(12) INTERNATIONAL APPLICATION PUBLISHED UNDER THE PATENT COOPERATION TREATY (PCT) (19) World Intellectual Property Organization International Bureau (10) International Publication Number (43) International Publication Date WO 2013/063263 Al May 2013 (02.05.2013) W P O P C T

(51) International Patent Classification: AO, AT, AU, AZ, BA, BB, BG, BH, BN, BR, BW, BY, A01N 37/18 (2006.01) A61K 31/16 (2006.01) BZ, CA, CH, CL, CN, CO, CR, CU, CZ, DE, DK, DM, DO, DZ, EC, EE, EG, ES, FI, GB, GD, GE, GH, GM, GT, (21) International Application Number: HN, HR, HU, ID, IL, IN, IS, JP, KE, KG, KM, KN, KP, PCT/US20 12/06 1922 KR, KZ, LA, LC, LK, LR, LS, LT, LU, LY, MA, MD, (22) International Filing Date: ME, MG, MK, MN, MW, MX, MY, MZ, NA, NG, NI, 25 October 2012 (25.10.2012) NO, NZ, OM, PA, PE, PG, PH, PL, PT, QA, RO, RS, RU, RW, SC, SD, SE, SG, SK, SL, SM, ST, SV, SY, TH, TJ, (25) Filing Language: English TM, TN, TR, TT, TZ, UA, UG, US, UZ, VC, VN, ZA, (26) Publication Language: English ZM, ZW. (30) Priority Data: (84) Designated States (unless otherwise indicated, for every 61/55 1,376 25 October 201 1 (25. 10.201 1) US kind of regional protection available): ARIPO (BW, GH, 61/619,405 2 April 2012 (02.04.2012) US GM, KE, LR, LS, MW, MZ, NA, RW, SD, SL, SZ, TZ, 61/660,765 17 June 2012 (17.06.2012) us UG, ZM, ZW), Eurasian (AM, AZ, BY, KG, KZ, RU, TJ, 61/665,296 27 June 2012 (27.06.2012) us TM), European (AL, AT, BE, BG, CH, CY, CZ, DE, DK, EE, ES, FI, FR, GB, GR, HR, HU, IE, IS, IT, LT, LU, LV, (71) Applicant: LYCUS LLC [US/US]; 4 Horace Court, Prin MC, MK, MT, NL, NO, PL, PT, RO, RS, SE, SI, SK, SM, ceton Junction, NJ 08550 (US). TR), OAPI (BF, BJ, CF, CG, CI, CM, GA, GN, GQ, GW, ML, MR, NE, SN, TD, TG). (72) Inventor; and (71) Applicant : SESHA, Ramesh [IN/US]; 4 Horace Court, Published: Princeton Junction, NJ 08550 (US). — with international search report (Art. 21(3)) (74) Agent: PROUT, William, F.; Prout International IP, LLC, — before the expiration of the time limit for amending the P.O. Box 761, Wayzata, MN 55391 (US). claims and to be republished in the event of receipt of (81) Designated States (unless otherwise indicated, for every amendments (Rule 48.2(h)) kind of national protection available): AE, AG, AL, AM,

© (54) Title: PHARMACEUTICAL COMPOSITIONS FOR TREATING PAIN

2 7) Abstract: A pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, and a therapeutically effective amount of a second active agent, wherein the second active agent is; a) an antiepileptic drug; b) a peroxi - some proliferator-activated receptors (PPAR) agonist; c) an opioid; or d) NSAID or pharmaceutically acceptable salts, isomers, or polymorphs thereof and optionally a pharmaceutically acceptable carrier useful for the prevention or treatment of pain and pain re - lated disorders is provided. The pharmaceutical compositions are useful in a method for treatment pain and pain related disorders, by administering the compositions to a patient in need thereof. PHARMACEUTICAL COMPOSITIONS FOR TREATING PAIN

Related Applications

This application claims priority under 35 U.S. C.§ 119 to U.S. Provisional Application No.:

61/551,376, filed on October 25, 201 1, U.S. Provisional Application No.: 61/660,765, filed on June 17, 2012, U.S. Provisional Application No.: 61/619,405, filed on April 2, 2012, and U.S. Provisional Application No.: 61/665,296, filed on June 27, 2012 the disclosures of which are incorporated by reference herein in their entirety.

Field of the Invention

[0001] The present invention provides pharmaceutical compositions, useful treating pain and pain related disorders. The invention further provides, methods for treating pain and pain related disorders using a therapeutically effective amount of the compounds and pharmaceutical compositions disclosed herein.

Background of the Invention

[0002] There are several types of pain. Various pain types include chronic pain, e.g., nociceptive, neuropathic, psychogenic pain, and mixed nociceptive and neuropathic pain. Examples of these types of pain include, but are not limited to, diabetic neuropathy, neurogenic pain, central pain, somatic pain, visceral and cancer pain, inflammatory pain, inflammatory bowel disease (IBD) pain, multiple sclerosis pain, post-operative pain, chronic low back pain, sciatica, cervical and lumbar pain, tension headaches, cluster headaches, chronic daily headaches, herpes neuralgia and post-herpetic neuralgia, facial and oral neuralgias and myofascial pain syndromes, phantom limb pain, stump pain and paraplegic pain, dental pain, opioid resistant pain, post-surgical pain including cardiac surgery and mastectomy, pain of labor and delivery, post-partum pain, post-stroke pain, angina pain, genitourinary tract pain including pelvic pain and cystitis and vulvar vestibulitis and orchialgia, irritable bowel syndrome, pre menstrual syndrome pain, pain resulting from burns or chemical injury or sunburn, and bone injury pain.

[0003] Fibromyalgia (FM) is a chronic pain illness. Symptoms of the disease include muscle aches, pain and stiffness of joints and muscles, soft tissue tenderness, general fatigue, and sleep disturbances. Common sites of this widespread pain include: neck, shoulders, back, pelvic girdle, and hands. The disease and its progression can affect any part of the body. The difficulty with fibromyalgia and pain levels the patient experiences can change over time. Sometime a patient will feel better and sometime a patient can feel worse since the pain waxes and wanes over time. [0004] Effective treatment options for fibromyalgia, particularly ones that are suitable for long-term use, are very limited. Non-limiting examples of drugs that have been used include, for example, alpha2delta agonists, such as pregabalin, gabapentin, or opioids such as tramadol, tapentadol, and tricyclic antidepressants such as nortriptytline. However all these medications have reported side effects.

[0005] Another disorder, Irritable bowel disease (IBD) is typically characterized by cramping, abdominal pain, bloating, constipation, and diarrhea. IBD may cause a great deal of discomfort and distress, but it is not believed to cause permanently harm to the intestines or lead to a serious disease, such as cancer. Many patients can control their symptoms with diet, stress management, and prescribed medications. For some patients, however, IBD can be disabling. They may be unable to work, attend social events, or even travel short distances. As many as 20 percent of the adult population, or one in five Americans, have symptoms of IBD, making it one of the most common disorders diagnosed by doctors.

[0006] Treatment options for irritable bowel disease (IBD) are limited. One medication available specifically to treat IBD is alosetron hydrochloride (Lotronex). Lotronex has been re- approved with significant restrictions by the U.S. Food and Drug Administration (FDA) for women with severe IBD who have not responded to conventional therapy and whose primary symptom is diarrhea. However, it is recommended that Lotronex should be used with great caution because it can cause serious side effects such as severe constipation or decreased blood flow to the colon.

[0007] Another type of pain is the neuropathic pain. It is caused by a primary lesion or dysfunction in the nervous system. Neuropathic pains are divided into peripheral neuropathic pain due to lesion of the peripheral nervous system and central pain following lesions of the central nervous system. Neuropathic pain commonly is described as hot burning, throbbing, shooting, lancinating, stabbing, sharp, cramping, gnawing, aching, heavy, tender, splitting, tiring, exhausting, sickening, fearful, punishing, cruel, icy cold, tingling, pins and needles, intense and itch like. Medical descriptors are allodynia (pain due to a stimulus which does not normally provoke pain), hyperalgesia (an increased response to a stimulus which is normally painful), hyperaesthesia (increased sensitivity to stimulation, excluding the special senses), dysaesthesia (an unpleasant abnormal sensation, whether spontaneous or evoked), hyperpathia (a painful syndrome characterized by an abnormally painful reaction to astimulus, especially a repetitive stimulus, as well as an increased threshold) and neuralgia (pain in the distribution of a nerve or nerves not necessarily of paroxysmal quality). Neuropathic pain may be associated with mood changes, sleep disturbance, fatigue and may have an impact on physical and social functioning. The prevalence of neuropathic pain is estimated to be about 1%. [0008] The treatment options for neuropathic pain include alpha2deltaagonists such as pregabalin, gabapentin, opioids such as morphine, dextromethorphan, and tapentadol etc.

