application to the skin are contemplated by the invention, including transdermal, topical, transmucosal, electroporation, sonophoresis, iontophoresis, localized electroporation and thermoporation. Common Parenteral Routes of Administration [00178] Administration of the present invention can be via any parenteral route of administration. Non-limiting examples of suitable parenteral routes of administration are described in general terms as follows. Each of the following routes of administration can be used in the present invention, in particular in each of the specific embodiments described. [00179] IM Administration. Once a popular method of drug administration, the intramuscular (IM) route is used considerably less frequently today due to improved availability of oral drugs and due to the ease of intravenous administration. This method of drug administration involves injecting drug directly into muscle mass, from where drug will gradually be absorbed systemically. For drugs that are not irritating when given by the IM route which require only a single injection, the IM route is still a viable route of administration, particularly in the outpatient setting. When repeated administration is required or a rapid and reliable onset is desired, the intravenous route is preferred as repeated IM administration can be painful and inconvenient. Commonly the deltoid, gluteus maximus and vastus lateralis are sites for IM injection. The tolerability of IM administration is partly a function of the dose and the injection volume. Additionally, IM administration is particularly attractive in the ambulatory care/out-patient setting, where venous access is lacking or impractical, and in settings where sterility cannot be absolutely assured. [00180] Subcutaneous Administration involves injection into the subcutaneous fatty tissue under the skin. It can be used for the intermittent administration and self-administration of insulin and other medicines. In a small number of patients, particularly outpatients, this route is also used for the continuous or intermittent administration of drugs, usually with a programmable subcutaneous infusion device. [00181] Epidural and Intrathecal Administration. Epidural and intrathecal infusions can provide effective analgesia, but require skilled personnel (usually an anesthetist) to put the systems in place. Catheters can be placed at any level of the spinal cord, although most commonly these techniques are used for pain in the lower part of the body. Epidural and intrathecal routes of administration are advantageous for difficult abdominal or pelvic pain. For short term use, epidural catheters can be placed percutaneously, and fixed either by secure taping or subcutaneous tunnelling. The drugs can then be delivered through a small pump or a syringe driver. Subjects can be ambulant and managed at home with these systems. However the treatment team must have the necessary training, knowledge and support. In patients with a longer prognosis, but who have a continuing source of pain, intrathecal systems, which can be fully implantable, have many advantages. These offer great freedom to the patient, as there is no external equipment and the pump only needs to be refilled every few weeks. Some of the pumps are programmable and offer great flexibility. In some preferred embodiments, epidural and especially intrathecal doses of selected combination analgesics can be lower than intravenous doses. Epidural and intrathecal administration of selected combination analgesics can be also be used in conjunction with intravenous selected combination analgesics to provide additive or synergistic analgesia. Patient-controlled epidural analgesia is abbreviated "PCEA". [00182] Intraarticular Administration. This method of administration can be used to provide analgesic and anti-inflammatory drugs directly into affected joints to relieve pain and inflammation, usually due to surgery, osteoarthritis or joint trauma. [00183] Surgical site or open wound. This method of administration can be used when localized attenuation of pain or inflammation is deemed desirable and is achieved by topical, dermal administration or infiltration of a dose to a surgical site or open wound. The term "infiltration", "local infiltration", "tissue infiltration" and "local tissue infiltration" shall mean administration into a discrete surgical site, open wound or at the location of pain in a human or animal. Common Methods of Intravenous Administration [00184] I V Drug Administration. The mode of IV drug administration depends on the particular selected combination analgesics used, the patient's condition, and the desired clinical effects of the selected combination analgesics. The four primary modes of IV drug administration are continuous infusion, intermittent infusion, direct injection, and patient-controlled analgesia. [00185] Continuous infusion typically refers to the admixture of a drug in a large volume of solution that is infused continuously over several hours to several days. The solution container is connected to an administration set, and the solubilized drug is infused through the venous access. The infusion may be administered by gravity feed or by use of electronic infusion control pump to deliver the drug accurately. Typically, continuous infusions can be used when the drug is highly diluted and constant plasma drug concentration should be maintained. Alternatively, continuous infusion can be used where large volumes of fluids and electrolytes need to be replenished along with the administration of the selected combination analgesics. Among the disadvantages with continuous infusion are possible fluid overload and potential incompatibilities between the infusion and other IV drugs administered through the same venous access device. Patient comfort may be compromised and patient mobility restricted. [00186] Intermittent infusion refers to the administration of the drug as a small volume of fluid, typically 25 to 250 mL, and infused over, for example, 15 to 120 minutes at periodic intervals. Among the advantages of the intermittent method are the ability of the drug to produce higher peak blood concentrations at periodic intervals (compared with a continuous infusion), decreased risk of fluid overload, and greater convenience for the patient. Intermittent infusions may be given in a number of ways, including "piggyback" infusions through the established pathway of a primary infusion solution. Although the primary infusion is interrupted during the piggyback infusion, the drug from the intermittent infusion container mixes with the primary solution below the piggyback injection level. Thus, if this method is used, the drug and the primary solution must be compatible. [00187] A second method to administer intermittent infusions is as a simultaneous infusion, where the drug is administered as a secondary infusion concurrently with the primary infusion. Instead of connecting the intermittent infusion at the piggyback port, it is attached to a lower secondary port. One potential disadvantage of this method is the tendency for blood to back up into the tubing once the secondary infusion has been completed, potentially occluding the venous access device. This generally does not occur with the piggyback method because the hydrostatic pressure closes the back check valve once the intermittent infusion is completed. [00188] A third method is the use of a volume control set. Although it was originally designed to control the fluid volume delivered to the patient, a drug may be added to a small amount of solution in the volume control set and infused at the desired rate. It is still used in some pediatric settings because it limits the amount of fluid the child receives. [00189] A fourth method for administering intermittent infusions is directly into the venous access device. The device is generally intended for intermittent administration, such as a peripheral heparin lock. The drug is added to a minibag or minibottle and infused intermittently. Between doses, the drug container and tubing are discarded. [00190] Technological advances have produced alternatives for providing intermittent IV doses, including drug powders that are attached between the primary solution and the infusion set. Once the drug vial is attached, the solution flows from the primary container through the drug vial and to the patient. Another innovation involves intermittent doses of drugs that are activated only at the time of use. Rather than preparing and refrigerating the drug before administration, the pharmacy simply dispenses the drug vial attached to a small container of solution. Immediately before administering the drug, the nurse activates the system by removing the barrier between the drug and the solution and agitating the container to achieve solubilization. [00191] Direct injection, also known as IV push, IV bolus, or slow IV injection, is the administration of a drug directly into the venous access device or through the proximal port of a continuous infusion set. A purpose is to achieve rapid plasma concentrations while avoiding costly and time consuming use of infusion devices. Instead of regulating drug administration by the infusion rate, a direct injection requires only the time it takes to push the syringe plunger. Since the drug may be incompatible with the infusing solution or heparin may be present in the intermittent device, the vascular access device can be flushed with normal saline before and after injecting the drug. Direct injections may require that the drug be drawn into a syringe before administration or that the drug be available in a prefilled syringe. A needle 1 inch or shorter should be used to.administer the medication because longer needles may puncture the IV tubing or the vascular access device. Another alternative is a needleless system, which also prevents inadvertent puncture of the tubing or device. [00192] Patient-controlled analgesia (PCA) is the fourth method of administration of drug administration which promotes patient comfort through the self-administration of analgesic agents. With this method, an automated pump (PCA pump) is programmed to administer a small bolus of the drug when activated by the patient. The bolus amount (demand dose) and the time between doses (lock-out interval) are predetermined and programmed into the pump. The term PCA as used herein refers to patient controlled intravenous analgesia.

DOSAGE LEVELS

[00193] In general, the alkylxanthine bronchodilator is administered according to the present invention at the lowest dose which produces an enhanced effect of the analgesic. In one embodiment, the method comprises administering a selected antiepileptic compound and an alkylxanthine bronchodilator, wherein said antiepileptic compound is administered at a subanalgesic dose. By subanalgesic dose, it is meant that the dose of antiepileptic compound aministered in the method is lower than the dose of the same antiepileptic compound required to produce an analgesic effect when administered alone. Such a subanalgesic dose is understood by one of skill in the art. [00194] In one embodiment, the method comprises administering a selected antiepileptic compound and an alkylxanthine bronchodilators, wherein said alkylxanthine bronchodilator is administered at a subanalgesic dose. By subanalgesic dose, it is meant that the dose of alkylxanthine bronchodilator administered in the method is lower than the dose of the same alkylxanthine bronchodilator required to produce an analgesic effect when administered alone. Such a subanalgesic dose is understood-by one of skill in the art. [00195] In adult humans, the dose of antiepileptic compound required varies considerably, depending on type of pain intensity, prior pain history and antiepileptic responsiveness. There are established standards to allow practitioners of the art to convert the dose of one antiepileptic analgesic, given by any route of administration, to an equivalent dose of another antiepileptic analgesic, given by any route of administration. These analgesic conversion tables provide what in the art is called "analgesic equivalence" or "equianalgesic doses." [00196] In one embodiment, the method comprises administering doses of antiepileptic compound/alkylxanthine bronchodilator, to be administered daily in single or divided doses as needed or on a scheduled basis ("around the clock") at doses equivalent to gabapentin 25 to 4000 mg of gabapentin, pregabalin 10 to 1200 mg per day or lacosamide 50 to 2000 mg per day with an alkylxanthine bronchodilator. [00197] For humans, in one embodiment, an average unit dosage analgesic composition typically contains from about 0.1 mg to about 4000 mg per day in single or divided doses and about from 0.001 mg/kg/day to 60 mg/kg/day of one or more alkylxanthine bronchodilator to provide the claimed effect. [00198] In another embodiment, the alkylxanthine bronchodilator is administered in a dose of about 0.01 mg/kg/day to 15 mg/kg/day. In another embodiment, the alkylxanthine bronchodilator is administered in a dose of about 0.2 mg/kg to about 20 mg/kg. In another embodiment, the alkylxanthine bronchodilator is administered in a dose of about 0.1 mg/kg, about 1 mg/kg, about 5 mg/kg, or about 10 mg/kg. [00199] In one aspect of the invention, the method comprises administering a dose of a selected antiepileptic and a dose of alkylxanthine bronchodilator, to be administered about every 4 to 24 hours. In another embodiment, the doses administered are as shown below in Table 1. [00200] Dosage ranges which illustrate the present invention are shown as follows. Table 1. Non-limiting Examples of Antiepileptic and Alkylxanthine Bronchodilator Combination and Doses

[00201] Parenteral doses of antiepileptic compounds and alkylxanthine bronchodilator are usually lower than oral doses. In one embodiment, the intravenous dose of an antiepileptic compound and an alkylxanthine bronchodilator may be the same as its oral dose. In another embodiment, the intravenous dose of an antiepileptic compound and an alkylxanthine bronchodilator may be 75% of the usual oral dose. In yet another embodiment, the intravenous dose of an antiepileptic compound and an alkylxanthine bronchodilator may be 50% of the usual oral dose. Intrathecal doses of drugs are usually substantially lower than oral or even intravenous doses of the same drug. In one embodiment, the intrathecal dose of an antiepileptic compound and an alkylxanthine bronchodilator may be the same as its oral dose. In another embodiment, the intrathecal dose of an antiepileptic compound and an alkylxanthine bronchodilator may be 25% of the usual oral dose. In a preferred embodiment, the intrathecal dose of an antiepileptic compound and an alkylxanthine bronchodilator may be between 0.001% and 5% of the usual oral dose. L a more preferred embodiment, the intrathecal dose of an antiepileptic compound and an alkylxanthine bronchodilator maybe between 0.01% and 2% of the usual oral dose. [00202] Dosage forms of the invention intended for application to the skin comprises doses of antiepileptic compounds and alkylxanthine bronchodilators may involve the same doses as described in Table 1, above or up to a maximum of 20 fold greater than the oral doses in Table 10.

METHODS OF CARRYING OUT THE INVENTION

Oral Immediate Release Dosage Forms and Rectal Dosage Forms [00203] Pharmaceutical composition and methods of the present invention may contain an antiepileptic compound and alkylxanthine bronchodilator or pharmaceutically acceptable salts in racemic or enantiomeric form, or mixtures thereof. [00204] All oral pharmaceutical dosage forms of the invention are contemplated, including oral suspensions, tablets, capsules, lozenges, effervescent tablets, effervescent powders, powders, solutions, powders for reconstitution, transmucosal films, buccal products, oral mucoretentive products, oral gastroretentive tablets and capsules, orally disintegrating tablets, fast dissolving tablets, fast dispersing tablets, fast disintegrating dosage forms, administered as immediate release, modified release, enteric coated, sustained release, controlled release, pulsatile release and extended release dosage form. [00205] All rectal pharmaceutical dosage forms of the invention are contemplated, including suppositories, suspensions, solutions, capsules and tablets, administered as immediate release, modified release, sustained release, controlled release, pulsatile release and extended release dosage forms. [00206] The preparation of oral immediate release dosage forms is well known in the art - see Remington: the science of Pharmacy Practice, 2 1st Edition, 2006, Lippincott, Williams & Wilkins, Baltimore, MD; Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate Drug Selection to Commercial Dosage Form. Gibson, M (ed). CRC Press, 2001; Niazi, S. Handbook of Pharmaceutical Manufacturing Formulations: Uncompressed Solid Products (Volume 2 of 6), CRC Press, 2004; Niazi, S. Handbook of Pharmaceutical Manufacturing Formulations: Compressed Solid Products (Volume 1 of 6), CRC Press, 2004; Mollet, H, Grubenmann A, Payne H. Formulation Technology: Emulsions, Suspensions, Solid Forms, Wiley-VCH, .2001; Niazi S and Niazi SK (all of which are hereby incorporated by reference). A majority of oral dosage forms commercially available world wide are formulated as immediate release products. A wide variety of immediate release dosage forms can be formulated, including oral suspensions, tablets, capsules, lozenges, effervescent tablets, effervescent powders, powders, solutions, powders for reconstitution, buccal products, oral mucoretentive products, orally disintegrating tablets, fast dissolving tablets, fast dispersing tablets, fast disintegrating dosage. [00207] The preparation of rectal dosage forms is well known in the art (see Remington: the Science of Pharmacy Practice, 2 1st Edition, 2006, Lippincott, Williams & Wilkins, Baltimore, MD; Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate Drug Selection to Commercial Dosage Form. Gibson, M (ed). CRC Press, 2001; Niazi, S. Handbook of Pharmaceutical Manufacturing Formulations: Compressed Solid Products (Volume 1 of 6), CRC Press, 2004; Mollet, H, Grubenmann A, Payne H. Formulation Technology: Emulsions, Suspensions, Solid Forms, Wiley-VCH, 2001; U.S. Patent No. 6,576,250, 6,136,337, 6,120,802, 5,725,872, 5,721,228, 5,705,506, 5,635,520, 5,491,171, 5,449,520, 5,433,958, 5,393,738,7,022,335, 6,740,333, 6,607,742, 6,488,954, 6,462,083, 6,270,789, 6,210,698, 6,200,590, 6,193,993, 5,741,806, 5,508,037, 5,500,221, 5,482,973, 5,413,793, 5,389,375, 5,215,758, 4,873,087, 4,871,777 and 4,837,214, and U.S. Patent Application No. 20060147541, 20050181042, 20050037072, 20030118645, 20030008012, 20020197320, 20040047910, 20030185861, 20020090397 and 20020048601 (all of which are hereby incorporated by reference). [00208] A majority of rectal dosage forms commercially available world wide are formulated as immediate release products. A wide variety of immediate release rectal dosage forms can be formulated, including suppositories, suspensions, solutions, capsules, tablets, foams, gels and effervescent tablets. Rectal suppositories may employ any of the wide range of bases, excipients and vehicles know in the art, including cocoa butter, hard fat, hydrogenated vegetable oil, semisynthetic glycerides, water miscible suppository bases, polyethyleneglycols, glycol-surfactant combinations, Carbowax, polyglycols, GEG-based water miscible suppository bases, polyoxyethylene sorbitan fatty acid esters, hydrogels, alginic acid and glycerinated gelatin. Rectal dosage forms may involve immediate release, controlled release, retentive, degradable, thermosensitive, bioadhesive, and retrievable compositions. Controlled-Release Dosage Forms [00209] The controlled-release dosage form may optionally include a controlled release material which is incorporated into a matrix along with the an antiepileptic compound and alkylxanthine bronchodilator, or which is applied as a sustained release coating over a substrate comprising the drug (the term "substrate" encompassing beads, pellets, spheroids, tablets, tablet cores, etc). The controlled release material may be hydrophobic or hydrophilic as desired. The oral dosage form according to the invention may be provided as, for example, granules, spheroids, pellets or other multiparticulate formulations. An amount of the multiparticulates which is effective to provide the desired dose of antiepileptic compound and alkylxanthine bronchodilator over time may be placed in a capsule or may be incorporated in any other suitable oral solid form, e.g., compressed into a tablet. On the other hand, the oral dosage form according to the present invention may be prepared as a tablet core coated with a controlled-release coating, or as a tablet comprising a matrix of drug and controlled release material, and optionally other pharmaceutically desirable ingredients (e.g., diluents, binders, colorants, lubricants, etc.). The controlled release dosage form of the present invention may also be prepared as a bead formulation or an osmotic dosage formulation. [00210] In certain preferred embodiments of the present invention, the controlled-release formulation is achieved via a matrix (e.g. a matrix tablet) which includes a controlled-release material as set forth below. A dosage form including a controlled-release matrix provides in-vitro dissolution rates of antiepileptic compound and alkylxanthine bronchodilator within the preferred ranges and that releases the antiepileptic compound and alkylxanthine bronchodilator in a pH-dependent or pH-independent manner. The materials suitable for inclusion in a controlled-release matrix will depend on the method used to form the matrix. The oral dosage form may contain between 1% and 99% (by weight) of at least one hydrophilic or hydrophobic controlled release material. [00211] A non-limiting list of suitable controlled-release materials which may be included in a controlled-release matrix according to the invention include hydrophilic and/or hydrophobic materials, such as gums, cellulose ethers, acrylic resins, protein derived materials, waxes, shellac, and oils such as hydrogenated castor oil, hydrogenated vegetable oil hydrogenated Type I or Type II vegetable oils, polyoxyethylene stearates and distearates, glycerol monostearate, and non-polymeric, non-water soluble liquids carbohydrate- based substances or poorly water soluble, high melting point (mp = 40 to 100° C) waxes and mixtures thereof. [00212] Hydrogenated vegetable oils of the present invention may include hydrogenated cottonseed oil (e.g., Akofϊne®; Lubritab®; Sterotex® NF), hydrogenated palm oil (Dynasan® P60; Softisan® 154), hydrogenated soybean oil (Hydrocote®; Lipovol HS-K®; Sterotex® HM) and hydrogenated palm kernel oil (e.g., Hydrokote ® 112). [00213] Polyoxyethylene stearates and distearates of the present invention include Polyoxyl 2, 4, 6, 8, 12, 20, 30, 40, 50, 100 and 150 stearates (e.g., Hodag® DGS; PEG-2 stearate; Acconon® 200-MS; Hodag® 20-S; PEG-4 stearate; Cerasynt® 616; Kessco® PEG 300 Monostearate; Acconon® 400-MS; Cerasynt® 660; Cithrol® 4MS; Hodag® 60-S; Kessco® PEG 600 Monostearate; Cerasynt® 840; Hodag 100-S; Myrj® 51; PEG-30 stearate; polyoxyethylene (30) stearate; Crodet® S40; E431; Emerest® 2672; Atlas G-2153; Crodet® S50) and polyoxyl 4, 8, 12, 32 and 150 distearates (e.g, Lipo-PEG® 100-S; Myrj® 59; Hodag® 600-S; Ritox® 59; Hodag® 22-S; PEG-4 distearate; Hodag® 42-S; Kessco® PEG 400 DS; Hodag® 62-S; Kessco® PEG 600 Distearate; Hodag® 154-S; Kessco® PEG 1540 Distearate; Lipo-PEG® 6000-DS; Protamate® 6000-DS). [00214] In one embodiment of the present invention, the antiepileptic compound and alkylxanthine bronchodilator is combined with beeswax, . hydroxypropyl methyl cellulose (e.g, HPMC Kl 5M), silicon dioxide (alone or ® ® ® in combination with Al2O3; e.g, Aerosil , Aerosil 200, Aerosil COK84). [00215] In one embodiment of the present invention, the antiepileptic compound and alkylxanthine bronchodilator is combined with hydrogenated cottonseed oil (e.g., Sterotex® NF), hydroxypropyl methyl cellulose (e.g, HPMC Kl 5M), coconut oil and silicon dioxide (alone or in combination with

Al2O ; e.g, Aerosil®, Aerosil® 200, Aerosil® COK84). [00216] In another embodiment of the present invention, the antiepileptic compound and alkylxanthine bronchodilator is combined with glycerol monostearate (e.g., Cithrol® GMS), hydroxypropyl methyl cellulose (e.g,

HPMC KlOOM) and silicon dioxide (alone or in combination with Al2O3; e.g, Aerosil®, Aerosil® 200, Aerosil® COK84). [00217] In yet another embodiment of the present invention, the antiepileptic compound and alkylxanthine bronchodilator is combined with hydrogenated palm kernel oil (e.g., Hydrokote ® 112), hydroxypropyl methyl cellulose (e.g, HPMC Kl 5M) and silicon dioxide (alone or in combination with Al2O ; e.g, Aerosil®, Aerosil® 200, Aerosil® COK84). [00218] In one embodiment of the present invention, release rate modifiers, including hydroxypropyl methyl cellulose (e.g, HPMC Kl 5M) may incorporated. Release rate modifiers can also have additional useful properties that optimize the formulation. [00219] A variety of agents may be incorporated into the invention as thixotropes (e.g., fumed silicon dioxides, Aerosil®, Aerosil® COK84, Aerosil® 200, etc.). Thixotropes enhance the pharmaceutical formulations of the invention by increasing the viscosity of solutions complementing the action of HPMCs. [00220] Any pharmaceutically acceptable hydrophobic or hydrophilic controlled-release material which is capable of imparting controlled-release of the antiepileptic compound and alkylxanthine bronchodilator may be used in accordance with the present invention. Preferred controlled-release polymers include alkylcelluloses such as ethylcellulose, acrylic and methacrylic acid polymers and copolymers, and cellulose ethers, especially hydroxyalkylcelluloses (e.g., hydroxypropylmethylcellulose) and carboxyalkylcelluloses. Preferred acrylic and methacrylic acid polymers and copolymers include methyl methacrylate, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, aminoalkyl methacrylate copolymer, poly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamine- copolymer, poly(methyl methacrylate), poly(methacrylic acid)(anhydride), polymethacrylate, polyacrylamide, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. Certain preferred embodiments utilize mixtures of any of the foregoing controlled-release materials in the matrices of the invention. [00221] The matrix also may include a binder. In such embodiments, the binder preferably contributes to the controlled-release of the antiepileptic compound and alkylxanthine bronchodilator from the controlled-release matrix. [00222] Preferred hydrophobic binder materials are water-insoluble with more or less pronounced hydrophilic and/or hydrophobic trends. Preferred hydrophobic binder materials which may be used in accordance with the

present invention include digestible, long chain (Cs-Cso, especially C1 -C O), substituted or unsubstituted hydrocarbons, such as fatty acids, fatty alcohols, glyceryl esters of fatty acids, mineral and vegetable oils, natural and synthetic waxes and polyalkylene glycols. Preferably, the hydrophobic binder materials useful in the invention have a melting point from about 30 to about 200 0C, preferably from about 45 to about 90 0C. When the hydrophobic material is a hydrocarbon, the hydrocarbon preferably has a melting point of between 25 and 90 0C. Of the long chain (Cg-Cso) hydrocarbon materials, fatty (aliphatic) alcohols are preferred. The oral dosage form may contain up to 98% (by weight) of at least one digestible, long chain hydrocarbon. [00223] The oral dosage form contains up to 98% (by weight) of at least one polyalkylene glycol. The hydrophobic binder material may comprise natural or synthetic waxes, fatty alcohols (such as lauryl, myristyl, stearyl, cetyl or preferably cetostearyl alcohol), fatty acids, including but not limited to fatty acid esters, fatty acid glycerides (mono-, di-, and tri-glycerides), hydrogenated fats, hydrocarbons, normal waxes, stearic acid, stearyl alcohol and hydrophobic and hydrophilic materials having hydrocarbon backbones. Suitable waxes include, for example, beeswax, glycowax, castor wax and camauba wax. For purposes of the present invention, a wax-like substance is defined as any material which is normally solid at room temperature and has a melting point of from about 30 to about 100 0C. [00224] In certain preferred embodiments, a combination of two or more hydrophobic binder materials are included in the matrix formulations. If an additional hydrophobic binder material is included, it is preferably selected from natural and synthetic waxes, fatty acids, fatty alcohols, and mixtures of the same. Examples include beeswax, camauba wax, stearic acid and stearyl alcohol. This list is not meant to be exclusive. [00225] One particular suitable controlled-release matrix comprises at least one

water soluble hydroxyalkyl cellulose, at least one C12-Cs , preferably C14-C22, aliphatic alcohol and, optionally, at least one polyalkylene glycol. The hydroxyalkyl cellulose is preferably a hydroxy (Ci to C ) alkyl cellulose, such as hydroxypropylcellulose, hydroxypropylmethylcellulose and, especially, hydroxyethyl cellulose. The amount of the at least one hydroxyalkyl cellulose in the present oral dosage form will be determined, inter alia, by the precise rate of the antiepileptic compound and alkylxanthine bronchodilator release required. The aliphatic alcohol may be, for example, lauryl alcohol, myristyl alcohol or stearyl alcohol. In particularly preferred embodiments of the present oral dosage form, however, the at least one aliphatic alcohol is cetyl alcohol or cetostearyl alcohol. The amount of aliphatic alcohol in the present oral dosage form will be determined, as above, by the precise rate of the antiepileptic compound and alkylxanthine bronchodilator release required. It will also depend on whether at least one polyalkylene glycol is present in or absent from the oral dosage form. In the absence of at least one polyalkylene glycol, the oral dosage form preferably contains between 20% and 50% (by wt) of the aliphatic alcohol. When a polyalkylene glycol is present in the oral dosage form, then the combined weight of the aliphatic alcohol and the polyalkylene glycol preferably constitutes between 20% and 50% (by wt) of the total dosage. [00226] In one preferred embodiment, the ratio of, e.g., the at least one hydroxyalkyl cellulose or acrylic resin to the at least r one aliphatic alcohol/polyalkylene glycol determines, to a considerable extent, the release rate of the antiepileptic compound and alkylxanthine bronchodilator from the formulation. A ratio of the hydroxyalkyl cellulose to the aliphatic alcohol/polyalkylene glycol of between 1:2 and 1:4 is preferred, with a ratio of between 1:3 and 1:4 being particularly preferred. [00227] The polyalkylene glycol maybe, for example, polypropylene glycol or, which is preferred, polyethylene glycol. The number average molecular weight of the at least one polyalkylene glycol is preferred between 1,000 and 15,000 especially between 1,500 and 12,000. [00228] Another suitable controlled-release matrix comprises an alkylcellulose

(especially ethylcellulose), a Ci to C36 aliphatic alcohol and, optionally, a polyalkylene glycol. [00229] Another method of producing the dosage form of the invention involves liquid fill compositions, including hydrogenated Type I or Type II vegetable oils (e.g., Hydrokote™ 112), polyoxyethylene stearates and distearates, glycerol monostearate (e.g., Cithrol™ GMS), non-polymeric, non- water soluble liquids carbohydrate-based substances, poorly water soluble, high melting point (mp = 40 to 100° C) waxes. [00230] Hydrogenated vegetable oils may include hydrogenated cottonseed oil (e.g., Akofine™; Lubritab™; Sterotex™ NF), hydrogenated palm oil (Dynasan™ P60; Softisan™ 154), hydrogenated soybean oil (Hydrocote™; Lipovol HS-K ; Sterotex™ HM) and hydrogenated palm kernel oil (e.g., Hydrokote™ 112). [00231] Polyoxyethylene stearates and distearates may include Polyoxyl 2, 4, 6, 8, 12, 20, 30, 40, 50, 100 and 150 stearates (e.g., Hodag™ DGS; PEG-2 stearate; Acconon™ 200-MS; Hodag™ 20-S; PEG-4 stearate; Cerasynt™ 616; Kessco PEG 300 Monostearate; Acconon 400-MS; Cerasynt 660; Cithrol™ 4MS; Hodag™ 60-S; Kessco™ PEG 600 Monostearate; Cerasynt™ 840; Hodag 100-S; Myrj™ 51; PEG-30 stearate; polyoxyethylene (30) stearate; Crodet™ S40; E431; Emerest™ 2672; Atlas G-2153; Crodet™ S50) and polyoxyl 4, 8, 12, 32 and 150 distearates (e.g, Lipo-PEG™ 100-S; Myrj™ 59; Hodag™ 600-S; Ritox™ 59; Hodag™ 22-S; PEG-4 distearate; Hodag™ 42-S; Kessco™ PEG 400 DS; Hodag™ 62-S; Kessco™ PEG 600 Distearate; Hodag™ 154-S; Kessco™ PEG 1540 Distearate; Lipo-PEG™ 6000-DS; Protamate™ 6000-DS). [00232] In one embodiment of the present invention, release rate modifiers, including hydroxypropyl methyl cellulose (e.g, HPMC K l 5M) may be incorporated. Release rate modifiers can also have additional useful properties that optimize the formulation. [00233] A variety of agents may be incorporated into the invention as thixotropes (e.g., fumed silicon dioxides, Aerosil™, Aerosil™ COK84, 1 1 Aerosil ' 200, etc.). Thixotropes enhance the pharmaceutical formulations of the invention by increasing the viscosity of solutions during attempted extraction, complementing the action of HPMCs. They may also provide a tamper resistance by helping to retain the structure of dosage units that have been heated to temperatures greater than the melting point of the base excipient (Aerosils are unaffected by heat). [00234] . In addition to the above ingredients, a controlled-release matrix may also contain suitable quantities of other materials, e.g., diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art. [00235] In order to facilitate the preparation of a solid, controlled-release oral dosage form according to the invention there is provided, in a further aspect of the present invention, a process for the preparation of a solid, controlled- release oral dosage form according to the present invention comprising incorporating the antiepileptic compound and alkylxanthine bronchodilator or a salt thereof in a controlled-release matrix. Incorporation in the matrix may be effected, for example, by (a) forming granules comprising at least one hydrophobic and/or hydrophilic material as set forth above (e.g., a water soluble hydroxyalkyl cellulose) together with the antiepileptic compound and alkylxanthine bronchodilator; (b) mixing the at least one hydrophobic and/or