[0009] Compounds of formula I, for example Agomelatine, A, a melatonergic agonist (MTi and MT2 receptors) and 5-HT2c antagonist are known for their antidepressant like properties.

A Agomelatine and similar compounds were disclosed in U.S. Patent No. 5,194,614 and U.S. Patent No. 5,224,442. The patents disclose several compounds of naphthalene structure including agomelatine, their pharmaceutical compositions and methods for treating a living animal afflicted with treatable disorder of the melatoninergic system. Agomelatine has been reported to re-synchronize circadian rhythms, based on animal models of delayed sleep phase syndrome and other circadian rhythm disruptions. It has also been reported to increase noradrenaline and dopamine release specifically in the frontal cortex and has no known influence on the extracellular levels of serotonin and to provide an antidepressant-like effect in animal depression models (learned helplessness test, despair test, chronic mild stress) as well as in models with circadian rhythm de-synchronization and in models related to stress and anxiety. In humans, agomelatine has been reported to provide positive phase shifting properties; it induces a phase advance of sleep, body temperature decline and melatonin onset. Thus, it has been marketed for the treatment of major depressive disorders and reported to have a reduced level of sexual side effects, as well as discontinuation effects, compared to other antidepressants. Agomelatine can also have beneficial effects on sleep associated with a number of disorders.

[0010] Published reports also indicate that agomelatine does not alter daytime vigilance and/or memory in healthy volunteers. In depressed patients, treatment with the drug increased slow wave sleep without significant modification of Rapid Eye Movement (REM) sleep amount or REM latency. Agomelatine is also reported to induce an advance of the time of sleep onset and of minimum heart rate. From the first week of treatment, onset of sleep and the quality of sleep were significantly improved without daytime clumsiness as assessed by patients. Agomelatine has no reported abuse potential as measured in healthy volunteer studies. The clinical studies on pain disorders indicate that non-response to antiepileptic drugs is substantial, up to 30%. Another critical factor in antiepileptic treatment is compliance, which has a rather profound effect on the patient's motivation to continue pharmacotherapy with antiepileptic drugs.

[0011] Peroxisome Proliferator- Activated Receptors belongs to a large family of nuclear receptors that have been reported to affect a wide range of disorders such as cancer, obesity, diabetes, inflammation, neurodegeneration and depressive disorders. The peroxisome proliferator-activated receptors (PPAR) include, alpha, beta and gamma subtype receptors. PPAR-alpha and PPAR-gamma are the molecular targets of a number of marketed drugs. For instance the hypolipidemic fibrates activate PPAR-alpha, and the antidiabetic thiazolidinediones activate PPAR-gamma. The synthetic chemical perfluorooctanoic acid activates PPAR-alpha while the synthetic perfluorononanoic acid activates both PPAR-alpha and PPAR-gamma. [0012] PPAR-alpha regulates the expression of genes involved in fatty acid beta-oxidation and is a major regulator of energy homeostasis. More recent research has demonstrated anti inflammatory and anti-thrombotic actions of PPAR-alpha agonists in the inflammation, depression, vessel wall as well. Thus, PPAR-alpha agonists decrease the progression of inflammation by modulating glial/mast cells and by their anti-inflammatory actions on the level of the vascular wall. There are reports that agonists of the nuclear receptor PPAR-alpha (peroxisome proliferator-activated receptor-alpha) suppress pain behaviors induced in mice by chemical tissue injury, nerve damage, or inflammation. However, there is not a single PPAR- alpha modulator been approved for treating pain and pain related disorder. [0013] Another major class of drugs that are used to treat chronic and acute pain include opioids. Opioid or opioid agonists class of drugs include morphine, the archetypical opioid, and various others such as, for example, codeine, dihydrocodeine, hydrocodone, hydromorphone, levorphanol, meperidine, buprenorphine, fentanyl, fentanyl derivatives, dipipanone, heroin, tapentadol tramadol, etorphine, dihydroetorphine, butorphanol, methadone, diamorphine, oxycodone, oxymorphone, pethidine and propoxyphene, etc. Opioid agonists chemically interact with areas or binding sites of the central nervous system related to the perception of pain, to movement, mood and behavior, and to the regulation of neuroendocrinological functions. Opioid agonists exhibit pharmacological properties that provide a range of therapeutic uses for patients in addition to analgesic use. Opioid agonists have been prescribed for effective use as hypnotics, sedatives, anti-diarrheal, anti-spasmodic, and anti-tussives. Unfortunately, the use of opioid agonists has also been associated with a number of undesirable side effects; constipation, respiratory depression, nausea, vomiting, dizziness, orthostatic hypotension, drowsiness, urinary retention, itch, dry mouth, headache, miosis, changes in mood and mental clouding resulting without resulting loss of consciousness in patients, and, due to the addictive properties, has been subjected to illegal diversion for abuse by addicts. [0014] Widely used opioid agonists include Morphine, Oxycodone, Tramadol and recently approved Tapentadol. Morphine has a high potential for addiction; tolerance and both physical and psychological dependence develop rapidly. It has side effects such constipation, addiction, tolerance and is prone for high abuse. Another widely used opioid agonist is Oxycodone, whose most commonly reported effects include constipation, fatigue, dizziness, nausea, lightheadedness, headache, dry mouth, anxiety, pruritus, euphoria, and diaphoresis. It has also been claimed to cause dimness in vision due to miosis. Some patients have also experienced loss of appetite, nervousness, abdominal pain, diarrhea, dyspnea, and hiccups, although these symptoms appear in less than 5% of patients taking oxycodone. Rarely, the drug can cause impotence, enlarged prostate gland, and decreased testosterone secretion. Tramadol is a centrally acting synthetic opioid analgesic. It is chemically (±) cis-2-[(dimethylamino) methyl]- 1-(3- methoxyphenyl) cyclo-hexanol hydrochloride. It is commercially available in form of its hydrochloride salt as Ultram tablets. Tramadol has certain commonly reported side effects include nausea, constipation, dizziness, headache, drowsiness, and vomiting. Less commonly reported side effects include itching, sweating, dry mouth, diarrhea, rash, visual disturbances, and vertigo. It is desirable to prevent these side effects by prescribing lower doses of tramadol without compromising the extent of pain relief. Tapentadol, 3-(3-Dimethylamino-l-ethyl-2- methyl-propyl)-phenol is a centrally acting analgesic with a dual mode of action: mu-opioid receptor agonism and noradrenaline reuptake inhibition. Its dual mode of action provides analgesia at similar levels of more potent narcotic analgesics such as hydrocodone, oxycodone, and morphine with a more tolerable side effect profile.

[0015] However, all these drugs like antiepileptic compounds, opioids, PPAR-alpha agonists are reported to have side effects and often the response rates among patients are low. Hence it is desirable to control their dosage to alleviate side effects in patients without comprising the extent of pain relief and improve the clinical efficacy.