hydrophilic material-containing granules with at least one Ci2-Cs aliphatic alcohol, and (c) optionally, compressing and shaping the granules. [00236] The granules may be formed by any of the procedures well-known to those skilled in the art of pharmaceutical formulation. For example, in one preferred method, the granules may be formed by wet granulating hydroxyalkyl cellulose/antiepileptic compound and alkylxanthine bronchodilator with water. In a particular preferred embodiment of this process, the amount of water added during the wet granulation step is preferably between 1.5 and 5 times, especially between 1.75 and 3.5 times, the dry weight of the antiepileptic compound and alkylxanthine bronchodilator. [00237] In certain embodiments, the dosage form comprises a plurality of matrices described above. [00238] The matrices of the present invention may also be prepared via a melt pellitization technique. In such circumstance, the antiepileptic compound and alkylxanthine bronchodilator in finely divided form is combined with a binder (also in particulate form) and other optional inert ingredients, and thereafter the mixture is pelletized, e.g., by mechanically working the mixture in a high shear mixer to form the pellets (granules, spheres). Thereafter, the pellets (granules, spheres) may be sieved in order to obtain pellets of the requisite size. The binder material is preferably in particulate form and has a melting point above about 40 °C. Suitable binder substances include, for example, hydrogenated castor oil, hydrogenated vegetable oil, other hydrogenated fats, fatty alcohols, fatty acid esters, fatty acid glycerides, and the like. [00239] Controlled-release matrices can also be prepared by, e.g., melt- granulation or melt-extrusion techniques. Generally, melt-granulation techniques involve melting a normally solid hydrophobic binder material, e.g. a wax, and incorporating a powdered drug therein. To obtain a controlled release dosage form, it may be necessary to incorporate a hydrophobic controlled release material, e.g. ethylcellulose or a water-insoluble acrylic polymer, into the molten wax hydrophobic binder material. [00240] The hydrophobic binder material may comprise one or more water- insoluble wax-like thermoplastic substances possibly mixed with one or more wax-like thermoplastic substances being less hydrophobic than said one or more water-insoluble wax-like substances. In order to achieve controlled release, the individual wax-like substances in the formulation should be substantially non-degradable and insoluble in gastrointestinal fluids during the initial release phases. Useful water-insoluble wax-like binder substances may be those with a water-solubility that is lower than about 1:5,000 (w/w). [00241] In addition to the above ingredients, a controlled release matrix may also contain suitable quantities of other materials, e.g., diluents, lubricants, binders, granulating aids, colorants, flavorants and glidants that are conventional in the pharmaceutical art in amounts up to about 50% by weight of the particulate if desired. The quantities of these additional materials will be sufficient to provide the desired effect to the desired formulation. [Θ0242] The preparation of a suitable melt-extruded matrix according to the present invention may, for example, include the steps of blending the antiepileptic compound and alkylxanthine bronchodilator, together with a controlled release material and preferably a binder material to obtain a homogeneous mixture. The homogeneous mixture is then heated to a temperature sufficient to at least soften the mixture sufficiently to extrude the same. The resulting homogeneous mixture is then extruded, e.g., using a twin- screw extruder, to form strands. The extrudate is preferably cooled and cut into multiparticulates by any means known in the art. The strands are cooled and cut into multiparticulates. The multiparticulates are then divided into unit doses. The extrudate preferably has a diameter of from about 0.1 to about 5 mm and provides controlled release of the therapeutically active agent for a time period of from about 6 to at least about 24 hours. [00243] An optional process for preparing the melt extrusioned formulations of the present invention includes directly metering into an extruder a hydrophobic controlled release material, a therapeutically active agent, and an optional binder material; heating the homogenous mixture; extruding the homogenous mixture to thereby form strands; cooling the strands containing the homogeneous mixture; cutting the strands into particles having a size from about 0.1 mm to about 12 mm; and dividing said particles into unit doses. In this aspect of the invention, a relatively continuous manufacturing procedure is realized. [00244] Plasticizers, such as those described herein, may be included in melt- extruded matrices. The plasticizer is preferably included as from about 0.1 to about 30% by weight of the matrix. Other pharmaceutical excipients, e.g., talc, mono or poly saccharides, colorants, flavorants, lubricants and the like may be included in the controlled release matrices of the present invention as desired. The amounts included will depend upon the desired characteristic to be achieved. [00245] The diameter of the extruder aperture or exit port can be adjusted to vary the thickness of the extruded strands. Furthermore, the exit part of the extruder need not be round; it can be oblong, rectangular, etc. The exiting strands can be reduced to particles using a hot wire cutter, guillotine, etc. [00246] A melt extruded multiparticulate system can be, for example, in the form of granules, spheroids or pellets depending upon the extruder exit orifice. For purposes of the present invention, the terms "melt-extruded multiparticulate^)" and "melt-extruded multiparticulate system(s)" and "melt- extruded particles" shall refer to a plurality of units, preferably within a range of similar size and/or shape and containing one or more active agents and one or more excipients, preferably including a hydrophobic controlled release material as described herein. Preferably the melt-extruded multiparticulates will be of a range of from about 0.1 to about 12 mm in length and have a diameter of from about 0.1 to about 5 mm. Li addition, it is to be understood that the melt-extruded multiparticulates can be any geometrical shape within this size range. Alternatively, the extrudate may simply be cut into desired lengths and divided into unit doses of the therapeutically active agent without the need of a spheronization step. [00247] In one preferred embodiment, oral dosage forms are prepared that include an effective amount of melt-extruded multiparticulates within a capsule. For example, a plurality of the melt-extruded multiparticulates may be placed in a gelatin capsule in an amount sufficient to provide an effective controlled release dose when ingested and contacted by gastric fluid. [00248] In another preferred embodiment, a suitable amount of the multiparticulate extrudate is compressed into an oral tablet using conventional tableting equipment using standard techniques. Techniques and compositions for making tablets (compressed and molded), capsules (hard and soft gelatin) and pills are also described in Remington's Pharmaceutical Sciences, 2 1st ed., 2005 incorporated by reference herein. [00249] In yet another preferred embodiment, the extrudate can be shaped into tablets as set forth in U.S. Pat. No. 4,957,681, hereby incorporated by reference. [00250] Optionally, the controlled-release matrix multiparticulate systems or tablets can be coated, or the gelatin capsule can be further coated, with a controlled release coating such as the controlled release coatings described above. Such coatings preferably include a sufficient amount of hydrophobic and/or hydrophilic controlled-release material to obtain a weight gain level from about 2 to about 25 percent, although the overcoat may be greater depending upon, e.g., the physical properties of the drug and the desired release rate, among other things. [00251] The dosage forms of the present invention may further include combinations of melt-extruded multiparticulates containing one or more drugs. Furthermore, the dosage forms can also include an amount of an immediate release therapeutically active agent for prompt therapeutic effect. The immediate release therapeutically active agent may be incorporated, e.g., as separate pellets within a gelatin capsule, or may be coated on the surface of, e.g., melt extruded multiparticulates. The unit dosage forms of the present invention may also contain a combination of, e.g., controlled release beads and matrix multiparticulates to achieve a desired effect. [00252] The controlled-release formulations of the present invention preferably slowly release the therapeutically active agent, e.g., when ingested and exposed to gastric fluids, and then to intestinal fluids. The controlled-release profile of the melt-extruded formulations of the invention can be altered, for example, by varying the amount of controlled-release material, by varying the amount of plasticizer relative to other matrix constituents, hydrophobic material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc. [00253] In other embodiments of the invention, melt-extruded formulations are prepared without the inclusion of the therapeutically active agent, which is added thereafter to the extrudate. Such formulations typically will have the therapeutically active agent blended together with the extruded matrix material, and then the mixture would be tableted in order to provide a slow release formulation. Such formulations may be advantageous, for example, when the therapeutically active agent included in the formulation is sensitive to temperatures needed for softening the hydrophobic material and/or the retardant material. [00254] Typical melt-extrusion production systems suitable for use in accordance with the present invention include a suitable extruder drive motor having variable speed and constant torque control, start-stop controls, and ammeter. In addition, the production system will include a temperature control console which includes temperature sensors, cooling means and temperature indicators throughout the length of the extruder. In addition, the production system will include an extruder such as twin-screw extruder which consists of two counter-rotating intermeshing screws enclosed within a cylinder or barrel having an aperture or die at the exit thereof. The feed materials enter through a feed hopper and are moved through the barrel by the screws and are forced through the die into strands which are thereafter conveyed such as by a continuous movable belt to allow for cooling and being directed to a pelletizer or other suitable device to render the extruded ropes into the multiparticulate system. The pelletizer can consist of rollers, fixed knife, rotating cutter and the like. Suitable instruments and systems will be apparent to those of ordinary skill in the art. [00255] A further aspect of the invention is related to the preparation of melt- extruded multiparticulates as set forth above in a manner which controls the amount of air included in the extruded product. By controlling the amount of air included in the extrudate, the release rate of the therapeutically active agent from the, e.g., multiparticulate extrudate, can be altered significantly. In certain embodiments, the pH dependency of the extruded product can be altered as well. [00256] Thus, in a further aspect of the invention, the melt-extruded product is prepared in a manner which substantially excludes air during the extrusion phase of the process. This may be accomplished, for example, by using a Leistritz extruder having a vacuum attachment. In certain preferred embodiments the extruded multiparticulates prepared according to the invention using the Leistritz extruder under vacuum provides a melt-extruded product having different physical characteristics. In particular, the extrudate is substantially non-porous when magnified, e.g., using a scanning electron microscope which provides an SEM (scanning electron micrograph). Such substantially non-porous formulations provide a faster release of the therapeutically active agent, relative to the same formulation prepared without vacuum. SEMs of the multiparticulates prepared using- an extruder under vacuum appear very smooth, and the multiparticulates tend to be more robust than those multiparticulates prepared without vacuum. In certain formulations, the use of extrusion under vacuum provides an extruded multiparticulate product which is more pH-dependent than its counterpart formulation prepared without vacuum. Alternatively, the melt-extruded product is prepared using a Werner-Pfleiderer twin screw extruder. [00257] In certain embodiments, a spheronizing agent is added to a granulate or multiparticulates of the present invention and then spheronized to produce controlled release spheroids. The spheroids are then optionally overcoated with a controlled release coating by methods such as those described herein. [00258] Spheronizing agents which may be used to prepare the multiparticulate formulations of the present invention include any art-known spheronizing agent. Cellulose derivatives are preferred, and microcrystalline cellulose is especially preferred. A suitable microcrystalline cellulose is, for example, the material sold as Avicel™ PH 101. The spheronizing agent is preferably included as about 1 to about 99% of the multiparticulate by weight. [00259] In addition to the active ingredient and spheronizing agent, the spheroids may also contain a binder. Suitable binders, such as low viscosity, water soluble polymers, will be well known to those skilled in the pharmaceutical art. However, water soluble hydroxy lower alkylcellulose, such as hydroxypropylcellulose, are preferred. [00260] In addition to the antiepileptic compound and alkylxanthine bronchodilator and spheronizing agent, the multiparticulate formulations of the present invention may include a controlled release material such as those described hereinabove. Preferred controlled-release materials for inclusion in the multiparticulate formulations include acrylic and methacrylic acid polymers or copolymers, and ethylcellulose. When present in the formulation, the controlled-release material will be included in amounts of from about ϊ to about 80% of the multiparticulate, by weight. The controlled-release material is preferably included in the multiparticulate formulation in an amount effective to provide controlled release of the antiepileptic compound and alkylxanthine bronchodilator from the multiparticulate. [00261] Pharmaceutical processing aids such as binders, diluents, and the like may be included in the multiparticulate formulations. Amounts of these agents included in the formulations will vary with the desired effect to be exhibited by the formulation. [00262] Specific examples of pharmaceutically acceptable carriers and excipients that may be used to formulate oral dosage forms of the present invention are described in the Handbook of Pharmaceutical Excipients, APhA Publications; 5 edition (January 5, 2006) incorporated by reference herein. [00263] The multiparticulates may be overcoated with a controlled-release coating including a controlled-release material such as those described hereinabove. The controlled-release coating is applied to a weight gain of from about 5 to about 30%. The amount of the controlled-release coating to be applied will vary according to a variety of factors, e.g., the composition of the multiparticulate and the chemical and/or physical properties of the drug. [00264] Matrix multiparticulates may also be prepared by granulating the spheronizing agent together with the antiepileptic compound and alkylxanthine bronchodilator, e.g. by wet granulation. The granulate is then spheronized to produce the matrix multiparticulates. The matrix multiparticulates are then optionally overcoated with the controlled release coating by methods such as those described hereinabove. [00265] Another method for preparing matrix multiparticulates, for example, by (a) forming granules comprising at least one water soluble hydroxyalkyl cellulose and the antiepileptic compound and alkylxanthine bronchodilator or the antiepileptic compound and alkylxanthine bronchodilator salt; (b) mixing

the hydroxyalkyl cellulose containing granules with at least one C1 -C aliphatic alcohol; and (c) optionally, compressing and shaping the granules. Preferably, the granules are formed by wet granulating the hydroxyalkyl cellulose/antiepileptic compound and alkylxanthine bronchodilator with water. In a particularly preferred embodiment of this process, the amount of water added during the wet granulation step is preferably between 1.5 and 5 times, especially between 1.75 and 3.5 times, the dry weight of the antiepileptic compound and alkylxanthine bronchodilator. [00266] In yet other alternative embodiments, a spheronizing agent, together with the active ingredient can be spheronized to form spheroids. Microcrystalline cellulose is preferred. A suitable microcrystalline cellulose is, for example, the material sold as Avicel™ PH 101. In such embodiments, in addition to the active ingredient and spheronizing agent, the spheroids may also contain a binder. Suitable binders, such as low viscosity, water soluble polymers, will be well known to those skilled in the pharmaceutical art. However, water soluble hydroxy lower alkyl cellulose, such as hydroxy propyl cellulose, are preferred. Additionally (or alternatively) the spheroids may contain a water insoluble polymer, especially an acrylic polymer, an acrylic copolymer, such as a methacrylic acid-ethyl acrylate co-polymer, or ethyl cellulose. In such embodiments, the sustained-release coating will generally include a water insoluble material such as (a) a wax, either alone or in admixture with a fatty alcohol; or (b) shellac or zein. [00267] Spheroids of the present invention comprise a matrix formulation as described above or bead formulation as described hereinafter having a diameter of between 0.1 mm and 2.5 mm, especially between 0.5 mm and 2 mm. [00268] The spheroids are preferably film coated with a controlled release material that permits release of the antiepileptic compound and alkylxanthine bronchodilator (or salt) at a controlled rate in an aqueous medium. The film coat is chosen so as to achieve, in combination with the other stated properties, the in-vitro release rate outlined above (e.g., at least about 12.5% released after 1 hour). The controlled-release coating formulations of the present invention preferably produce a strong, continuous film that is smooth and elegant, capable of supporting pigments and other coating additives, non-toxic, inert, and tack-free. Preparation of Coated Bead Formulations [00269] In certain preferred embodiments of the present invention the oral solid controlled release dosage form of the present invention comprises a plurality of coated substrates, e.g., inert pharmaceutical beads such as nu pariel 18/20 beads. An aqueous dispersion of hydrophobic material is used to coat the beads to provide for the controlled release of the antiepileptic compound and alkylxanthine bronchodilator. In certain preferred embodiments a plurality of the resultant stabilized solid controlled-release beads may be placed in a gelatin capsule in an amount sufficient to provide an effective controlled- release dose when ingested and contacted by an environmental fluid, e.g., gastric fluid or dissolution media. [00270] The stabilized controlled-release bead formulations of the present invention slowly release the antiepileptic compound and alkylxanthine bronchodilator, e.g., when ingested and exposed to gastric fluids, and then to intestinal fluids. The controlled-release profile of the formulations of the invention can be altered, for example, by varying the amount of overcoating with the aqueous dispersion of hydrophobic controlled release material, altering the manner in which the plasticizer is added to the aqueous dispersion of hydrophobic controlled release material, by varying the amount of plasticizer relative to hydrophobic controlled release material, by the inclusion of additional ingredients or excipients, by altering the method of manufacture, etc. The dissolution profile of the ultimate product may also be modified, for example, by increasing or decreasing the thickness of the controlled release coating. [00271] Substrates coated with a therapeutically active agent are prepared, e.g. by dissolving the therapeutically active agent in water and then spraying the solution onto a substrate, for example, nu panel 18/20 beads, using a Wuster insert. Optionally, additional ingredients are also added prior to coating the beads in order to assist the binding of the antiepileptic compound and alkylxanthine bronchodilator to the beads, and/or to color the solution, etc. For example, a product which includes hydroxypropyl methylcellulose, etc. with or without colorant (e.g., Opadry™) may be added to the solution and the solution mixed (e.g., for about 1 hour) prior to application of the same onto the substrate. The resultant coated substrate may then be optionally overcoated with a barrier agent, to separate the therapeutically active agent from the hydrophobic controlled-release coating. [00272] An example of a suitable barrier agent is one which comprises hydroxypropyl methylcellulose. However, any film-former known in the art may be used. It is preferred that the barrier agent does not affect the dissolution rate of the final product. [00273] The substrates may then be overcoated with an aqueous dispersion of the hydrophobic controlled release material as described herein. The aqueous dispersion of hydrophobic controlled release material preferably further includes an effective amount of plasticizer, e.g. tri-ethyl citrate. Pre- formulated aqueous dispersions of ethylcellulose, such as Aquacoat™ or Surelease™, may be used. If Surelease™ is used, it is not necessary to separately add a plasticizer. Alternatively, pre-formulated aqueous dispersions of acrylic polymers such as Eudragit™ can be used. [00274] The coating solutions of the present invention preferably contain, in addition to the film-former, plasticizer, and solvent system (i.e., water), a colorant to provide elegance and product distinction. Color may be added to the solution of the therapeutically active agent instead, or in addition to the aqueous dispersion of hydrophobic material. For example, color can be added to Aquacoat™ via the use of alcohol or propylene glycol based color dispersions, milled aluminum lakes and opacifiers such as titanium dioxide by adding color with shear to water soluble polymer solution and then using low shear to the plasticized Aquacoat™. Alternatively, any suitable method of providing color to dioxide and color pigments, such as iron oxide pigments. The incorporation of pigments, may, however, increase the retard effect of the coating. [00275] The plasticized aqueous dispersion of hydrophobic controlled release material may be applied onto the substrate comprising the therapeutically active agent by spraying using any suitable spray equipment known in the art. In a preferred method, a Wurster fluidized-bed system is used in which an air jet, injected from underneath, fluidizes the core material and effects drying while the acrylic polymer coating is sprayed on. A sufficient amount of the aqueous dispersion of hydrophobic material to obtain a predetermined controlled-release of said therapeutically active agent when said coated substrate is exposed to aqueous solutions, e.g. gastric fluid, is preferably applied, taking into account the physical characteristics of the therapeutically active agent, the manner of incorporation of the plasticizer, etc. After coating with the hydrophobic controlled release material, a further overcoat of a film- former, such as Opadry™, is optionally applied to the beads. This overcoat is provided, if at all, in order to substantially reduce agglomeration of the beads. [00276] Another method of producing controlled release bead formulations suitable for about 24-hour administration is via powder layering. The powder- layered beads are prepared by spraying an aqueous binder solution onto inert beads to provide a tacky surface, and subsequently spraying a powder that is a homogenous mixture of the antiepileptic compound and alkylxanthine bronchodilator and hydrous lactose impalpable onto the tacky beads. The beads are then dried and coated with a hydrophobic material such as those described hereinabove to obtain the desired release of drug when the final formulation is exposed to environmental fluids. An appropriate amount of the controlled release beads are then, e.g. encapsulated to provide a final dosage form which provides effective plasma concentrations for the intended duration of effect or dosing frequency. Controlled Release Osmotic Dosage [00277] Controlled release dosage forms according to the present invention may also be prepared as osmotic dosage formulations. The osmotic dosage forms preferably include a bilayer core comprising a drug layer and a delivery or push layer, wherein the bilayer core is surrounded by a semipermeable wall and optionally having at least one passageway disposed therein. In certain embodiments, the bilayer core comprises a drug layer with the antiepileptic compound and alkylxanthine bronchodilator or a salt thereof and a displacement or push layer. In certain preferred embodiments the drug layer may also comprise at least one polymer hydrogel. The polymer hydrogel may have an average molecular weight of between about 500 and about 6,000,000. Examples of polymer hydrogels include but are not limited to a maltodextrin