[0016] Combinations of two drugs for the treatment of disorders are well established, e.g., opioids have been combined with other drugs including non-opioid analgesic agents, to try to lower the amount of opioid needed to produce an equivalent degree of analgesia and reduce side effects from opioids. It has been reported that some of these combination products also have a synergistic analgesic effect. U.S. Patent No. 4,571,400 discloses a combination of dihydrocodeine, an opioid analgesic, and ibuprofen, a non-opioid analgesic. In addition, see for example, U.S. Patent No. 4,587,252 and U.S. Patent No. 4,569,937, which disclose other ibuprofen - opioid combinations. Combinations of non-opioid analgesics have also been prepared to avoid the side effects associated with opioids, and the combinations are noted to have the benefit of requiring less of each ingredient and may provide additive effects. See, for example, U.S. Patent. No. 4,260,629 and U.S. Patent No. 4,132,788. However, there have been warnings against the daily consumption of non-opioid analgesic mixtures and of the consumption of a single non-opioid analgesic in large amounts or over long periods. In addition, ibuprofen, aspirin and some other NSAIDs may cause gastrointestinal side effects especially if used repeatedly. [0017] There are no reports of pharmaceutical compositions comprising a therapeutically effective amount of a compound of formula I, and a therapeutically effective amount of a second active agent, wherein the second active agent is; a) an antiepileptic drug; b) a peroxisome proliferator-activated receptors (PPAR) agonist; c) an opioid; or d) NSAID useful for preventing or treating pain and pain related disorders, in a patient need of such treatment. Further, methods for preventing or treating pain and pain related disorders, comprising administering a pharmaceutical composition comprising therapeutically effective amount of two or more of the disclosed compounds have not been reported. A composition comprising a therapeutically effective amount of a compound of formula I, and a therapeutically effective amount of a second active agent, wherein the second active agent is; a) an antiepileptic drug; b) a peroxisome proliferator-activated receptors (PPAR) agonist; c) an opioid; or d) NSAID; that provides surprisingly useful clinical benefits is disclosed herein. The instant invention provides a composition having one or more of the disclosed compounds that provides clinical benefits when used to treat patients with pain and pain related disorders. [0018] Thus, there is a need for high efficacy medications that provide relief for patients with pain and pain related disorders, where the medication has reduced undesirable side effects. Further, there is an unmet medical need for compositions and/or dosage forms for the treatment of pain and pain related disorders that are free from or have limited side effects associated with other pain drugs. Finally, there is a need for clinically superior drugs for the treatment of pain and pain related disorders.

Summary of the Invention

[0019] The present invention provides pharmaceutical compositions comprising a therapeutically effective amount of a na hthalene compound having formula I :

I

wherein R1 is substituted or unsubstituted (Ci-C6 )alkyl; R2 is hydrogen or substituted or

unsubstituted (Ci-C )alkyl; and R is hydrogen, substituted or unsubstituted (Ci-C )alkyl, or

substituted or unsubstituted (C3-Cio )cycloalkyl, substituted or unsubstituted (C -Cio )aryl,

substituted or unsubstituted (C7-Ci6 )arylalkyl, substituted or unsubstituted (Cs-C ^heteroaryl,

substituted or unsubstituted (C6-C2i )heteroarylalkyl, substituted or unsubstituted heterocyclic

group or substituted or unsubstituted (C6-Ci5 )heterocycloalkyl group; wherein the substituents for the alkyl, aryl, cycloalkyl, or heterocyclic groups include

(Ci-C )alkyl, fluoro, chloro, or bromo; and a therapeutically effective amount of a second active agent, wherein the second active agent is;

a) an antiepileptic drug; b) peroxisome proliferator-activated receptors (PPAR) agonist; or, c) an an opioid; or d) d) NSAID; and optionally at least one pharmaceutically acceptable carrier; or pharmaceutically acceptable salts, isomers, or polymorphs thereof; wherein the compositions are useful for treating useful for treating pain or pain related disorders. [0020] In another aspect, the invention provides pharmaceutical compositions comprising naphthalene compounds having formula I-A,

I-A wherein, R1 is methyl, ethyl, n-propyl, or 1-methylethyl (isopropyl), and R is methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, isobutyl, n-pentyl, t-butyl (1,1- dimethylethyl), or phenyl, or pharmaceutically acceptable salts, isomers, or polymorphs thereof; and a second agent wherein second agent is a) an antiepileptic drug; b) a peroxisome proliferator-activated receptors (PPAR) agonist; c) an opioid or d) NSAID; useful for pain and pain related disorders. [0021] In another aspect, the invention provides pharmaceutical compositions comprising naphthalene compounds having formula I-A, wherein R1 is methyl and R is methyl, ethyl, isopropyl, isobutyl or phenyl. [0022] In another aspect, the invention provides a method for preventing or treating pain or pain related disorders in a mammal, comprising administering to said mammal a pharmaceutical composition comprising therapeutically effective amount of a compound of formula I, and a therapeutically effective amount of a second active agent, wherein the second active agent is; a) an antiepileptic drug; b) a peroxisome proliferator-activated receptors (PPAR) agonist; or c) an opioid; or pharmaceutically acceptable salts, isomers, or polymorphs thereof and optionally a pharmaceutically acceptable carrier. Preferably, the mammal is a human.

[0023] In another aspect, the present invention provides a method for the prevention or treatment of pain or pain related disorders, wherein the method comprises administration of a therapeutically effective amount of a compound of formula I, and a therapeutically effective amount of second active agent, wherein the second active agent is; a) an antiepileptic drug; b) a peroxisome proliferator-activated receptors (PPAR) agonist; or c) an opioid; or pharmaceutically acceptable salts, isomers, or polymorphs thereof, to a patient in need thereof. Non-limiting examples of pain that can be prevented or treated include neuropathic pain, neurogenic pain, central pain, somatic pain, visceral and cancer pain, inflammatory pain, post-operative pain, chronic low back pain, sciatica, cervical and lumbar pain, tension headaches, cluster headaches, chronic daily headaches, herpes neuralgia and post-herpetic neuralgia, facial and oral neuralgias and myofascial pain syndromes, phantom limb pain, stump pain and paraplegic pain, dental pain, opioid resistant pain, post-surgical pain including cardiac surgery and mastectomy, pain of labor and delivery, post-partum pain, post-stroke pain, angina pain, genitourinary tract pain including pelvic pain, cystitis, vulvar vestibulitis, orchialgia, irritable bowel syndrome, pre-menstrual syndrome pain, pain resulting from burns, e.g., sunburn, or chemical injury, bone injury pain, and the like. Preferably, the pain can be from neuropathic pain, fibromyalgia, diabetic and peripheral neuropathic pain, rheumatoid arthritis, irritable bowel syndrome, osteoarthritis and the like.

[0024] In another aspect, the invention provides both a compound of formula I, and an antiepileptic agent (or pharmaceutically acceptable salts thereof) in a pharmaceutical composition for treating epilepsy or painful conditions. The pain can be from any cause, e.g., neuropathic pain, fibromyalgia, diabetic and peripheral neuropathic pain, rheumatoid arthritis, irritable bowel syndrome, osteoarthritis, and the like.

[0025] In another aspect, the invention provides both a compound of formula I, and a peroxisome proliferator-activated receptors (PPAR) agonist; (or pharmaceutically acceptable salts thereof) in a pharmaceutical composition for treating epilepsy or painful conditions. The pain can be from any cause, e.g., neuropathic pain, fibromyalgia, diabetic and peripheral neuropathic pain, rheumatoid arthritis, irritable bowel syndrome, osteoarthritis, and the like. [0026] In another aspect, the invention provides both a compound of formula I, and an opioid; (or pharmaceutically acceptable salts thereof) in a pharmaceutical composition for treating epilepsy or painful conditions. The pain can be from any cause, e.g., neuropathic pain, fibromyalgia, diabetic and peripheral neuropathic pain, rheumatoid arthritis, irritable bowel syndrome, osteoarthritis, and the like. [0027] In another aspect, the invention provides a pharmaceutical composition having a therapeutically effective amount of a compound of formula I, and a therapeutically effective amount of an antiepileptic administered in suboptimal dosages. Preferably, the compound of formula I, and the antiepileptic are administered in amounts and for a sufficient time to provide a synergistic effect. [0028] In another aspect, the invention provides the use of a pharmaceutical composition comprising a therapeutically effective amount of a first drug and a therapeutically effective amount of a second drug, where the first drug is a compound of formula I, and the second drug is an antiepileptic, for the manufacture of a medicament for the treatment of epilepsy. [0029] In another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, and a therapeutically effective amount of second active agent, wherein the second active agent is; a) an antiepileptic drug; b) a peroxisome proliferator-activated receptors (PPAR) agonist; or c) an opioid; or pharmaceutically acceptable salts, isomers, or polymorphs thereof, useful for treatment of pain and pain related disorders. A preferred indication is fibromyalgia. [0030] In another aspect, the preferred indication is neuropathic pain. In another aspect, the preferred indication is irritable bowel syndrome. [0031] In yet another aspect, the invention provides a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, and a therapeutically effective amount of second active agent, wherein the second active agent is; a) an antiepileptic drug; b) a peroxisome proliferator-activated receptors (PPAR) agonist; or c) an opioid;, or pharmaceutically acceptable salts thereof, for use in medical treatment (for example, treatment of pain, e.g., fibromyalgia).