polymer comprising the formula (C H 2Os)n. H2O, wherein n is 3 to 7,500, and the maltodextrin polymer comprises a 500 to 1,250,000 number-average molecular weight; a poly(alkylene oxide) represented by, e.g., a poly(ethylene oxide) and a poly(propylene oxide) having a 50,000 to 750,000 weight- average molecular weight, and more specifically represented by a polyethylene oxide) of at least one of 100,000, 200,000, 300,000 or 400,000 weight-average molecular weights; an alkali carboxyalkylcellulose, wherein the alkali is sodium or potassium, the alkyl is methyl, ethyl, propyl, or butyl of 10,000 to 175,000 weight-average molecular weight; and a copolymer of ethylene-acrylic acid, including methacrylic and ethacrylic acid of 10,000 to 500,000 number-average molecular weight. [00278] In certain preferred embodiments of the present invention, the delivery or push .layer comprises an osmopolymer. Examples of an osmopolymer include but are not limited to a member selected from the.group consisting of a polyalkylene oxide and a carboxyalkylcellulose. The polyalkylene oxide possesses a 1,000,000 to 10,000,000 weight-average molecular weight.. The polyalkylene oxide may be a member selected from the group consisting of polymethylene oxide, polyethylene oxide, polypropylene oxide, polyethylene oxide having a 1,000,000 average molecular weight, polyethylene oxide comprising a 5,000,000 average molecular weight, polyethylene oxide comprising a 7,000,000 average molecular weight, cross-linked polymethylene oxide possessing a 1,000,000 average molecular weight, and polypropylene oxide of 1,200,000 average molecular weight. Typical osmopolymer carboxyalkylcellulose comprises a member selected from the group consisting of alkali carboxyalkylcellulose, sodium carboxymethylcellulose, potassium carboxymethylcellulose, sodium carboxyethylcellulose, lithium carboxymethylcellulose, sodium carboxyethylcellulose, carboxyalkylhydroxyalkylcellulose, carboxyrnethylhydroxyethyl cellulose, carboxyethylhydroxyethylcellulose and carboxymethylhydroxypropylcellulose. The osmopolymers used for the displacement layer exhibit an osmotic pressure gradient across the semipermeable wall. The osmopolymers imbibe fluid into dosage form, thereby swelling and expanding as an osmotic hydrogel (also known as osmogel), whereby they push the antiepileptic compound and alkylxanthine bronchodilator or pharmaceutically acceptable salt thereof from the osmotic dosage form. [00279] The push layer may also include one or more osmotically effective compounds also known as osmagents and as osmotically effective solutes. They imbibe an environmental fluid, for example, from the gastrointestinal tract, into dosage form and contribute to the delivery kinetics of the displacement layer. Examples of osmotically active compounds comprise a member selected from the group consisting of osmotic salts and osmotic carbohydrates. Examples of specific osmagents include but are not limited to sodium chloride, potassium chloride, magnesium sulfate, lithium phosphate, lithium chloride, sodium phosphate, potassium sulfate, sodium sulfate, potassium phosphate, glucose, fructose and maltose. [00280] The push layer may optionally include a hydroxypropylalkylcellulose represented by a member selected from the group consisting of hydroxypropylmethylcellulose, hydroxypropylethylcellulose, hydroxypropyl isopropylcellulose, hydroxypropylbutylcellulose, and hydroxypropyl pentylcellulose. [00281] The push layer optionally may comprise a nontoxic colorant or dye. Examples of colorants or dyes include but are not limited to Food and Drug Administration Colorant (FD&C), such as FD&C No. 1 blue dye, FD&C No. 4 red dye, red ferric oxide, yellow ferric oxide, titanium dioxide, carbon black, and indigo. [00282] The push layer may also optionally comprise an antioxidant to inhibit the oxidation of ingredients. Some examples of antioxidants include but are not limited to a member selected from the group consisting of ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, a mixture of 2 and 3 tertiary- butyl-4-hydroxyanisole, butylated hydroxytoluene, sodium isoascorbate, dihydroguaretic acid, potassium sorbate, sodium bisulfate, sodium metabisulfate, sorbic acid, potassium ascorbate, vitamin E, 4-chloro-2,6- ditertiarybutylphenol, alphatocopherol, and propylgallate. [00283] In certain alternative embodiments, the dosage form comprises an homogenous core comprising the antiepileptic compound and alkylxanthine bronchodilator or a pharmaceutically acceptable salt thereof, a pharmaceutically acceptable polymer (e.g., polyethylene oxide), optionally a disintegrant (e.g., polyvinylpyrrolidone), optionally an absorption enhancer (e.g., a fatty acid, a surfactant, a chelating agent, a bile salt, etc.). The homogenous core is surrounded by a semipermeable wall having a passageway (as defined above) for the release of the antiepileptic compound and alkylxanthine bronchodilator or pharmaceutically acceptable salt thereof. [00284] In certain embodiments, the semipermeable wall comprises a member selected from the group consisting of a cellulose ester polymer, a cellulose ether polymer and a cellulose ester-ether polymer. Representative wall polymers comprise a member selected from the group consisting of cellulose acylate, cellulose diacylate, cellulose triacylate, cellulose acetate, cellulose diacetate, cellulose triacetate, mono-, di- and tricellulose alkenylates, and mono-, di- and tricellulose alkinylates. The poly(cellulose) used for the present invention comprises a number-average molecular weight of 20,000 to 7,500,000. [00285] Additional semipermeable polymers for the purpose of this invention comprise acetaldehyde dimethycellulose acetate, cellulose acetate ethylcarbamate, cellulose acetate methylcarbamate, cellulose diacetate, propylcarbamate, cellulose acetate diethylaminoacetate; semipermeable polyamide; semipermeable polyurethane; semipermeable sulfonated polystyrene; semipermeable cross-linked polymer formed by the coprecipitation of a polyanion and a polycation as disclosed in U.S. Pat. Nos. 3,173,876; 3,276,586; 3,541,005; 3,541,006 and 3,546,876; semipermeable polymers as disclosed by Loeb and Sourirajan in U.S. Pat. No. 3,133,132; semipermeable crosslinked polystyrenes; semipermeable cross-linked poly(sodium styrene sulfonate); semipermeable crosslinked poly(vinylbenzyltrimethyl ammonium chloride); and semipermeable polymers possessing a fluid permeability of 2.5 x 10 8 to 2.5 x 10 2 (cm2/hr.atm) expressed per atmosphere of hydrostatic or osmotic pressure difference across the semipermeable wall. Other polymers useful in the present invention are known in the art in U.S. Pat. Nos. 3,845,770; 3,916,899 and 4,160,020; and in Handbook of Common Polymers, Scott, J. R. and W. J. Roff, 1971, CRC Press, Cleveland, Ohio. [00286] In certain embodiments, preferably the semipermeable wall is nontoxic, inert, and it maintains its physical and chemical integrity during the . dispensing life of the drug. In certain embodiments, the dosage form comprises a binder as described above. [00287] In certain embodiments, the dosage form comprises a lubricant, which may be used during the manufacture of the dosage form to prevent sticking to die wall or punch faces. Examples of lubricants include but are not limited to magnesium stearate, sodium stearate, stearic acid, calcium stearate, magnesium oleate, oleic acid, potassium oleate, caprylic acid, sodium stearyl fumarate, and magnesium palmitate. Coatings [00288] The dosage forms of the present invention may optionally be coated with one or more coatings suitable for the regulation of release or for the protection of the formulation. In one embodiment, coatings are provided to permit either pH-dependent or pH-independent release, e.g., when exposed to gastrointestinal fluid. When a pH-independent coating is desired, the coating is designed to achieve optimal release regardless of pH-changes in the environmental fluid, e.g., the GI tract. Other preferred embodiments include a pH-dependent coating that releases the antiepileptic compound and alkylxanthine bronchodilator in desired areas of the gastrointestinal (GI) tract, e.g., the stomach or small intestine, such that an absorption profile is provided which is capable of providing at least about twelve hour and preferably up to twenty-four hour analgesia to a patient. It is also possible to formulate compositions which release a portion of the dose in one desired area of the GI tract, e.g., the stomach, and release the remainder of the dose in another area of the GI tract, e.g., the small intestine. [00289] Formulations according to the invention that utilize pH-dependent coatings may also impart a repeat-action effect whereby unprotected drug is coated over an enteric coat and is released in the stomach, while the remainder, being protected by the enteric coating, is released further down the gastrointestinal tract. Coatings which are pH-dependent may be used in accordance with the present invention include a controlled release material such as, e.g., shellac, cellulose acetate phthalate (CAP), polyvinyl acetate phthalate (PVAP), hydroxypropyl methylcellulose phthalate, and methacrylic acid ester copolymers, zein, and the like. [00290] In another preferred embodiment, the present invention is related to a stabilized solid controlled dosage form comprising the antiepileptic compound and alkylxanthine bronchodilator coated with a hydrophobic controlled release material selected from (i) an alkylcellulose; (ii) an acrylic polymer; or (iii) mixtures thereof. The coating may be applied in the form of an organic or aqueous solution or dispersion. [00291] In certain preferred embodiments, the controlled release coating is derived from an aqueous dispersion of the hydrophobic controlled release material. The coated substrate containing the antiepileptic compound and alkylxanthine bronchodilator (e.g., a tablet core or inert pharmaceutical beads or spheroids) is then cured until an endpoint is reached at which the substrate provides a stable dissolution. The curing endpoint may be determined by comparing the dissolution profile (curve) of the dosage form immediately after curing to the dissolution profile (curve) of the dosage form after exposure to accelerated storage conditions of, e.g., at least one month at a temperature of 40 0C and a relative humidity of 75%. [00292] In preferred embodiments, the controlled release coatings include a plasticizer such as those described herein. [00293] In certain embodiments, it is necessary to overcoat the substrate comprising the antiepileptic compound and alkylxanthine bronchodilator with a sufficient amount of the aqueous dispersion of e.g., alkylcellulose or acrylic polymer, to obtain a weight gain level from about 2 to about 50%, e.g., about 2 to about 25% in order to obtain a controlled-release formulation. The overcoat may be lesser or greater depending upon the physical properties of the therapeutically active agent and the desired release rate, the inclusion of plasticizer in the aqueous dispersion and the manner of incorporation of the same, for example. Alkylcellulose Polymers [00294] Cellulosic materials and polymers, including alkylcelluloses are controlled release materials well suited for coating the substrates, e.g., beads, tablets, etc. according to the invention. Simply by way of example, one preferred alkylcellulosic polymer is ethylcellulose, although the artisan will appreciate that other cellulose and/or alkylcellulσse polymers may be readily employed, singly or on any combination, as all or part of a hydrophobic coating according to the invention. [00295] One commercially-available aqueous dispersion of ethylcellulose is Aquacoat™. Aquacoat™ is prepared by dissolving the ethylcellulose in a water-immiscible organic solvent and then emulsifying the same in water in the presence of a surfactant and a stabilizer. After homogenization to generate submicron droplets, the organic solvent is evaporated under vacuum to form a pseudolatex. The plasticizer is not incorporated in the pseudolatex during the manufacturing phase. Thus, prior to using the same as a coating, it is necessary to intimately mix the Aquacoat™ with a suitable plasticizer prior to use. [00296] Another aqueous dispersion of ethylcellulose is commercially available as Surelease™. This product is prepared by incorporating plasticizer into the dispersion during the manufacturing process. A hot melt of a polymer, plasticizer (dibutyl sebacate), and stabilizer (oleic acid) is prepared as a homogeneous mixture, which is then diluted with an alkaline solution to obtain an aqueous dispersion which can be applied directly onto substrates. Acrylic Polymers [00297] In other preferred embodiments of the present invention, the controlled release material comprising the controlled-release coating is a pharmaceutically acceptable acrylic polymer, including but not limited to acrylic acid and methacrylic acid copolymers, methyl methacrylate copolymers, ethoxyethyl methacrylates, cynaoethyl methacrylate, ρoly(acrylic acid), poly(methacrylic acid), methacrylic acid alkylamide copolymer, ρoly(methyl methacrylate), polymethacrylate, poly(methyl methacrylate) copolymer, polyacrylamide, aminoalkyl methacrylate copolymer, poly(methacrylic acid anhydride), and glycidyl methacrylate copolymers. [00298] In certain preferred embodiments, the acrylic polymer is comprised of one or more ammonio methacrylate copolymers. Ammonio methacrylate copolymers are well known in the art, and are described in NF XVII as fully polymerized copolymers of acrylic and methacrylic acid esters with a low content of quaternary ammonium groups. [00299] In order to obtain a desirable dissolution profile, it may be necessary to incorporate two or more ammonio methacrylate copolymers having differing physical properties, such as different molar ratios of the quaternary ammonium groups to the neutral (meth)acrylic esters. [00300] Certain methacrylic acid ester-type polymers are useful for preparing pH-dependent coatings which may be used in accordance with the present invention. For example, there are a family of copolymers synthesized from diethylaminoethyl methacrylate and other neutral methacrylic esters, also known as methacrylic acid copolymer or polymeric methacrylates, commercially available as Eudragit™. There are several different types of Eudragit™. For example, Eudragit™ E is an example of a methacrylic acid copolymer which swells and dissolves in acidic media. Eudragit™ L is a methacrylic acid copolymer which does not swell at about pH<5.7 and is soluble at about pH>6. Eudragit™ S does not swell at about pH<6.5 and is soluble at about pH>7. Eudragit™ RL and Eudragit™ RS are water swellable, and the amount of water absorbed by these polymers is pH-dependent, however, dosage forms coated with Eudragit™ RL and RS are pH- independent. [00301] In certain preferred embodiments, the acrylic coating comprises a mixture of two acrylic resin lacquers commercially available as Eudragit™ RL30D and Eudragit™ RS30D, respectively. Eudragit™ RL30D and Eudragit™ RS30D are copolymers of acrylic and methacrylic esters with a low content of quaternary ammonium groups, the molar ratio of ammonium groups to the remaining neutral (meth)acrylic esters being 1:20 in Eudragit™ RL30D and 1:40 in Eudragit™ RS30D. The mean molecular weight is about 150,000. The code designations RL (high permeability) and RS (low permeability) refer to the permeability properties of these agents. Eudragit™ RL/RS mixtures are insoluble in water and in digestive fluids. However, coatings formed from the same are swellable and permeable in aqueous solutions and digestive fluids. [00302] The Eudragit™ RL/RS dispersions of the present invention may be mixed together in any desired ratio in order to ultimately obtain a controlled- release formulation having a desirable dissolution profile. Desirable controlled-release formulations may be obtained, for instance, from a retardant coating derived from 100% Eudragit™ RL, 50% Eudragit™ RL and 50% Eudragit™ RS, and 10% Eudragit™ RL:Eudragit™ 90% RS. Of course, one skilled in the art will recognize that other acrylic polymers may also be used, such as, for example, Eudragit™ L. Plasticizers [00303] In embodiments of the present invention where the coating comprises an aqueous dispersion of a hydrophobic controlled release material, the inclusion of an effective amount of a plasticizer in the aqueous dispersion of hydrophobic material will further improve the physical properties of the controlled-release coating. For example, because ethylcellulose has a relatively high glass transition temperature and does not form flexible films under normal coating conditions, it is preferable to incorporate a plasticizer into an ethylcellulose coating containing controlled-release coating before using the same as a coating material. Generally, the amount of plasticizer included in a coating solution is based on the concentration of the film-former, e.g., most often from about 1 to about 50 percent by weight of the film-former. Concentration of the plasticizer, however, can only be properly determined after careful experimentation with the particular coating solution and method of application. [00304] Examples of suitable plasticizers for ethylcellulose include water insoluble plasticizers such as dibutyl sebacate, diethyl phthalate, triethyl citrate, tibutyl citrate, and triacetin, although it is possible that other water- insoluble plasticizers (such as acetylated monoglycerides, phthalate esters, castor oil, etc.) may be used. Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention. [00305] Examples of suitable plasticizers for the acrylic polymers of the present invention include, but are not limited to citric acid esters such as triethyl citrate NF XVI, tributyl citrate, dibutyl phthalate, and possibly 1,2- propylene glycol. Other plasticizers which have proved to be suitable for enhancing the elasticity of the films formed from acrylic films such as Eudragit™ RL/RS lacquer solutions include polyethylene glycols, propylene glycol, diethyl phthalate, castor oil, and triacetin. Triethyl citrate is an especially preferred plasticizer for the aqueous dispersions of ethyl cellulose of the present invention. [00306] In certain embodiments, the addition of a small amount of talc to the controlled release coating reduces the tendency of the aqueous dispersion to stick during processing, and acts as a polishing agent. [00307] The release of the therapeutically active agent from the controlled- release formulation of the present invention can be further influenced, i.e., adjusted to a desired rate, by the addition of one or more release-modifying agents, or by providing one or more passageways through the coating. The ratio of hydrophobic controlled release material to water soluble material is determined by, among other factors, the release rate required and the solubility characteristics of the materials selected. [00308] The release-modifying agents which function as pore-formers may be organic or inorganic, and include materials that can be dissolved, extracted or leached from the coating in the environment of use. The pore-formers may comprise one or more hydrophilic materials such as hydroxypropylmethylcellulose. [00309] The controlled-release coatings of the present invention can also include erosion-promoting agents such as starch and gums. [00310] The controlled-release coatings of the present invention can also include materials useful for making microporous lamina in the environment of use, such as polycarbonates comprised of linear polyesters of carbonic acid in which carbonate groups reoccur in the polymer chain. [00311] The release-modifying agent may also comprise a semi-permeable polymer. In certain preferred embodiments, the release-modifying agent is selected from hydroxypropylmethylcellulose, lactose, metal stearates, and mixtures of any of the foregoing. [00312] The controlled-release coatings of the present invention may also include an exit means comprising at least one passageway, orifice, or the like. The passageway may be formed by such methods as those disclosed in U.S. Pat. Nos. 3,845,770; 3,916,889; 4,063,064; and 4,088,864, all of which are hereby incorporated by reference. The passageway can have any shape such as round, triangular, square, elliptical, irregular, etc. [00313] These and other embodiments of the present invention will readily occur to those of ordinary skill in the art in view of the disclosure herein. [00314] A wide variety of materials can be used for preparing the dosage form according to this invention. This invention therefore contemplates the use of materials other than those specifically disclosed herein, including those which may hereafter become known to the art to be capable of performing the necessary functions. Parenteral Formulations [00315] The preparation of parenteral pharmaceutical composition is well known in the art —see Niazi, S. Handbook of Pharmaceutical Manufacturing Formulations: Sterile Products, (Volume 6), CRC Press, 2004; Remington: The Science of Pharmacy Practice, 2 1st Edition, 2006, Lippincott, Williams & Wilkins, Baltimore, MD; Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate Drug Selection to Commercial Dosage Form. Gibson, M (ed). CRC Press, 2001; Pharmaceutical Dosage Forms: Parenteral Medications, Volume I. Avis KE, Lieberman HA, and Lachman L (eds), Marcel Dekker; 2nd revised and expanded edition (1992); Pharmaceutical Dosage Forms Parenteral Medications, Lieberman HA, Marcel Dekker Inc (1992); Development of Biopharmaceutical Parenteral Dosage Forms, Bontempo CJ, Informa Healthcare (1997) (all of which are hereby incorporated by reference). [00316] Liquid carriers and excipients are known in the art. .See, e.g., Remington's. Suitable liquid carriers and excipients include, but are not limited to, water, saline, ethanol, benzyl alcohol, etc., and mixtures thereof. [00317] In one embodiment, a preferred carrier is water, in particular water for injection (WFI). [00318] The pharmaceutical composition may contain a buffer. The term "buffer" refers to a pharmaceutically acceptable excipient that helps to maintain the pH of the solution within a particular range specific to the buffering system. The buffer is present for example at a concentration in the range from about 0.03% to about 5.0% w/v, or about 0.1% to about 2.0% w/v. Non-limiting illustrative examples of pharmaceutically acceptable buffering agents include phosphates, 2-amino-2-(hydroxymethyl)- 1,3-propanediol ("tris"), ascorbate, acetates, citrates, tartrates, lactates, succinates, amino acids and maleates and the like. Buffers are known in the art. See, e.g., Remington's. [00319] The pH of a liquid formulation of the present invention in preferred embodiments is generally from about 5 to about 9, preferably from about 6 to about 8. In other embodiments, the pH of the liquid formulation is about 5, 6, 7, 8, or 9. Alternatively, the pH of the liquid formulation is about 7.5. Alternatively, the pH of the liquid formulation may be selected from the following ranges: 6.0 to 6.9; 6.5 to 6.9; 7 to 7.5; 7.6 to 8.0; 7.6 to 8.5; and 7.6 to 9.0. [00320] The concentration and dosage of the antiepileptic compound and alkylxanthine bronchodilator .in the liquid parenteral formulation can vary as needed. For example, the antiepileptic compound and alkylxanthine bronchodilator can be in an amount of about from about 0.000001 to about 1000 mg/mL, alternatively from about 0.001 mg/mL to about 200 mg/mL, based for example on the mass of the antiepileptic compound and alkylxanthine bronchodilator, its solubility, the route of administration, the choice of dose, patient characteristics and the purpose of drug administration. Furthermore, the liquid formulation may be packaged in any suitable container, for example, a vial, ampoule, bag, bottle, prefilled syringe, and the like. Preferably, the liquid formulation comprises a physiologically compatible fluid, such as sterile, buffered saline. [00321] The liquid carrier used in preferred embodiments is preferably injection-quality water, by itself or preferably with the addition of conventional, physiologically tolerated solvents and/or solύbilizing agents, e.g., propylene glycol, polyols such as glycerol, polyoxyalkylenes, e.g., poly(oxyethylene)-poly(oxypropylene) polymers, glycerol-formal, benzyl alcohol, or butanediol. The addition of solubilizing agents produces a composition which is stable at low temperatures and minimizes or prevents partial crystallization of the antiepileptic compound and alkylxanthine bronchodilator, in spite of the high concentration of drug that maybe present. [00322] In each of the embodiments described herein, the liquid pharmaceutical formulation may be characterized in terms of its osmolarity. hi certain preferred embodiments, the osmolarity of the pharmaceutical formulation is from about 50 to about 1000 mOsm/L, preferably about 100 to about 500 mOsm/L. In other embodiments, the pharmaceutical compositions of the present invention are prepared such that the osmolarity is about 200 to about 300 mOsm/L, about 250 to about 350 mOsm/L, about 270 to about 330 mOsm/L, about 270 to about 290 mOsm/L, or about 280 to about 300 mOsm/L, or is 270, 280, 290, 300, or 310 mOsm/L. Alternative preferred embodiments include compositions which have a lower osmolarity than physiological osmolarity. [00323] For therapeutic use, the injection preparations according to the invention can be sterilized by conventional methods or filled under sterile conditions. [00324] The concentration of the antiepileptic compound and alkylxanthine bronchodilator in the liquid pharmaceutical composition can vary and may depend on the intended use. In certain preferred embodiments, the injection solutions according to the -invention contain from about 0.0001 to about 90% of the antiepileptic compound and alkylxanthine bronchodilator. [00325] According to the invention, liquid formulations of invention may employ one or more stabilizing agents. A stabilizing agent may slow, delay, reduce, or prevent the precipitation of one or more analgesics. It will be understood that the effectiveness of such means for stabilizing the analgesic salt, illustrative examples of which are individually described in further detail below, depend on, inter alia, composition of the particular solvent liquid, selection and amount of analgesic salt, and desired final presentation of the composition. [00326] One class of suitable salt stabilizing means, particularly for a PEG- containing composition of the invention, is a means for limiting effective exposure of the composition to oxygen. The term "limiting effective exposure of the composition to oxygen" includes placing the composition in contact with an oxygen-limited microatmosphere and/or including in the composition one or more excipients or agents that mitigate potential deleterious effects of oxygen. Limiting the effective exposure of the composition to oxygen can be accomplished by one or more of the illustrative, nonlimiting means described more fully immediately below. [00327] One means for limiting effective exposure of the composition to oxygen is to place the composition in contact with an oxygen-limited microatmosphere in a sealed container. Such a container can have a substantial internal headspace occupied by a microatmosphere having low oxygen pressure. Alternatively, the container can have very little or no headspace, in which case effective exposure of the composition to oxygen is limited largely by the barrier effect provided by the sealed container itself Any suitable pharmaceutical container can be used to prepare an article of manufacture according to this embodiment. The container can be a multi-dose container, enclosing an amount of the composition preferably corresponding to 2 to about 30, for example about 4 to about 20, unit doses. Alternatively, the container encloses an amount of the composition corresponding to a single un it dose. Such a single-dose article of manufacture has the further advantage of eliminating a measuring step before administration of the composition. Since compositions of the invention are desirable for parenteral administration, the container preferably is sufficient to maintain sterility of a composition contained therein. The container can also be used to facilitate direct administration (without need for transfer to another vessel or container) of a composition of the invention, e.g., a syringe. Non-limiting examples of suitable containers for an article of manufacture of this invention include vials of any shape and/or size, ampoules, syringes, packets, pouches, auto-injectors, etc. In one embodiment, the container further comprises means to protect the composition from exposure to light, e.g., amber glass walls. [00328] A composition of the invention can be sealed in a container in any suitable manner including but not limited to frictionally- and/or hermetically- induced seals. Such a seal can illustratively be provided by a stopper made of rubber or other polymeric material. A preferred seal comprises an inert coating, for example a coating of a fluoropolymer such as polytetrafluoroethylene, e.g., Teflon®, to prevent chemical interaction between the composition and the seal. The seal can illustratively be secured by a metal over-cap and/or an external cover, e.g., plastic, until use. Optionally, the seal can comprise at least one septum or thinner area of sealing material through which a needle can be inserted to extract the composition without cracking or breaking any glass or plastic portion of container wall. Regardless of what form of seal is used, such a seal should substantially inhibit movement of gas into or out of the container until the seal is penetrated for use of the composition present in the container. [00329] Even where the composition is enclosed in a sealed container with an oxygen limited micro atmosphere, effective exposure of the composition to oxygen can be further limited by one or more of the following means: 1) a container size and/or shape that substantially maximizes fill volume and/or substantially minimizes headspace volume; 2) low oxygen pressure in the headspace; 3) use in the solvent liquid of water which has been purged of molecular oxygen; and 4) use of a grade of PEG having a low peroxide content, for example not greater than about 1.5 meq/kg and preferably not greater than about 1.0 meq/kg. [00330] The term "headspace" or "headspace volume" with respect to an article of manufacture of the invention refers to any interior volume of the container that is not occupied by, but is in contact with, the composition. Generally, the headspace volume is occupied by a gaseous medium. The term "fill volume" with respect to an article of manufacture of the invention refers to any interior volume of the container that is occupied by the composition. [00331] The term "total volume" refers to the entire interior volume of the container and may also be referred to elsewhere as overflow volume; total volume generally equals the sum of the fill and headspace volumes. [00332] Yet another suitable means for limiting effective exposure of a composition, particularly a PEG-containing composition, of the invention to oxygen, and thereby providing said analgesic salt stabilizing means, comprises one or more pharmaceutically acceptable antioxidants, preferably free-radical scavenging antioxidants, as a component of the solvent liquid. Non-limiting illustrative examples of suitable antioxidants include a-tocopherol (vitamin E), ascorbic acid (vitamin C) and salts thereof including sodium ascorbate and ascorbic acid palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), cystein, cysteinate HCl, dithionite sodium, ethylenediamine tetraacetic acid, fumaric acid, gentisic acid and salts thereof, hypophosphorous acid, malic acid, methionine, monothioglycerol, N-acetyl- cysteine, alkyl gallates, for example propyl gallate, octyl gallate and lauryl gallate, sodium sulfite, sodium bisulfite, sodium and potassium metabisulfite, thioglycolate sodium, ethanolamine, glutamate monosodium, formaldehyde, sulfoxylate sodium and monothioglycerol. Preferred free radical-scavenging antioxidants are alkyl gallates, vitamin E, BHA, BHT, ascorbate and methionine, more especially BHA, ascorbate and methionine. Preferably, an antioxidant is selected that is substantially soluble in the particular solvent liquid employed and does not result in changes to the composition which are detectable by unaided sensory organs (e.g., color or odor changes). BHA is an illustrative preferred antioxidant for use in a composition of the invention. If included, one or more antioxidants are preferably present in a composition of the invention in a total antioxidant amount of about 0.001% to about 5%, preferably about 0.001% to about 2.5%, and still more preferably about 0.001% to about 1%, by weight [00333] When freeze dried, the formulations may optionally contain a bulking agent. The term "bulking agent" refers to a pharmaceutically acceptable excipient that adds bulk to a formulation which results in a well-formed cake upon freeze drying. The bulking agent is for example present in a formulation at a concentration in the range from about 1% to about 60% w/v, or about 3% to about 50% w/v. Nonlimiting examples of suitable bulking agents include mannitol, glycine, lactose, sucrose, trehalose, dextran, hydroxyethyl starch, ficoll and gelatin. [00334] The solid composition also may include a tonicity agent. Suitable tonicity agents include, but are not limited to, glycerin, lactose, mannitol, dextrose, sodium chloride, sodium sulfate, and sorbitol. [00335] Non-limiting examples of suitable nonaqueous solubilizers that can be present in the solvent liquid include polyethylene glycol (PEG), ethanol, dimethylacetamide (DMAC), propylene glycol, and mixtures thereof. It is preferred that the solvent liquid comprise at least one of PEG, DMAC, and ethanol. [00336] Yet another means for stabilizing the formulation in a PEG-containing composition is a metal sequestering agent or chelating agent. Non-limiting examples of suitable sequestering agents include ethylenediamine tetraacetic acid (EDTA), potassium polyphosphate, sodium polyphosphate, potassium metaphosphate, sodium metaphosphate, dimethylglyoxirne, 8- hydroxyquinoline, nitrilotriacetic acid, dihydroxyethylglycine, gluconic acid, citric acid and tartaric acid. [00337] The composition of the present invention can optionally contain a surfactant. Non-limiting examples of suitable surfactants include cetrimide, docusate sodium, glyceryl monooleate, sodium lauryl sulfate, or sorbitan esters. The surfactant may optionally b e a polyoxyethylenesorbitan fatty acid ester. Polyoxyethylenesorbitan fatty acid esters are also referred to as polysorbates, e.g., polysorbate 80 (polyoxyethylene sorbitan monooleate, Tween 80), polysorbate 40 and polysorbate 20. [00338] The composition of the present invention can optionally b e manufactured in glass-lined or a "greater than or equal to 316 temper-grade" steel tank. [00339] Oxygen pressure in a container headspace of an article of manufacture of the invention can b e limited in any suitable manner, illustratively by placing nitrogen and/or a noble gas (collectively referred to herein as "inert gases") in the container headspace. In this embodiment, the headspace volume preferably comprises one or more inert gases selected from the group consisting of nitrogen, helium, neon and argon. One way to ensure low oxygen pressure in the headspace is to prepare, fill and seal the container under an atmosphere of inert gas and/or to flush the container headspace with inert gas after filling, illustratively using parallel in-line flushing. An inert gas atmosphere can illustratively be provided using a zero oxygen tunnel commercially available from Modified Atmosphere Packaging Systems of Des

Plaines, 111., or by using a nitrogen or noble gas atmosphere glove bag. [00340] Various polymorphs of this invention may b e prepared b y crystallization under different conditions. For example, using different solvents commonly used or their mixtures for recrystallization; crystallizations at different temperatures; various modes of cooling, ranging from very fast to very slow cooling during crystallizations. Polymorphs may also be obtained by heating or melting the compound followed b y gradual or slow cooling. The presence of polymorphs may be determined b y solid probe NMR spectroscopy, IR spectroscopy, differential scanning calorimetry, powder X - ray data or such other techniques. [00341] Pharmaceutically acceptable solvates of the invention may b e prepared by conventional methods such as dissolving the compounds in solvents such as water, methanol, ethanol etc., and recrystallizing by using different crystallization techniques. [00342] In an additional embodiment, the composition of the present invention comprises: (i) the antiepileptic compound and alkylxanthine bronchodilator ; (ii) sterile water; (iii) optionally one or more pharmaceutically acceptable buffers; (iv) optionally one or more pharmaceutically acceptable antioxidants; (v) optionally one or more pharmaceutically acceptable tonicity adjusters; (vi) optionally one or more pharmaceutically acceptable solubility enhancers; and (vi) optionally one or more pharmaceutically acceptable preservatives; and wherein: (a) the pH is preferably from about 6.5 to about 8.5, more preferably from about 7.0 to about 8.0; and/or (b) the concentration of said antiepileptic compound and alkylxanthine bronchodilator is about 0.00001 mg/mL to about 1000 mg/mL, preferably about 0.001, 0.01, 0.1, 1, 5, 10, 20, 25, 40, 50, 60, 75, 100, 200, 300 or 400 mg/mL; and/or (c) the composition shows no substantial visible signs of crystallization and/or significant deviation, e.g., less than or equal to 10% of original value, in pH and/or osmolality, and/or contains 100% ± 10% original content of the antiepileptic compound and alkylxanthine bronchodilator. [00343] In some preferred embodiments, the composition is contained in a sealed glass vial or a prefϊlled syringe. [00344] Additionally, the present invention is directed to sealed syringe comprising a sterile solution comprising one of more antiepileptic compounds and alkylxanthine bronchodilators pharmaceutically acceptable salts thereof, and mixtures thereof. [00345] In some embodiments, the osmolality of the solution in the sealed syringe may be from about 200 to about 400, preferably from about 280 to about 300 mOsm/L. [00346] The precise procedure and process form manufacture, including the order of mixing and choice and quantity of pharmaceutical excipients, adjuvants, auxiliary agents and enabling agents (e.g., buffers, stabilizing agents, tonicity agents, antioxidants, preservatives, solubilizing agents, stabilizing agents, diluents or bulking agent) will vary depending on the dose, route of administration and choice of the antiepileptic compound and alkylxahthine bronchodilator [00347] To practice the invention, it is not necessary to incorporate the antiepileptic compound and alkylxanthine bronchodilator within a single container. In some embodiments, preferably the antiepileptic compound and alkylxanthine bronchodilator are in the form of a solid, semisolid, suspension emulsion or solution within a single container (e.g., ampoule, vial, prefilled- syringe, or minibag). In some embodiments, the one or more of the a antiepileptic compound and alkylxanthine bronchodilator of the invention may be in separate containers. This may be preferred in some embodiments when there is physical or chemical incompatibility with between the antiepileptic compound and alkylxanthine bronchodilator. hi some embodiments, the antiepileptic compound and alkylxanthine bronchodilator are mixed just prior to parenteral administration. In some embodiments, the antiepileptic compound and alkylxanthine bronchodilator may be in separate containers. To practice the invention, it is not necessary to administer the antiepileptic compound and alkylxanthine bronchodilator at the same time. In some embodiments, the antiepileptic compound and alkylxanthine bronchodilator may be administered separately (e.g., sequentially, consecutively, contemporaneously or temporally related, e.g., seconds, minutes or hours apart). Product for Application to the Skin [00348] Pharmaceutical composition and methods of the present invention antiepileptic compound and alkylxanthine bronchodilator, pharmaceutically acceptable salts or mixtures thereof and they are intended for application to the skin. All pharmaceutical compositions and dosage forms for application to the skin are contemplated by the invention, including topical patch, transdermal patch, plaster, pastes, gel, liposomes, a liquid, semisolid, solution, suspension, lotion, cream, ointment, foam, sprayable aerosol, and sprayable non-aerosol. Methods for the preparation of dosage forms for application to the skin, including those in the form of topical patch, transdermal patch, plaster, pastes, gel, liposomes, a liquid, semisolid, solution, suspension, lotion, cream, ointment, foam, sprayable aerosol, sprayable non-aerosol are disclosed in patents and in the art [e.g., Williams AC. Transdermal and Topical Drug Delivery, Pharmaceutical Press, London, 2003; Remington: The Science and Practice of Pharmacy,21 st Edition, Lippincott Williams & Wilkins, Baltimore, 2005; Walters KA. Dermatological and Transdermal Formulations, Informa Healthcare, I Edition, 2002; Transdermal Drug Delivery, Hadgraft J (ed), 2nd Edition, 2002; Transdermal and Topical Drug Delivery Systems, Ghosh TK, Pfister W & Yum SI (eds), CRC, 1997; Transdermal Controlled Systemic Medications; Chien YW (ed), Marcel Dekker, 1987; Topical Drug Delivery Formulations, Osbome DW and Amann AH (eds), Informa Healthcare, 1989; Topical Drug Bioavailability, Bioequivalence, and Penetration, Shah VP and Maibach HI (eds), Springer, 1993; Jaroszeski MJ. Electrochemotherapy, Electrogenetherapy, and Transdermal Drug Delivery: Electrically Mediated Delivery of Molecules to Cells. Humana Press, 1st edition 2000; Wille JJ. Skin Delivery Systems: Transdermals, Dermatologicals, and Cosmetic Actives. Blackwell Publishing, 1st edition, 2006; Gurny R and Teubner A (Eds). Dermal and Transdermal Drug Delivery: New Insights and Perspectives. CRC Press, 1993], hereby incorporated by reference in their entirety and U.S. Pat. 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[00349] These and other embodiments of the present invention will readily occur to those of ordinary skill in the art in view of the disclosure herein. DETERMINATION OF ANALGESIC ACTIVITY [00350] The analgesic effects of the compositions of the present invention can be evaluated in one or more of the tests described below: Rat TaU Flick Test [00351] The tail flick test was first described by D'Amour and Smith (1941), and remains essentially unchanged in application. (See generally D'Amour, F.E. and Smith, D.L., "A method for determining loss of pain sensation", J. Pharmacol. Exp. Therap., 72:74-79(1941); Dewey, D.L. and Harris, L.S., The Tail-flick test. In: S. Ehrenpreis and A. Neidle (Eds.), Methods in Narcotic Research, Marcel Dekker, Inc., New York, 1975, pp. 101-109; and Dubner, R. and Ren, K., "Assessing transient and persistent pain in animals." In: P.D. Wall and R. Melzack (Eds.), Textbook of Pain, Churchill Livingstone, London, 1999, pp. 359-369). Quite simply, the tail of a rat or mouse is exposed to radiant heat, and the latency to withdraw is determined. The basal heat intensity is set so that naϊve rats withdraw their tails within 2 to 3 sec. A cut-off latency of 10 sec (i.e., 3 to 4 times basal control value) is commonly employed to prevent tissue damage. An alternative to using radiant heat is to dip the tail into a water bath maintained at a fixed temperature, usually in the moderately noxious range of about 52°C or 55°C. One advantage of a water bath is that the temperature is kept constant. [00352] The tail-flick test is considered to be very robust in that weak analgesic agents are not detected by this test. In contrast, it is considered highly selective. There is a high degree of correlation between drugs that are identified as antinociceptive in the tail-flick test and clinically active analgesic agents. It is especially predictive of rank-order of potency of opioid-type analgesic agents, and the clinically effective dose of a novel opioid may be predicted by the relative potency of the drug to a known substance, such as morphine, based on this assay. Importantly, agents that are sedating and may produce a positive response in the writhing test or hot plate test do not show antinociceptive activity in the tail-flick test. It is even possible to perform the tail-flick test in lightly anesthetized animals. [00353] Data obtained from the rat tail-flick test conform to a graded dose- response curve. The raw tail withdrawal latencies are converted to a %MPE (% maximal possible effect) by the formula: [00354] % MPE = 100 x (test latency - basal latency)/(cut-off - basal latency). [00355] This formula constrains the data to fit between 0% MPE and 100 % MPE. This allows the generation of dose-response curves and the calculation