[0032] In another aspect, the invention provides a method for management of pain, pain related disorders, or treatment of epilepsy, comprising administering to a subject in need thereof, a pharmaceutical composition comprising a first agent (drug), a second active agent, and optionally a pharmaceutically acceptable carrier, wherein the first agent (drug) is a compound of formula I, and the second agent is an antiepileptic (or pharmaceutically acceptable salts thereof). [0033] In another aspect, the present invention provides a method for the treatment of pain and pain related diseases, wherein the method comprises administration of a therapeutically effective amount of a compound of formula I, and a therapeutically effective amount of second active agent, wherein the second active agent is; a) an antiepileptic drug; b) a peroxisome proliferator-activated receptors (PPAR) agonist; or c) an opioid;, to a patient in need thereof. [0034] In another aspect, the present invention provides a method, for the treatment of the treatment of epilepsy, wherein the method comprises administration of therapeutically effective amount of a compound of formula I, and a therapeutically effective amount of an antiepileptic, to a patient in need thereof. [0035] In another aspect, the invention provides a method for management of pain comorbid with epilepsy. [0036] In another aspect, the invention provides a method for the manufacture of a medicament for the treatment of chronic pain in which the active agent is a pharmacologically acceptable salt of a compound of formula I, and an antiepileptic drug wherein the antiepileptic drug is pregabalin, gabapentin, topiramate, baclofen, or gabapentin enacarbil, for treating pain. Preferably, the compound of formula I is agomelatine and the antiepileptic is pregabalin. [0037] In another aspect, the invention provides a method for the use of a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, and a therapeutically effective amount of palmitoylethanolamide, or pharmaceutically acceptable salts thereof for the preparation of a medicament for treatment of pain and pain related disorders in a mammalian species (for example, a human).

[0038] In another aspect, the invention provides a preferred combination of a low dose of agomelatine and palmitoylethanolamide (PEA). The combination of a therapeutically effective amount agomelatine and a therapeutically effective amount of palmitoylethanolamide (PEA) provides surprisingly useful clinical benefits over the single drugs are disclosed herein. [0039] In another aspect, the invention provides a composition dosage form wherein the form is a bilayer composition, where one layer includes comprising a therapeutically effective amount of agomelatine, and one layer comprises a therapeutically effective amount of palmitoylethanolamide (PEA).

[0040] In another aspect, the invention provides a method for the use of a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I, and a therapeutically effective amount of an opioid, or pharmaceutically acceptable salts thereof for the preparation of a medicament for treatment of pain and pain related disorders in a mammalian species (for example, a human). [0041] In another aspect, the present invention provides a method for the prevention or treatment of pain or a pain related disorder, wherein the disorder is fibromyalgia, comprising administration of a therapeutically effective amount of a compound of formula I, and a therapeutically effective amount of a second active agent, wherein the second active agent is; a) an antiepileptic drug; b) a peroxisome proliferator-activated receptors (PPAR) agonist; or c) an opioid;; or pharmaceutically acceptable salts, isomers, or polymorphs thereof and optionally a pharmaceutically acceptable carrier, to a patient in need thereof. [0042] In another aspect, the present invention provides a method for the prevention or treatment of pain or a pain related disorder, wherein the disorder is neuropathic pain, comprising administration of a therapeutically effective amount of a compound of formula I, and a therapeutically effective amount of a second active agent, wherein the second active agent is; a) an antiepileptic drug; b) a peroxisome proliferator-activated receptors (PPAR) agonist; or c) an opioid;; or pharmaceutically acceptable salts, isomers, or polymorphs thereof and optionally a pharmaceutically acceptable carrier, to a patient in need thereof. [0043] In another aspect, the present invention provides a method for the prevention or treatment of pain or a pain related disorder, wherein the disorder is cancer related pain, comprising administration of a therapeutically effective amount of a compound of formula I, and a therapeutically effective amount of a second active agent, wherein the second active agent is; a) an antiepileptic drug; b) a peroxisome proliferator-activated receptors (PPAR) agonist; or c) an opioid;; or pharmaceutically acceptable salts, isomers, or polymorphs thereof and optionally a pharmaceutically acceptable carrier, to a patient in need thereof. [0044] In another aspect, the present invention provides a method for the prevention or treatment of pain or a pain related disorder, wherein the disorder is arthritis, comprising administration of a therapeutically effective amount of a compound of formula I, and a therapeutically effective amount of a second active agent, wherein the second active agent is; a) an antiepileptic drug; b) a peroxisome proliferator-activated receptors (PPAR) agonist; or c) an opioid;; or pharmaceutically acceptable salts, isomers, or polymorphs thereof and optionally a pharmaceutically acceptable carrier. In another aspect, the arthritis is rheumatoid arthritis or osteoarthritis.

[0045] In another aspect, the invention provides a pharmaceutical composition comprising a compound of formula I, and a therapeutically effective amount of a second active agent, wherein the second active agent is; a) an antiepileptic drug; b) a peroxisome proliferator-activated receptors (PPAR) agonist; or c) an opioid; or pharmaceutically acceptable salts, isomers, or polymorphs thereof and optionally a pharmaceutically acceptable carrier, for treating pain and pain related disorders. The pharmaceutical composition is suitable for administration by oral, intravenous, intraarterial, intraperitoneal, intradermal, buccal, transdermal, intrathekal (intrathecal), intramuscular, intranasal, transmucosal, subcutaneous, or rectal routes.

[0046] In another aspect, the invention provides a method for the use of a therapeutically effective amount of a compound of formula I, and a therapeutically effective amount of a second active agent, wherein the second active agent is; a) an antiepileptic drug; b) a peroxisome proliferator-activated receptors (PPAR) agonist; or c) an opioid; or pharmaceutically acceptable salts, isomers, or polymorphs thereof and optionally a pharmaceutically acceptable carrier, for the preparation of a medicament for the prevention or treatment of pain or pain related disorders.

[0047] In another aspect, the invention provides a compound having formula I, and a therapeutically effective amount of a second active agent, wherein the second active agent is; a) an antiepileptic drug; b) a peroxisome proliferator-activated receptors (PPAR) agonist; or c) an opioid;; or pharmaceutically acceptable salts, isomers, or polymorphs thereof and optionally a pharmaceutically acceptable carrier, for use in a method for the prevention or treatment of pain or pain related disorders in a mammal, and wherein the medicament optionally comprises a solid or liquid carrier, comprising administering to said mammal an effective amount of a said compound or said pharmaceutically acceptable salt or ester thereof. Preferably, the mammal is a human.

[0048] In another aspect, the present invention provides the use of a pharmaceutical composition, as disclosed herein, for the prevention or treatment of pain and pain related disorders. [0049] In another aspect, the invention provides a titration-dosing regimen for the administration of a compound of formula I, and an antiepileptic, a peroxisome proliferator- activated receptors (PPAR) agonist, or an opioid to patients. The titration-dosing regimen provides a significant reduction in the occurrence of adverse effects from the introduction of an active agent in a slow release dosing, thus increasing patient compliance and medication tolerability.

[0050] In another aspect the second agent is an antiepileptic, where is the antiepileptic drug is aminobutyric acid, baclofen, beclamide, barbexaclone, brivaracetam, clonazepam, carbamazepine, ethotoin, ethadione, ethosuximide, eslicarbazepine, felbamate, fosphenytoin, gabapentin, gabapentin enacarbil, lamotrigine, levetiracetam, lacosamide, mephenytoin, methylphenobarbital, metharbital, mesuximide, oxcarbazepine, phenytoin, phenobarbital, primidone, paramethadione, phenacemide, pheneturide, phensuximide, pregabalin, progabide rufinamide, selectracetam, stiripentol, sultiame, topiramate, trimethadione, tiagabine, valproic acid, amino(diphenylhydantoin) valeric acid, valpromide, vigabatrin or zonisamide, or pharmaceutically acceptable salts thereof [0051] In another aspect the second agent is an opioid, where is the opioid drug is alfentanil, allylprodine, alphaprodine, anileridine, asimadoline, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, faxeladol, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tapentadol, axamadol, and, tramadol, pharmaceutically acceptable salts thereof and mixtures thereof.