of ED50 values (50% effective doses) with attendant confidence intervals. These calculations then allow for the determination of relative potencies of different drugs and allow for the isobolographic determination of possible synergistic effects. Instances where the test latency is less than the basal latency produces a negative % MPE, which is meaningless unless one is measuring hyperalgesia. By convention, these values are set to 0% MPE when the expected drug effect is antinociception or no activity. Kim and Chung Model [00356] Dose-response curve against tactile hyperesthesia and thermal hyperalgesia caused by peripheral nerve injury are generated. The peripheral nerve injury is established by tight ligation of the L5 and L6 spinal nerves, according to the techniques established by Chung and colleagues (Kim and Chung Pain, 1992: 50, 355-363.). Spinal nerve- ligation (SNL) reliably produces tactile hyperesthesia and thermal hyperalgesia in rats. Tactile hyperesthesia is widely accepted as a model of allodynia to light touch often reported by patients with nerve injury. Thermal hyperalgesia represents a model of enhanced sensitivity to pain. The standard protocol for the evaluation of tactile hyperesthesia is to determine the paw withdrawal threshold of the hindpaw of the rats in response to probing with von Frey filaments. Thermal hyperalgesia is indicated by a significant reduction in paw withdrawal latency to noxious radiant heat projected onto the plantar aspect of the hindpaw of the rat. Tests are conducted with systemic (SC) and intrathecal (IT) administration. In order to properly conduct this study, sham-operated animals are also required. Since sham-operated rats do not develop tactile hyperesthesia, only responses to thermal stimuli are tested. Testing of sham- operated rats requires an additional 48 animals. Approximately 26 rats are be used for initial dose-finding experiments. Animals are tested within 7 to 10 days of SNL. Surgery and testing may be staggered to optimize testing efficiency. The intrathecal drug administration studies require implantation of catheters 7 days prior to the SNL surgery, and testing at 10 days after SNL surgery. Rat TaU Flick Test [00357] The tail flick test was first described by D'Amour and Smith (1941), and remains essentially unchanged in application. (See generally D'Amour, F.E. and Smith, D.L., "A method for determining loss of pain sensation", J. Pharmacol Exp. Therap., 72:74-79(1941); Dewey, DX. and Harris, L.S., The Tail-flick test. In: S. Ehrenpreis and A. Neidle (Eds.), Methods in Narcotic Research, Marcel Dekker, Inc., New York, 1975, pp. 101-109; and Dubner, R. and Ren, K., "Assessing! transient and persistent pain in animals." In: P.D. Wall and R. Melzack (Eds.), Textbook of Pain, Churchill Livingstone, London, 1999, pp. 359-369). Quite simply, the tail of a rat or mouse is exposed to radiant heat, and the latency to withdraw is determined. The basal heat intensity is set so that naϊve rats withdraw their tails within 2 to 3 sec. A cut-off latency of 10 sec (i.e., 3 to 4 times basal control value) is commonly employed to prevent tissue damage. An alternative to using radiant heat is to dip the tail into a water bath maintained at a fixed temperature, usually in the moderately noxious range of about 52°C or 55°C. One advantage of a water bath is that the temperature is kept constant. [00358] The tail-flick test is considered to be very robust in that weak analgesic agents are not detected by this test. In contrast, it is considered highly selective. There is a high degree of correlation between drugs that are identified as antinociceptive in the tail-flick test and clinically active analgesic agents. .It is especially predictive of rank-order of potency of opioid-type analgesic agents, and the clinically effective dose of a novel opioid may be predicted by the relative potency of the drug to a known substance, such as morphine, based on this assay. Importantly, agents that are sedating and may produce a positive response in the writhing test or hot plate test do not show antinociceptive activity in the tail-flick test. It is even possible to perform the tail-flick test in lightly anesthetized animals. [00359] Data obtained from the rat tail-flick test conform to a graded dose- response curve. The raw tail withdrawal latencies are converted to a %MPE (% maximal possible effect) by the formula: [00360] % MPE = 100 x (test latency - basal latency)/(cut-off - basal latency). [00361] This formula constrains the data to fit between 0% MPE and 100 % MPE. This allows the generation of dose-response curves and the calculation of ED50 values (50% effective doses) with attendant confidence intervals. These calculations then allow for the determination of relative potencies of different drugs and allow for the isobolographic determination of possible synergistic effects. Instances where the test latency is less than the basal latency produces a negative % MPE, which is meaningless unless one is measuring hyperalgesia. By convention, these values are set to 0 % MPE when the expected drug effect is antinociception or no activity. Carrageenan-Induced Inflamed Paw Model [00362] Models of inflammation that produce more persistent pain include the injection of carrageenan into the footpad of the limb; the potential analgesic and/or anti-inflammatory properties of putative analgesics substances can be evaluated in this model. See generally Bhalla T.N. & Tangri, K.K. "The time course of the carrageenan-induced oedema of the paw of the rat." J. Pharm. Pharmacol. 22:721 (1970); Randall, L.O. & Selitto, JJ., "A method for measurement of analgesic activity on inflamed tissue," Arch. Int. Pharmacodyn. Ther. 777:409-419 (1957); Hargreaves, K., et al. "A new and sensitive method for measuring thermal nociception in cutaneous hyperalgesia." Pain 32:77-88 (1988). [00363] Typically, rats are handled and acclimatized to the behavioral testing equipment over a minimum of 2 days prior to testing. Behavioral tests are performed on all rats on the day prior to dosing to establish baseline values, and the animals are randomized into treatment groups based on these pre-dose responses. An assessment of the inflammatory agent (carrageenan) is performed prior to the main study, using the chosen behavioral tests. On the day of dosing, an inflammatory response is induced in the left hind paw of each rat by an intraplantar injection (approx. 0.05 mL) of carrageenan (0.6% w/v), under brief anesthesia. The test substance, reference substance, or vehicle is generally administered 30 minutes prior to carrageenan administration for oral dosing. [00364J The following tests may be performed. A minimum period of 5 minutes is allowed between each type of test (or repeat challenges to the same paw) to reduce the risk of sensitization. [00365] Paw Volume: Each animal is gently restrained, their hind limb extended, and the paw placed in the pre-filled chamber of a Digital Plethysmometer. The paw volume is then calculated based on the volume of liquid displaced in the chamber, for both the ipsilateral and contralateral hind paws. [00366] Mechanical hyperalgesia test: Each rat is gently restrained, their hind limb extended, and the paw placed lightly on the Randall-Selitto device. A progressively increasing pressure is then applied to the dorsal surface of the paw via a blunt peg attached to a weight level, and the withdrawal threshold calculated for both the ipsilateral and contralateral hind paws. The maximum pressure applied is about 250 g. The withdrawal threshold is defined as the minimum force (in grams) required to elicit a reflex withdrawal response. Typical end points are a struggle response, paw withdrawal or a squeak response. [00367] Thermal hyperalgesia test: Rats are placed in clear plastic chambers with a glass floor and allowed a short period to acclimatize to their environment prior to testing (approximately 2-5 minutes). The animals are then challenged with a radiant infrared heat source, directed at the plantar surface of their hind paw from below, and the withdrawal latency calculated for both the ipsilateral and contralateral hind paw [00368] Standard statistical methods are employed to evaluate test substance related effects. Data are analyzed for homogeneity and either parametric or non-parametric methods applied. Third Molar Extraction Model [00369] Male and female patients with acute postsurgical pain following the removal of one or more bony impacted third molars are participants. Within 4 to 6 hours after completion of surgery, patients who are experiencing moderate or severe pain, as measured by a visual analog pain intensity scale (VAS > 50 mm) and by a categorical pain intensity scale (moderate or severe pain descriptor), and who meet all other inclusion/exclusion criteria are admitted to the study. Patients are randomly assigned to receive drug or placebo. Pain intensity (VAS and categorical), pain relief (categorical) and whether pain is half-gone is recorded by the patient under the supervision of the investigator or study coordinator at the various time points: Baseline (0 hour —pain intensity only), 15, 30 and 45 minutes, and at 1, 1.5, 2, 3, 4, 5, 6, 7, 8 and 12 hours after administration of study medication, and immediately prior to the first rescue dose. Time to onset of perceptible and meaningful pain relief is evaluated using the two stopwatch method. Patients record their global evaluation of study medication at the completion of the 8-hour assessment or at the time of first rescue medication use. Efficacy endpoints include Total Pain Relief (TOTPAR), Sum of Pain Intensity Difference (SPID) and Sum of Pain Relief Intensity Difference (SPRID) at various time points, Time to First Rescue, Time Specific Pain Intensity Difference (PID), Time Specific Pain Relief (PR), Peak Pain Intensity Difference (PPID), Peak Pain Relief (PPR), Time to Confirmed Perceptible Pain Relief (stopwatch) and Time to Meaningful Pain Relief (stopwatch) and Patient Global Evaluation. Bunionectomy Surgery Model [00370] Male or female patients requiring primary unilateral first metatarsal bunionectomy surgery alone or with ipsilateral hammertoe repair (without additional collateral procedures) under regional anesthesia (Mayo block) are participants. [00371] Patients who experience moderate or severe pain on a categorical scale (moderate or severe descriptor) and on a visual analog pain intensity scale (VAS; >50 mm) within 6 hours following completion of bunionectomy W

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surgery are randomly assigned to receive study drugs or placebo. Patients are encouraged to wait at least 60 minutes before requesting remedication for pain. At the completion of the single-dose phase (8 hours) or at first request for remedication (whichever is earlier), patients enter into a multiple-dose phase lasting approximately 72 hours. During the multiple dose phase, patients receive study medication or placebo at a fixed dose interval (e.g., every 8, 12 or 24 hours). Once the multiple dose phase of the study has begun, patients experiencing pain between scheduled doses of study medication are provided access to supplemental open-label (rescue) analgesia. Patients whose pain cannot be adequately managed on a combination of study medication and rescue medication or who develop unacceptable side effects during the study are discontinued from further study participation and their pain managed conventionally. [00372] Pain intensity (VAS and categorical), pain relief (categorical) and whether pain is half-gone is recorded by the patient under the supervision of the investigator or study coordinator at representative time points, e.g., Baseline (pain intensity only), 15, 30 and 45 minutes and 1, 1.5, 2, 3, 4, 5, 6, 7 and 8 hours after administration of study medication and immediately prior to the first remedication. Time to onset of perceptible and meaningful pain relief is evaluated using the double-stopwatch method. Patients complete a global evaluation of study medication at the completion of the 8-hour assessment or just prior to the first remedication. Following completion of the single-dose phase (8 hours or just prior to first remedication, if = 8 hours), patients begin the multiple dose phase of the study. During the multiple dose phase, patients record their overall pain intensity since the previous scheduled dose, their current pain intensity and a patient global, immediately prior to each scheduled dose of study medication and at early termination. [00373] Measures of efficacy in the single-dose phase include Sum of Pain Intensity Difference (SPID), Total Pain Relief (TOTPAR), Sum of Pain Relief Intensity Difference (SPRID), Time to First Remedication, Time Specific Pain Intensity Difference (PID), Time Specific Pain Relief (PR), Peak Pain Intensity Difference (PPID), Peak Pain Relief (PPR), Time to Confirmed Perceptible Pain Relief (stopwatch) and Time to Meaningful Pain Relief (stopwatch) and Patient Global Evaluation. Measures of efficacy in the multiple-dose phase include the time specific overall pain intensity, current pain intensity and patient global at the time of scheduled remedication, the average of overall pain intensity, current pain intensity and patient global over 0-24, 24-48 and 48-72 and number of doses of rescue analgesic over 0-24, 24- 48 and 48-72 and 0-72 hours. Chronic Pain of Osteoarthritis [00374] The increased therapeutic benefits associated with the administration of a composition of the invention may, in some preferred embodiments, be demonstrated in repeated dose randomized, double-blind, controlled studies comparing subanalgesic and analgesic doses of the invention. Typically, patients who meet the American College of Rheumatology criteria for knee and/or hip OA are washed off their analgesics for 2 to 7 days to allow for pain of moderate to severe intensity to return. Once a stable baseline pain score is established, patients are randomized to treatment, usually for a period of one to 12 weeks. Pain, joint stiffness and physical function can be measured with a multidimensional instrument, such as the WOMAC, quality of life with the SF-12 or SF-36 and adverse events with a non-directed questionnaire at baseline and at post-baseline return visits. Response to pain, stiffness, physical function, quality of life and adverse events are calculated as change from baseline and compared between treatments. Sample sizes in the studies are sufficient to demonstrate the increased therapeutic benefit of the invention. Migraine [00375] The increased therapeutic benefits associated with the administration of a composition of the invention may, In some preferred embodiments, be demonstrated in patients with migraine headaches, typically in a prospective, randomized, double-blind, parallel group, single-dose, placebo-controlled, study. Crossover studies are also possible. The study population consists of male and non-pregnant female subjects, 18 to 65 years of age with a primary headache diagnosis of either migraine attack without aura or migraine attack with aura, as diagnosed according to the International Classification of Headache Disorders-2 criteria. To qualify, the subject must typically have a history, on average, of at least one migraine attack per month, but an average of no more than 6 migraine attacks each month during the past year. Using a headache diary subjects are instructed to treat and evaluate the headache pain and symptoms associated with one eligible migraine attack, with or without aura, with at least moderate headache pain intensity. Eligible subjects are randomly assigned to receive the test drug or placebo to treat one migraine attack, with or without aura, with headache pain of at least moderate pain intensity as determined by them migraine questionnaire they are asked to take a single dose of study drug, according to their randomized treatment assignment. Headache pain intensity, nausea, photophobia, phonophobia, vomiting, and ability to function are assessed at baseline, 0.25, 0.5, 0.75, 1, 1.5, 2, 2.5, 3, 4, 8, 16 and 24 hours post-dose. In addition, the recurrence of pain and use of any rescue mediation is documented. Primary efficacy variables typically consist of the percent of subjects who are without: (i) pain; (ii) nausea; (iii) photophobia and, (iv) phonophobia, each at 2 hours post- dosing. Secondary efficacy variables typically consist of headache pain intensity and associated symptoms at each evaluation time point, incidence of vomiting, patient function, sum of pain intensity difference at each evaluation time (SPID), percent of subjects who experience headache recurrence up to 24 hours, and the median time to recurrence. Recurrence is defined as the reduction in pain from moderate or severe pain to none at 2 hours after taking study drug, followed by: (i) an increase to mild, moderate or severe pain within 24 hours after taking the study drug, or (ii) consuming a rescue medication within 24 hours after taking the study drug. Postherpetic Neuralgia [00376] The analgesic efficacy of the invention may be demonstrated in repeated dose randomized double-blind, controlled studies. Patients are randomized to receive the dosage form of the invention given intact or J placebo, in some preferred embodiments, and the dosage form of the invention given intact or dosage form of the invention given in tampered form in other embodiments. Patients with a history of postherpetic neuralgia = 3 months and pain of at least moderate intensity are enrolled in the study. Patients with hypersensitivity to study medications, a history of drug or alcohol abuse and significant pain of alternate etiology are generally excluded. Patients meeting study eligibility criteria are "washed off' their analgesics in some embodiments, generally for 2 to 7 days to allow for pain of moderate to severe intensity to return. Once a stable baseline pain score is established, patients are randomized to treatment, usually for a period of 4 to 12 weeks. Pain intensity is assessed one to several times a day and in some cases only once weekly using VAS, categorical or numerical rating scales. Various dimensions of neuropathic pain may be assessed, including steady pain (ongoing pain), brief pain (paroxysmal pain) and skin pain (allodynia). Pain may also be assessed at scheduled clinic study visits. Pain may also be assessed using standardized pain scales such as the Neuropathic Pain Scale (Galer et al., Neurology 1997;48:332-8), the Neuropathic Pain Symptom Inventory (Bouhassira et al., Pain 2004; 108:248-57), interference measures of the Brief Pain Inventory (Cleeland, CRC Press, 1991:293-305 and Ann Acad Med Singapore 1994;23:129-38) or the McGiIl Pain Questionnaire Short- Form (Melzack, Pain 1987;30:191-7). Patient global assessment may be measured using a number of available tools, for example Patient Global Impression of Change (Farrar et al., Pain 2001 ;94: 149-580). Quality of life may similarly be assessed using number of available tools, for example the SF-36, SF-12 or SF-8. Examples of randomized, placebo or active studies conducted in postherpetic neuralgia are known in the art (e.g., Watson and Babul, Neurology 1998;50:1837-41; Sabatowski et al., Pain. 2004; 109:26-35; Rowbotham et al., JAMA. 1998;280: 183 7-42). Adverse events may be assessed using a non-directed questionnaire, a symptom checklist or specific queries on adverse signs and symptoms. Response to pain, function, quality of life and adverse events are calculated as change from baseline and compared between treatments. Sedation and nausea may be evaluated using VAS or categorical scales. [00377] The included examples are illustrative but not limiting of the methods and composition of the present invention. Other suitable modifications and adaptations of the variety of conditions and parameters normally encountered and obvious to those skilled in the art are within the spirit and scope of the invention. EXAMPLES EXAMPLE 1 ADMINISTRATION OF PREGABALIN AND THEOPHYLLINE [00378] To a 75-kg patient in need of analgesic treatment is administered concurrently 400 mg of pregabalin and 100 mg of theophylline as a unit dosage capsule. EXAMPLE 2 [00379] PHARMACEUTICAL CAPSULE COMPRISING GABAPENTIN AND THEOPHYLLINE [00380] To a 70-kg patient in need of analgesic treatment is administered concurrently 400 mg of gabapentin and 100 mg of theophylline as a unit dosage capsule. EXAMPLE 3 [00381] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, W