[0052] In another aspect the second agent is a peroxisome proliferator-activated receptors (PPAR) agonist, where is the peroxisome proliferator-activated receptors (PPAR) agonist is palmitoylethanolamide, anandamide, stearoyl ethanolamine, Oleoylethanolamine, fenofibrate, bezafibrate, ciprofibrate, clofibrate, gemfibrozil, and ureido-fibrate-5 (UF-5)

[0053] The details of one or more embodiments of the invention are set forth in the accompanying description below. Other features, objects, and advantages of the invention will be apparent from the description and drawings, and from the claims.

BRIEF DESCRIPTION OF THE FIGURES

[0054] Figure 1 is an illustration of the weekly change in the mean pain score comparing the agomelatine and palmitoylethanolamide (PEA) combination treated patients. [0055] Figure 2 is an illustration of the weekly trend in change in mean sleep quality score comparing the agomelatine and palmitoylethanolamide (PEA) combination treated patients. [0056] Figure 3 is an illustration of the change in the mean pain score comparing the agomelatine and pregabalin combination with agomelatine, pregabalin and a placebo.

[0057] Figures 4 and 5 are illustrations of the percent of patients with or without improvement in pain relief, reported by the patients in the treatment groups.

[0058] Figure 6 is an illustration of the weekly trend in change in mean sleep quality score comparing the agomelatine and pregabalin combination with agomelatine, pregabalin and a placebo.

[0059] Figure 7 is an illustration of mean pain scores plotted against time for the neuropathic pain study.

[0060] Figure 8 is an illustration of mean pain scores plotted against time for the neuropathic pain study using three different combinations

DETAILED DESCRIPTION

DEFINITIONS [0061] In describing and claiming the invention, unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this invention belongs. Although any materials and methods similar or equivalent to those described herein can be used in the practice or testing of the present invention, the preferred materials and methods are described herein. Each of the following terms has meaning associated with it in this section. Exemplary and preferred values listed below for radicals, substituents, and ranges are for illustrations only; they do not exclude other defined values or other values within defined ranges for the radicals and substituents.

[0062] The terms "a," "an," "the," "at least one," and "one or more" are used interchangeably. Thus, for example, a composition that comprises "an" element means one element or more than one element.

[0063] The term "Analgesic" as used herein, means to include any drug used to relieve pain including paracetamol (acetaminophen), the non-steroidal anti-inflammatory drugs (NSAIDs) for example, the salicylates, narcotic drugs for example, morphine, synthetic drugs with narcotic properties for example, tramadol, tapentadol, asimadoline, antiepileptics (e.g., pregabalin, gabapentin) and various others other classes of drugs not normally considered analgesics are used to treat neuropathic pain syndromes; for example, tricyclic antidepressants and anticonvulsants. [0064] A disease or disorder is "alleviated" if the severity of a symptom of the disease or disorder, the frequency with which such a symptom is experienced by a patient, or both, is reduced. [0065] A "disorder" in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health.

[0066] The terms "medicament", "drug" or "active agent" are used interchangeably, and as used herein are defined to include at least one form of a compound of formula I, antiepileptic drug; palmitoylethanolamide (PEA); or opioid; chosen from their respective salts, their respective optically active enantiomers, racemic mixtures thereof, isomers, polymorphs, prodrugs, active metabolites, pharmaceutically acceptable salts thereof, such as, for example, acid addition or base addition salts of the disclosed compounds salts, optically active enantiomers, racemic mixtures thereof, prodrugs, active metabolites, pharmaceutically acceptable salts thereof, such as, for example, acid addition or base addition salts of the disclosed compounds, which can be used to prepare the disclosed pharmaceutical compositions. [0067] The term "agomelatine" as used herein is defined to mean at least one form of agomelatine chosen from agomelatine salts, polymorphs, prodrugs, active metabolites, pharmaceutically acceptable salts thereof, such as for example, acid addition or base addition salts of agomelatine.

[0068] The term, "antiepileptic (drugs)", "antiepileptic compounds", or "anticonvulsant(s)" are used interchangeably and as used herein, includes compounds that reduce or prevent seizures. The antiepileptics also encompass all the modulators of voltage gated calcium channels, their pharmaceutically equivalent salts, isomers, polymorphs, hydrates, complexes, clatharates and the like. Non-limiting examples include, but are not limited to, aminobutyric acid, baclofen, beclamide, barbexaclone, brivaracetam, clonazepam, carbamazepine, ethotoin, ethadione, ethosuximide, eslicarbazepine, felbamate, fosphenytoin, gabapentin, gabapentin enacarbil, lamotrigine, levetiracetam, lacosamide, mephenytoin, methylphenobarbital, metharbital, mesuximide, oxcarbazepine, phenytoin, phenobarbital, primidone, paramethadione, phenacemide, pheneturide, phensuximide, pregabalin, progabide rufinamide, selectracetam, stiripentol, sultiame, topiramate, trimethadione, tiagabine, valproic acid, amino(diphenyl- hydantoin) valeric acid, valpromide, vigabatrin or zonisamide, or pharmaceutically acceptable salts thereof, and the like. Preferred antiepileptic drugs include pregabalin, gabapentin, gabapentin enacarbil, topiramate, baclofen or pharmaceutically acceptable salts thereof, and the like.

[0069] Preferred examples of the antiepileptic drugs include gabapentin, gabapentin enacarbil, pregabalin and pharmaceutically acceptable salts thereof. The preferred combination is agomelatine and pregabalin. [0070] The term "Non-steroidal anti-inflammatory drug" or "NSAID" as used herein means any non-steroidal anti-inflammatory drug. Non-limiting examples include Celecoxib, Diclofenac, Diflunisal, Etodolac, Fenoprofen, Flurbirofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Mefenamic acid, Meloxicam, Nabumetone, Naproxen, Oxaprozin, Piroxicam, Sulindac and Tolmetin and their pharmaceutically equivalent salts.

[0071] The terms "opioid or opioids" as used herein, include but are not limited to, alfentanil, allylprodine, alphaprodine, anileridine, benzyl-morphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, cyclazocine, desomorphine, dextromethorphan, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioaphetylbutyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levallorphan, levorphanol, levophenacylmorphan, lofentanil, loperamide, meperidine (pethidine), meptazinol, metazocine, methadone, metopon, morphine, myrophine, nalbuphine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, normorphine, norpinanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phanazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propiram, propoxyphene, sulfentanil, tilidine, tramadol, tapentadol, axomadol, faxeladol, diastereoisomers thereof, pharmaceutically acceptable salts thereof, complexes thereof; and mixtures thereof. In some embodiments, the opioid is selected from morphine, codeine, oxycodone, hydrocodone, dihydrocodeine, propoxyphene, fentanyl, tapentadol, tramadol, or mixtures thereof.

[0072] The term "peroxisome proliferator-activated receptors (PPAR) agonist" used used here mean a modulator of peroxisome proliferator-activated receptors (PPAR). The exemplary peroxisome proliferator-activated receptors (PPAR) agonists are palmitoylethanolamide, anandamide, stearoyl ethanolamine, Oleoylethanolamine, fenofibrate, bezafibrate, ciprofibrate, clofibrate, gemfibrozil, and ureido-fibrate-5 (UF-5). [0073] The term "band range" as used herein, is defined as the difference in in vitro dissolution measurements of the controlled release formulations when comparing the dissolution profile (curve) obtained by the formulation upon completion of the manufacturing of the coated product (prior to storage) and the dissolution profile obtained after the coated product is exposed to accelerated storage conditions, expressed as the change in percent of the active agent released from the coated product at any dissolution time point along the dissolution curves.

[0074] The term "co-administration" as used herein means administration of the two drugs (agents) together {e.g., simultaneously as a mixture) or administration can be sequential. The sequential administration of the agomelatine can be prior to or after administration of the second analgesic agent, within minutes of each other or up to about 48 hours after the administration of the other agent. Preferably the administration of the agomelatine will be within about 24 hours of administration of the second analgesic agent and more preferably within about 1 hours of administration of the second analgesic agent.

[0075] The term "effective amount" as used herein, means an amount sufficient to produce a selected effect. For example, an effective amount of a compound of formula I, and an optional second agent are amounts that is sufficient in order to relieve the pain symptoms of the patient to be controlled when compared with no treatment. [0076] The term "therapeutically effective amount" as used herein, means an amount that elicits a biological response in a mammal, including the effect from a suboptimal amount.

[0077] The term "suboptimal dosage or suboptimal amount" us used herein means a dosage, which is below the optimal dosage for that compound when used in single-compound therapy. [0078] The term "additive effect" as used herein means the effect resulting from the sum of the effects obtained from the individual compounds. [0079] The term "synergistic effect" as used herein means an effect from two drugs (active agents), which is greater than the additive effect that results from the sum of the effects of the two individual agents. [0080] The term "treatment of a disease" as used herein, means the management and care of a patient having developed the disease, condition or disorder. The purpose of treatment is to combat the disease, condition or disorder. Treatment includes the administration of the active compounds to eliminate or control the disease, condition or disorder as well as to alleviate the symptoms or complications associated with the disease, condition or disorder.

[0081] The term "prevention of a disease" as used herein, is defined as the management and care of an individual at risk of developing the disease prior to the clinical onset of the disease. The purpose of prevention is to combat the development of the disease, condition or disorder, and includes the administration of the active compounds to prevent or delay the onset of the symptoms or complications and to prevent or delay the development of related diseases, conditions or disorders.

[0082] The terms "epilepsy" or "epileptic disorders" are used interchangeably and as used herein, means disorders that result from the surges in electrical signals inside the brain, causing recurring seizures. Seizure symptoms vary. Some people with epilepsy can simply stare blankly for a few seconds during a seizure, while others have full-fledged convulsions. The condition may be co-morbid with other psychiatric conditions such as pain, depression, anxiety, and the like.

[0083] The term "pain and pain related disorder" as used herein, includes all types of pain, e.g., chronic pain such as nociceptive, neuropathic, psychogenic pain, and mixed category pain (nociceptive and neuropathic components). This terms, pain or pain related disorder, include in particular, but are not limited to, diabetic neuropathy, neurogenic pain, central pain, somatic pain, visceral and cancer pain, inflammatory pain, inflammatory bowel disease (IBD) pain, post operative pain, chronic low back pain, sciatica, cervical and lumbar pain, tension headaches, cluster headaches, chronic daily headaches, herpes neuralgia and post-herpetic neuralgia, facial and oral neuralgias and myofascial pain syndromes, phantom limb pain, stump pain and paraplegic pain, dental pain, opioid resistant pain, post-surgical pain including cardiac surgery and mastectomy, pain of labor and delivery, post-partum pain, post-stroke pain, angina pain, genitourinary tract pain including pelvic pain and cystitis and vulvar vestibulitis and orchialgia, irritable bowel syndrome, pre-menstrual syndrome pain, pain resulting from burns or chemical injury or sunburn, and bone injury pain.

[0084] Specific examples of pain that can be treated include but are not limited to inflammatory pain, neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain, cancer pain, depression, epilepsy, pain comorbid with depression, pain comorbid with epilepsy, epilepsy comorbid with depression and the like.

[0085] Preferably, pain which can be treated includes but is not limited to inflammatory pain, neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain, cancer pain and the like. Non-limiting examples of chronic pain, to be treated by the disclosed compositions is nociceptive pain. Preferred indications of nociceptive pain are inflammatory and post-operative pain. In another aspect, it is preferred that the chronic pain to be treated is neuropathic pain. Preferred indications of neuropathic pain are neurogenic pain and facial and oral neuralgias.

[0086] The terms "slow-release" or "controlled release" are used interchangeably and as used herein, applies to any release from a formulation that is other than an immediate release, wherein the release of the active ingredient is slow in nature. This includes various terms used interchangeably in the pharmaceutical context such as, extended release, delayed release, sustained release, controlled release, timed release, specific release and targeted release, and the like.

[0087] The term "extended release material" as used herein, in an inner solid particulate phase or an outer solid continuous phase refers to one or more hydrophilic polymers and/or one or more hydrophobic polymers and/or one or more other type hydrophobic materials, such as, for example, one or more waxes, fatty alcohols and/or fatty acid esters. The "extended release material" present in the inner solid particulate phase may be the same as or different from the "extended release material" present in the outer solid continuous phase.

[0088] The term "hydrophilic polymers" as used herein, include, but are not limited, to hydroxypropylmethylcellulose, hydroxypropylcellulose, sodium, carboxymethylcellulose, carboxymethylcellulose calcium, ammonium alginate, sodium alginate, potassium alginate, calcium alginate, propylene glycol alginate, alginic acid, polyvinyl alcohol, povidone, carbomer, potassium pectate, potassium pectinate, and the like.

[0089] The term "hydrophobic polymers" as used herein, include, but are not limited, to ethyl cellulose, hydroxyethylcellulose, ammonio methacrylate copolymer (Eudragit™ RL or Eudragit™ RS), methacrylic acid copolymers (Eudragit™ L or Eudragit™ S), methacrylic acid- acrylic acid ethyl ester copolymer (Eudragit™ L 100-5), methacrylic acid esters neutral copolymer (Eudragit™ NE 30D), dimethylaminoethylmethacrylate-methacrylic acid esters copolymer (Eudragit™ E 100), vinyl methyl ether/malefic anhydride copolymers, their salts and esters (Gantrez™), and the like.

[0090] Other hydrophobic materials which may be employed in the inner solid particulate phase and/or outer solid continuous phase include, but are not limited, to waxes such as beeswax, carnauba wax, microcrystalline wax, and ozokerite; fatty alcohols such as cetostearyl alcohol, stearyl alcohol; cetyl alcohol myristyl alcohol etc; and fatty acid esters such as glyceryl monostearate, glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, hydrogenated castor oil, and the like.

[0091] The term "candidate for sustained release" as used herein, encompasses all the characteristics of a drug which make it a candidate for formulating it into an extended release fashion like a short elimination half life and consequent dosing of more than once a day, a single dose product given in an extended fashion to achieve better clinical results and avoid side effects associated with an immediate release etc.

[0092] The term "binding agent" as used herein, refers to any conventionally known pharmaceutically acceptable binder such as polyvinyl pyrrolidone, hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropyl methylcellulose, ethylcellulose, polymethacrylate, polyvinyl alcohol, waxes and the like. Mixtures of the aforementioned binding agents may also be used. The preferred binding agents include water-soluble materials such as, for example, polyvinyl pyrrolidone having a weight average molecular weight of 25,000 to 3,000,000. The binding agent may comprise approximately about 0 to about 40% of the total weight of the core and preferably about 3% to about 15% of the total weight of the core. In one embodiment, the use of a binding agent in the core is optional.

[0093] The term "pharmaceutically acceptable derivative" as used herein, means various pharmaceutical equivalent isomers, enantiomers, complexes, salts, hydrates, polymorphs, esters, and the like, e.g., of agomelatine. [0094] The term "pharmaceutically-acceptable salt" as used herein, refers to salts that retain the biological effectiveness and properties of the disclosed compounds and which are not biologically or otherwise undesirable. In many cases, the disclosed compounds are capable of forming acid or base salts by virtue of the presence of amino or carboxyl groups or groups similar thereto. The preparation of the salts and suitable acids or bases is known in the art. [0095] The term "combination therapy" as used herein, means a therapy where two or more active ingredients are administered separately or are administered in the form of a pharmaceutical composition for the treatment and/or prophylaxis of a disease.

[0096] The term "monotherapy" as used herein, means a therapy that uses only one active ingredient for treatment and/or prophylaxis of a disease or disorder.

[0097] The term "Sleep Disorder" as used herein, means any disorder that affects, or disrupts, sleep. They include any disorder affecting five stages (Stage 1 non-rapid eye movement (NREM) sleep, Stage 2 non-rapid eye movement (NREM) sleep, Stage 3 non-rapid eye movement (NREM) sleep, Stage 4 non-rapid eye movement (NREM) sleep and Rapid Eye Movement (REM) sleep) of sleep.