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bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 100 mg and said alkylxanthine bronchodilator is in the amount of 100 mg. EXAMPLE 4 [00382] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 200 mg and said alkylxanthine bronchodilator is in the amount of 200 mg. EXAMPLE 5 [00383] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 300 mg and said alkylxanthine bronchodilator is in the amount of 300 mg. EXAMPLE 6 [00384] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 400 mg and said alkylxanthine bronchodilator is in the amount of 400 mg. EXAMPLE 7 [00385] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 500 mg and said alkylxanthine bronchodilator is in the amount of 500 mg. EXAMPLE 8 [00386] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 600 mg and said alkylxanthine bronchodilator is in the amount of 100 mg. EXAMPLE 9 [00387] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 600 mg and said alkylxanthine bronchodilator is in the amount of 200 mg. EXAMPLE 10 [00388] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic -Ill-

compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 500 mg and said alkylxanthine bronchodilator is in the amount of 50 mg. EXAMPLE 11 [00389] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, .analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 500 mg and said alkylxanthine bronchodilator is in the amount of 100 mg. EXAMPLE 12 [00390] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 500 mg and said alkylxanthine bronchodilator is in the amount of 150 mg. EXAMPLE 13 [00391] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 500 mg and said alkylxanthine bronchodilator is in the amount of 200 mg. EXAMPLE 14 [00392] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 400 mg and said alkylxanthine bronchodilator is in the amount of 200 mg. EXAMPLE S [00393] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 400 mg and said alkylxanthine bronchodilator is in the amount of 300 mg. EXAMPLE 16 [00394] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofyllme, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 300 mg and said alkylxanthine bronchodilator is in the amount of 100 mg. EXAMPLE 17 [00395] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 200 mg and said alkylxanthine bronchodilator is in the amount of 100 mg. EXAMPLE 18 [00396] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 200 mg and said alkylxanthine bronchodilator is in the amount of 50 mg. EXAMPLE 19 [00397] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 200 mg and said alkylxanthine bronchodilator is in the amount of 400 mg. EXAMPLE 20 [00398] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 100 mg and said alkylxanthine bronchodilator is in the amount of 400 mg. EXAMPLE 21 [00399] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 100 mg and said alkylxanthine bronchodilator is in the amount of 500 mg. EXAMPLE 22 [00400J Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 100 mg and said alkylxanthine bronchodilator is in the amount of 600 mg. EXAMPLE 23 [00401] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 200 mg and said alkylxanthine bronchodilator is in the amount of 600 mg. EXAMPLE 24 [00402] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 100 mg and said alkylxanthine bronchodilator is in the amount of 800 mg. EXAMPLE 25 [00403] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate. vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 300 mg and said alkylxanthine bronchodilator is in the amount of 400 mg. EXAMPLE 26 [00404] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 250 mg and said alkylxanthine bronchodilator is in the amount of 250 mg. EXAMPLE 27 [00405] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 200 mg and said alkylxanthine bronchodilator is in the amount of 50 mg. EXAMPLE 28 W

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[00406] Tablet or capsule formulations for oral administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 300 mg and said alkylxanthine bronchodilator is in the amount of 50 mg. EXAMPLE 29 [00407] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 200 mg and said alkylxanthine bronchodilator is in the amount of 200 mg. EXAMPLE 30 [00408] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 300 mg and said alkylxanthine bronchodilator is in the amount of 300 mg. EXAMPLE 31 [00409] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 400 mg and said alkylxanthine bronchodilator is in the amount of 400 mg. EXAMPLE 32 [00410] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 500 mg and said alkylxanthine bronchodilator is in the amount of 500 mg. EXAMPLE 33 [00411] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 600 mg and said alkylxanthine bronchodilator is in the amount of 100 mg. EXAMPLE 34 [00412] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 600 mg and said alkylxanthine bronchodilator is in the amount of 200 mg. EXAMPLE 35 [00413] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 500 mg and said alkylxanthine bronchodilator is in the amount of 50 mg. EXAMPLE 36 [00414] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 500 mg and said alkylxanthine bronchodilator is in the amount of 100 mg. EXAMPLE 37 [00415] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 500 mg and said alkylxanthine bronchodilator is in the amount of 150 mg. EXAMPLE 38 [00416] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 500 mg and said alkylxanthine bronchodilator is in the amount of 200 mg. EXAMPLE 39 [00417] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 400 mg and said alkylxanthine bronchodilator is in the amount of 200 mg. EXAMPLE 40 [00418] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 400 mg and said alkylxanthine bronchodilator is in the amount of 300 mg. EXAMPLE 41 [00419] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 300 mg and said alkylxanthine bronchodilator is in the amount of 100 mg. EXAMPLE 42 [00420] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 200 mg and said alkylxanthine bronchodilator is in the amount of 100 mg. EXAMPLE 43 [00421] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, dσxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 200 mg and said alkylxanthine bronchodilator is in the amount of 50 mg. EXAMPLE 44 [00422] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 200 mg and said alkylxanthine bronchodilator is in the amount of 400 mg. EXAMPLE 45 [00423] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at- least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 100 mg and said alkylxanthine bronchodilator is in the amount of 400 mg. EXAMPLE 46 [00424] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 100 mg and said alkylxanthine bronchodilator is in the amount of 500 mg. EXAMPLE 47 [00425] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 100 mg and said alkylxanthine bronchodilator is in the amount of 600 mg. EXAMPLE 48 [00426] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or i enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 200 mg and said alkylxanthine bronchodilator is in the amount of 600 mg. EXAMPLE 49 [00427] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 100 mg and said alkylxanthine bronchodilator is in the amount of 800 mg. EXAMPLE 50 [00428] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate,

vigabatrin, . valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 300 mg and said alkylxanthine bronchodilator is in the amount of 400 mg. EXAMPLE 51 [00429] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 250 mg and said alkylxanthine bronchodilator is in the amount of 250 mg. EXAMPLE 52 [00430] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 200 mg and said alkylxanthine bronchodilator is in the amount of 50 mg. EXAMPLE 53 [00431] Parenteral formulations for intravenous administration can be prepared in accordance with the present invention containing at least one antiepileptic compound selected from the group comprising gabapentin, lacosamide, lamotrigine, levetiracetam, oxcarbazepine, pregabalin, tiagabine, topiramate, vigabatrin, valproate, and zonisamide, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof and at least one alkylxanthine bronchodilator selected from the group comprising theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, as well as their pharmaceutically acceptable salts, prodrugs, esters, analogs, derivatives, solvates, complexes, polymorphs, hydrates and metabolites, as racemates or an individual diastereoisomers or enantiomeric isomers thereof or mixture thereof; wherein said antiepileptic compound is in the amount of 300 mg and said alkylxanthine bronchodilator is in the amount of 50 mg. Having now fully described the invention, it will be understood to those of ordinary skill in the art that the same can be performed within a wide and equivalent range of conditions, formulations, and other parameters without affecting the scope of the invention or any embodiment thereof. All patents and publications cited herein are fully incorporated by reference herein in their entirety. WHAT IS CLAIMED IS:

1. A method of treating or preventing pain comprising administering to a subject in need of pain treatment or pain prevention (a) one or more of (i) an antiepileptic compound, wherein said antiepileptic compound is selected from the group consisting of gabapentin, pregabalin, lacosamide, lamotrigine, carbamazepine, oxcarbazepine, valproic acid, tiagabine, topiramate, phenytoin, divalproex, and levetiracetam; (ii) a compound of Formula I

wherein Ri is hydrogen or a lower alkyl, n is an integer of from 4 to 6, and the cyclic ring is optionally substituted; a pharmaceutically acceptable salt thereof, or an individual diastereoisomer or enantiomeric isomer thereof; and (iii) a compound of Formula II

H2NCH C CH2COOH

wherein R.2 is a straight or branched alkyl of from 1 to 6 carbon atoms,

phenyl, or cycloalkyl having from 3 to 6 carbon atoms, R3 is hydrogen

or methyl, and R4 is hydrogen, methyl, or carboxyl; an individual diastereomeric or enantiomeric isomer thereof; or a pharmaceutically acceptable salt thereof; and (b) one or more alkylxanthine bronchodilators. 2. The method of claim 1, wherein the compound of Formula I is selected from the group consisting of l-(aminomethyl)cyclohexane acetic acid, ethyl 1-aminomethyl-l-cyclohexaneacetate, 1-aminomethyl-l cycloheptane-acetic acid, 1-aminomethyl-l -cyclopentane-acetic acid, methyl- 1-aminomelhyl-l-cyclohexane- acetate, n-butyl 1-aminomethyl- 1-cyclohexane-acetate, methyl 1-aminomethyl-l-cycloheptane-acetate, n-butyl 1-aminomethyl-l-cycloheptane-acetate, toluene sulfonate, 1- aminomethyl-1-cyclopentane-acetate, benzene-sulfonate, n-butyl 1- aminomethyl- 1-cyclopentane-acetate, 1-aminomethyl-3- methylcyclohexyl acetic acid, l-aminomethyl-3 -methyl cyclopentyl acetic acid, and l-aminomethyl-3,4-dimethylcyclopentyl)acetic acid.

3. The method of claim 1, wherein said compound of Formula II is selected from the group consisting of 3-aminomethyl-5-methyl-hexanoic acid, (S)- 3-(aminomethyl)-5-methylhexanoic acid, and 3 (l-aminoethyl)-5- methylhexanoic acid.

4. The method of claim 1, wherein said antiepileptic compound is administered concurrently with said alkylxanthine bronchodilator.

5. The method of claim 1, wherein said enhanced effect is a faster onset of action.

6. The method of claim 1, wherein said enhanced effect is an increased duration of action.

7. The method of claim 1, wherein said enhanced effect is a reduction of one or more side effects of said analgesic.

8. The method of claim 1, wherein said effect is an increased maximal analgesic effect of said antiepileptic compound. 9. The method of claim 1, wherein said antiepileptic compound is administered in a subanalgesic amount.

10. The method of claim 1, wherein said alkylxanthine bronchodilator is administered in a subanalgesic amount.

11. The method of claim 1, wherein said alkylxanthine bronchodilator is administered in an amount sufficient to reduce analgesic tolerance.

12. The method of claim 1, wherein said antiepileptic compound is selected from the group consisting of gabapentin, pregabalin, lacosamide, lamotrigine, carbamazepine, oxcarbazepine, valproic acid, tiagabine, topiramate, phenytoin, divalproex or levetiracetam.

13. The method of claim 1, wherein said antiepileptic compound is gabapentin.

14. The method of claim 1, wherein said antiepileptic compound is pregabalin.

15. The method of claim 1, wherein said antiepileptic compound is lamotrigine.

16. The method of claim I 5 wherein said antiepileptic compound is oxcarbazepine.

17. The method of claim 1, wherein said antiepileptic compound is valproic acid.

18. The method of claim 1, wherein said antiepileptic compound is topiramate. 19. The method of claim 1, wherein said antiepileptic compound is carbamazepine.

20. The method of claim 1, wherein said antiepileptic compound is lamotrigine.

21. The method of claim 1, wherein said antiepileptic compound is divalproex.

22. The method of claim 1, wherein said antiepileptic compound is tiagibine.

23. The method of claim 1, wherein said alkylxanthine bronchodilator is selected from the group consisting of theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline, etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, their pharmaceutically acceptable salts, solvates, polymorphs, hydrates, in racemic or enantiomeric form, or mixture thereof.

24. The method of claim 23, wherein said alkylxanthine bronchodilator is selected from the group consisting of theophylline, theobromine or dyphylline.

25. The method of claim 24, wherein said alkylxanthine bronchodilator is theophylline.

26. The method of claim 1, wherein said subject is a mammal.

27. The method of claim 26, wherein said mammal is a human. 28. The method of claim 1, wherein said antiepileptic compound and said alkylxanthine bronchodilator are administered to said subject by a route selected from the group consisting of oral, subcutaneous, intravenous, intramuscular, topical, transdermal, transmucosal, buccal, inhalation, epidural, intrathecal, rectal, intrarticular, and ocular.

29. The method of claim 28, wherein said alkylxanthine bronchodilator is administered orally.

30. The method of claim 28, wherein said antiepileptic compound is administered orally.

31. The method of claim 1, wherein said antiepileptic compound and said alkylxanthine bronchodilator are administered as a single pharmaceutical composition.

32. The method of claim 1, wherein said antiepileptic compound and said alkylxanthine bronchodilator . are administered as separate pharmaceutical compositions.

33. The method of claim 1, wherein said antiepileptic compound and said alkylxanthine bronchodilator are coadministered as a sustained release dosage form.

34. The method of claim 1, wherein said alkylxanthine bronchodilator is administered orally in an amount of about 1 to 4000 mg, preferably 1 mg to about 1000 mg per dose, preferably 10 mg to about 800 mg per dose.

35. The method of claim 1, wherein said alkylxanthine bronchodilator is administered intrathecally in an amount of about 0.00001 to 800 mg, preferably 0.0001 mg to about 400 mg per dose, preferably 0.001 mg to about 40 mg per dose.

36. A composition comprising, (a) one or more of (i) an antiepileptic compound, wherein said antiepileptic compound is selected from the group consisting of gabapentin, pregabalin, lacosamide, lamotrigine, carbamazepine, oxcarbazepine, valproic acid, tiagabine, topiramate, phenytoin, divalproex, and levetiracetam; (ii) a compound from Formula I

H2N CH2- C-T-CH 2 COOR1

H2Yn

wherein Ri is hydrogen or a lower alkyl, n is an integer of from 4 to 6, and the cyclic ring is optionally substituted; a pharmaceutically acceptable salt thereof, or an individual diastereoisomer or enantiomeric isomer thereof; and (iii) a compound of Formula II

wherein R.2 is a straight or branched alkyl of from 1 to 6 carbon atoms,

phenyl, or cycloalkyl having from 3 to 6 carbon atoms, R3 is hydrogen or methyl, and R4 is hydrogen, methyl, or carboxyl; an individual diastereomeric or enantiomeric isomer thereof; or a pharmaceutically acceptable salt thereof; and (b) one or more alkylxanthine bronchodilators.

37. The composition of claim 36, wherein said alkylxanthine bronchodilators is in an amount which enhances the activity of said antiepileptic compound.

38. The composition of claim 36, wherein said alkylxanthine bronchodilators is in an amount which enhances the activity of said antiepileptic compound.

39. The composition of claim 36, wherein said alkylxanthine bronchodilators is in an amount which hastens the onset of activity of said antiepileptic compound.

40. The composition of claim 36, wherein said alkylxanthine bronchodilators is in an amount which increases the duration of the activity of said antiepileptic compound.

41. The composition of claim 36, wherein said alkylxanthine bronchodilators is selected from the group consisting of theophylline, theobromine, aminophylline, dyphylline, oxtriphylline, etofylline, enprophylline,- etamiphylline, pyridophylline, doxofylline, bamifylline, proxyphylline, diprophylline, pentoxifylline, propentofylline, pentifylline and lisofylline, their pharmaceutically acceptable salts, solvates, polymorphs, hydrates, in racemic or enantiomeric form, or mixture thereof

42. The composition of claim 41, wherein said alkylxanthine bronchodilators is selected from the group consisting of theophylline, theobromine or dyphylline. 43. The composition of claim 41, wherein said alkylxanthine bronchodilators is theophylline.

44. The composition of claim 36, further comprising one or more excipients and optionally one or more inert carrier. 45. A kit for use in treating or preventing the pain with administering an antiepileptic compound and an alkylxanthine bronchodilator, or pharmaceutically acceptable salts thereof or mixtures thereof for a subject in need of such treatment, comprising: (i) a dosage form of the invention; (ii) a container for the dosage form; and optionally, any of (iii) to (vi): (iii) a container for individual units of the dosage form (e.g., individual tablets or capsules in blisters); (iv) educational instructions in any media about various medical conditions, their etiology, pathophysiology, consequences and treatment, and information on the proper use and disposal of the medication; (v) containers or bags for the safe disposal of any used or remaining unused dosage form, preferably child proof and flushable; (vi) tamper evident and child proof packaging for the kit and its contents.