Pharmaceutical Compositions of the Present Invention [0098] The present invention provides compositions comprising a therapeutically effective amount of a compound of formula I, and a therapeutically effective amount of a second active agent, wherein the second active agent is; a) an antiepileptic drug; b) a peroxisome proliferator- activated receptors (PPAR) agonist; or c) an opioid; or a pharmaceutically equivalent salt, isomer, or polymorph thereof, for treating pain and pain related disorders. The disclosed compositions can be formulated for any route of administration (e.g., the formulations described herein) and can be administered in a single dose or multiple doses to a subject in need thereof. [0099] The active ingredients, for the disclosed method, a compound of formula I, and second active agent, wherein the second active agent is; a) an antiepileptic drug; b) a peroxisome proliferator-activated receptors (PPAR) agonist; or c) an opioid; are preferably used in the free amphoteric form. Pharmaceutically acceptable salts that retain the biological effectiveness and properties of the compounds of formula I, and second active agent that are not biologically or otherwise undesirable, can also be used and can show superior bioavailability. [00100] The pharmaceutical compositions are intended for parenteral, intranasal, topical, oral, buccal, or local administration, such as by a transdermal means, for prophylactic and/or therapeutic treatment. Commonly, the pharmaceutical compositions are administered parenterally (e.g., by intravenous, intramuscular, or subcutaneous injection), or by oral ingestion, or by topical application at areas affected by pain and pain related disorders. [00101] In the preparation of pharmaceutical formulations can be mixed with solid, powdered ingredients, such as lactose, microcrystalline cellulose, maltodextrin, saccharose, sorbitol, mannitol, starch, amylopectin, cellulose derivatives, gelatin, or another suitable ingredient, as well as with disintegrating agents and lubricating agents such as magnesium stearate, calcium stearate, sodium stearyl fumarate and polyethylene glycol waxes. The mixture is then processed into granules or pressed into tablets such as chewable and oral disintegrating tablets.

[00102] The compound of formula I, can be an acid addition salt. Acids commonly employed to form acid addition salts are inorganic acids, such as for example, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid, phosphoric acid, and the like, and organic acids such as p-toluenesulfonic, methanesulfonic acid, oxalic acid, p-bromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid, acetic acid, and the like. Examples of such pharmaceutically acceptable salts are the sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutylate, caproate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne-l,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dinitrobenzoate, hydroxybenzoate, methoxybenzoate, phthalate, sulfonate, xylenesulfonate, phenylacetate, phenylpropionate, phenylbutylate, citrate, lactate, g- hydroxybutylate, glycolate, tartrate, methanesulfonate, propanesulfonate, naphthalene- 1- sulfonate, napththalene-2-sulfonate, mandelate and the like. [00103] The compound of formula I can be a base addition salt. Base addition salts include those derived from inorganic bases, such as for example, ammonium or alkali or alkaline earth metal hydroxides, carbonates, bicarbonates, and the like. Such bases useful in preparing the salts of this invention thus include sodium hydroxide, potassium hydroxide, ammonium hydroxide, potassium carbonate, sodium carbonate, sodium bicarbonate, potassium bicarbonate, calcium hydroxide, calcium carbonate, and the like. [00104] Soft gelatin capsules can be prepared by mixing the active agent and vegetable oil, fat, or other suitable vehicle. Hard gelatin capsules can contain granules of the active agent, alone or in combination with solid powdered ingredients such as lactose, saccharose, sorbitol, mannitol, potato starch, corn starch, amylopectin, cellulose derivatives or gelatin. [00105] Liquid preparations for oral administration can be prepared in the form of syrups or suspensions, e.g., solutions or suspensions containing about 0.2-20 wt % of the active agent and the remainder consisting of sugar or sugar alcohols and a mixture of ethanol, water, glycerol, propylene glycol and polyethylene glycol. If desired, such liquid preparations can contain coloring agents, flavoring agents, saccharin and carboxymethyl cellulose or other thickening agents. Liquid preparations for oral administration can also be prepared in the form of a dry powder to be reconstituted with a suitable solvent prior to use.

Methods for Treatment of pain and pain related disorders. [00106] The present invention provides methods for prevention or treatment of pain and pain related disorders in a patient, by administering a pharmaceutical composition comprising a therapeutically effective amount of a compound of formula I and a therapeutically effective amount of a second active agent, wherein the second active agent is; a) an antiepileptic drug; b) a peroxisome proliferator-activated receptors (PPAR) agonist; or c) an opioid;. The disclosed compositions can be administered to a patient to treat, prevent, ameliorate, inhibit the progression of, or reduce the severity of one or more symptoms of pain and pain related disorders in a human patient. [00107] Non-limiting examples of pain or pain related disorders that can be treated using the disclosed compositions include: lack of sleep, difficulty in falling asleep, sleep awakenings, disturbed sleep, pain, tingling, numbness, tremors, loss of balance, weakness in one or more limbs, fatigue, muscle spasms, that are associated with pain. A physician can measure the symptoms of pain or pain related disorders, and their resolution during treatment, during a physical examination.

[00108] The compositions and methods of this invention can also further include the addition of one or more therapeutic agents with a compound of formula I treatment as discussed below.

[00109] In the disclosed method, a patient can be administered a dosage form comprising a compound of formula I and optionally an additional therapeutic agents such as, analgesics, antiepileptic, opioids, NSAIDS, to prevent or treat pain or a pain related disorder.

[00110] The second active agents can be administered at the same time or at a different time than the administration of a compound of formula I, and will depend upon the nature of the disease being treated as well as the agent itself. For example, when the additional agent is an anti-epileptic, a twice-daily dose is sufficient and it can be administered at the same time or at a different time than a compound of formula I. For purposes of facilitating patient compliance, administration of any of the aforementioned additional agents at the same time is preferred. [00111] The combination compositions can allow a decrease in the dosage of active agents, such as, the compound of formula I (e.g., agomelatine), or antiepileptic, to a patient and can improved patient compliance. Further, the disclosed compositions, for management of pain and pain related disorders, comprise from about 0.1 mg to about 1500 mg of a compound of formula I (agomelatine), from about 0.1 mg to about 1500 mg of an antiepileptic and optionally a pharmaceutically acceptable carrier. Preferably, the disclosed pharmaceutical composition comprises from 1 to about 500 mg of a compound of formula I (agomelatine) and from about 5 to about 1000 mg of an antiepileptic. More preferably, the disclosed pharmaceutical composition comprises from 5 to about 100 mg of a compound of formula I (agomelatine) and from about 10 to about 600 mg of an antiepileptic. Most preferably, the disclosed pharmaceutical composition comprises from about 10 to about 50 mg of a compound of formula I (agomelatine) and from about 250 to about 350 mg of pregabalin. [00112] In another embodiment of the disclosed pharmaceutical composition, one active agent is in a controlled release form and one active agent in an immediate release form, extended (controlled) release form or delayed release form, with an optional pharmaceutically acceptable carrier.

[00113] In another embodiment, the disclosed method comprises administering to a subject in need of relief from pain and pain related disorders, a pharmaceutical composition comprising from about 0.1 mg to about 1500 mg of a compound of formula I (agomelatine), from about 0.1 mg to about 1500 mg of an antiepileptic and optionally a pharmaceutically acceptable carrier. Preferably, the disclosed pharmaceutical composition comprises from about 1 mg to about 500 mg of a compound of formula I (agomelatine) and from about 5 to about 1000 mg of an antiepileptic. More preferably, the disclosed pharmaceutical composition comprises from about 5 mg to about 100 mg of a compound of formula I (agomelatine) and from about 10 to about 600 mg of an antiepileptic. Most preferably, the disclosed pharmaceutical composition comprises from 10 to about 50 mg of a compound of formula I (agomelatine) and from about 250 to about 350 mg of pregabalin.

[00114] In another embodiment, the disclosed method comprises administering to a subject in need of relief from pain and pain related disorders, a pharmaceutical composition comprising from about 0.1 mg to about 1500 mg of a compound of formula I (agomelatine), from about 0.1 mg to about 1500 mg of an antiepileptic and optionally a pharmaceutically acceptable carrier. Preferably, the disclosed pharmaceutical composition comprises from about 1 mg to about 500 mg of a compound of formula I (agomelatine) and from about 5 to about 1000 mg of an antiepileptic. More preferably, the disclosed pharmaceutical composition comprises from about 5 mg to about 100 mg of a compound of formula I (agomelatine) and from about 10 to about 600 mg of an antiepileptic. Most preferably, the disclosed pharmaceutical composition comprises from 10 to about 50 mg of a compound of formula I (agomelatine) and from about 250 to about 350 mg of gabapentin.

[00115] When the composition comprising a compound of formula I, is administered with an opioid, the dosage of an opioid that can be administered to a patient is from about 0.1 mg to about 1,500 mg per dose one or more times per week, from about 0.1 mg to about 750 mg per dose one or more times per week, from about 0.1 mg to about 350 mg per dose one or more times per week.

[00116] When the composition comprising a compound of formula I, is administered with an opioid, wherein the opioid is tapentadol, the dosage of tapentadol that can be administered to a patient is from about 0.1 mg to about 500 mg per dose one or more times per week, from about 0.1 mg to about 250 mg per dose one or more times per week, from about 0.1 mg to about 100 mg per dose one or more times per week. [00117] When the composition comprising a compound of formula I, is administered with an opioid, wherein the opioid is morphine, the dosage of morphine that can be administered to a patient is from about 0.1 mg to about 250 mg per dose one or more times per week, from about 0.1 mg to about 100 mg per dose one or more times per week, from about 0.1 mg to about 50 mg per dose one or more times per week.

[00118] When the composition comprising a compound of formula I, is administered with an opioid, wherein the opioid is oxycodone, the dosage of oxycodone that can be administered to a patient is from about 0.1 mg to about 250 mg per dose one or more times per week, from about 0.1 mg to about 100 mg per dose one or more times per week, from about 0.1 mg to about 50 mg per dose one or more times per week. [00119] The amount of agomelatine in the disclosed compositions is in the range of from about 0.1 mg to about 500 mg, preferably from about 1 mg to about 100 mg and most preferably from about 5 mg to about 50 mg, per dosage unit. The amount of palmitoylethanolamide (PEA) in the disclosed compositions is in the range of from about from about 0.1 to about 1500 mg, more preferably, from about 5 to about 1000 mg of an palmitoylethanolamide (PEA), and most preferably, from about 10 to about 600 mg, per dosage unit, still most preferably from about 50 to about 600mg of palmitoylethanolamide (PEA). [00120] The disclosed compositions can allow a decrease in the dosage of active agents, such as, agomelatine or palmitoylethanolamide (PEA), to a patient, which can promote better patient compliance. Further, the disclosed compositions comprise from about 0.1 mg to about 500 mg of agomelatine, from about 0.1 mg to about 1500 mg of palmitoylethanolamide (PEA) and optionally a pharmaceutically acceptable carrier, for management of pain, depression, and pain related disorders. Preferably, the disclosed pharmaceutical composition comprises from 1 to about 100 mg of agomelatine and from about 5 to about 1000 mg of palmitoylethanolamide (PEA). More preferably, the disclosed pharmaceutical composition comprises from 5 to about 50 mg of agomelatine and from about 10 to about 600 mg of palmitoylethanolamide (PEA). Most preferably, the disclosed pharmaceutical composition comprises from 10 to about 20 mg of agomelatine and from about 250 to about 300 mg of palmitoylethanolamide (PEA). In another embodiment of the disclosed pharmaceutical composition, one active agent is in a controlled release form and one active agent in an immediate release form, extended (controlled) release form or delayed release form, with an optional pharmaceutically acceptable carrier. [00121] When the disclosed compositions are administered with a NSAID, the amount of NSAID administered to the patient is from about 0.1 mg to about 1,500 mg per dose one or more times per week, from about 0.1 mg to about 800 mg per dose one or more times per week, from about 0.1 mg to about 400 mg per dose one or more times per week, from about 0.1 mg to about 200 mg per dose one or more times per week, from about 0.1 mg to about 100 mg per dose one or more times per week, from about 0.1 mg to about 50 mg per dose one or more times per week, or from about 0.1 mg to about 25 mg per dose one or more times per week.

[00122] The disclosed pharmaceutical compositions can be prepared by methods known in the art. Such methods are well known in the art for example in "Remington's Pharmaceutical Sciences", A.R. Gennaro (ed.), 17th edition, Mack Publishing Company, Easton, Pa. (1985), in particular in part 8, chapters 76 to 93. [00123] One or both of the active agents can be present in the disclosed pharmaceutical formulations at least partially in controlled-release form. Moreover, any controlled release/ immediate release combination of the agents can also be present in the disclosed pharmaceutical formulation. For example, one or both of the components can be released from the disclosed formulations with a delay, e.g., if administered orally, rectally or percutaneously. Such formulations are particularly useful for "once-daily" or "twice-daily" preparations, which only have to be taken once a day, or twice a day, respectively. Suitable controlled-release materials are well known to those skilled in the art.

[00124] The disclosed pharmaceutical compositions can be prepared in various forms such as, for example, granules, spheroids, pellets, multiparticulates, capsules, patches tablets, sachets, controlled release suspensions, or in any other suitable dosage form incorporating such granules, spheroids, pellets or multiparticulates. The compositions can be, for example, a tablet formed from granules, spheroids, pellets, multiparticulates and the like or the granules, spheroids, pellets, multiparticulates can be in pellets [00125] The disclosed solid pharmaceutical compositions can be tablets, for example, the components of the pharmaceutical composition can be granulated with a pharmaceutical carrier, for example, conventional tablet ingredients such as corn starch, lactose, saccharose, sorbitol, talcum, magnesium stearate, dicalcium phosphate or pharmaceutically acceptable gums, and pharmaceutical diluents, for example, water, in order to form a solid composition which can be divided into unit dosage forms such as tablets, or capsules, and the like. The disclosed tablets or capsules prepared can be coated suitably to provide an osmotic delivery system. Non-limiting examples of osmotically driven release systems are, for example, disclosed in U.S. patent no. 4,765,989, U.S. patent no. 4,783,337 and U.S. patent no. 4,612,008.

[00126] The disclosed compositions can be in dosage forms, e.g., coated tablets wherein the coating includes at least one water-insoluble, water permeable film-forming polymer, at least one plasticizer and at least one water-soluble polymer, and the second active agent. In a preferred form the coating can have at least one water-insoluble, water-permeable film-forming polymer varies from about 20% to about 90% of the coating dry weight, the proportion of the at least one plasticizer varies from about 5% to about 30% of the coating dry weight, and the proportion of the at least one water-soluble polymer varies from about 10% to about 75% of the coat dry weight. [00127] One or more of active ingredients in the disclosed compositions can also be incorporated in a matrix. Non-limiting examples of matrices are provided in U.S. patent no. 5,330,761, U.S. Patent No. 5,399,362, U.S. Patent No. 5,472,71 1 and U.S. Patent No. 5,455,046. The matrix can be any type known to a person skilled the art, that affords slow release active agent over at least about a twelve-hour period and preferably that affords in-vitro dissolution rates and in vivo absorption rates of an agomelatine or secondary agent within the therapeutically effective ranges. The disclosed composition can preferably use a slow release matrix. Alternatively, normal release matrices having a coating that provides for slow release of the active agents can be used. [00128] The slow release matrices that can be employed in the disclosed compositions can also contain other pharmaceutically acceptable ingredients which are conventional in the pharmaceutical art such as diluents, lubricants, binders, granulating aids, colorants, flavorants, surfactants, pH adjusters, anti-adherents and glidants, e.g., dibutyl sebacate, ammonium hydroxide, oleic acid and colloidal silica. Any known diluent e.g., microcrystalline cellulose, lactose and dicalcium phosphate can be used to prepare this composition. Non-limiting examples of lubricants are, e.g., magnesium stearate and sodium stearyl fumarate. Non-limiting examples of binding agents are, e.g., hydroxypropyl methylcellulose, polyvidone and methyl- cellulose. Suitable disintegrating agents include starch, sodium starch glycolate, crospovidone, croscarmellose sodium and the like. [00129] Alternatively, the composition comprising a compound of formula I, and the second agent, wherein one of the active agents is in slow release form, can comprise a normal release matrix having a slow release coating. Preferably the combination comprises film-coated spheroids containing the active ingredient and a spheronising agent. The spheronising agent can be any suitable pharmaceutically acceptable material that can be combined with the active ingredient to form spheroids.

[00130] The amount of the disclosed pharmaceutical composition to be administered to the patient can vary as is well known to those skilled in the art. Factors such as, for example, the weight of the patient, the route of administration, or the severity of the illness can affect the exact amount administered. Suitable methods of delivering the disclosed composition include, but are not limited to oral, intravenous, intraarterial, intraperitoneal, intradermal, transdermal, intrathekal (intrathecal), intramuscular, intranasal, transmucosal, subcutaneous, or rectal administration.

[00131] The following Examples are for illustrating the invention related to compositions comprising agomelatine and no intended to limit the scope of the invention. The experimental examples disclose the preparation and use of a composition comprising a combination of agomelatine and an immunomodulatory DMARD, antiepileptic, opioid, NSAID and corticosteroid agent for treating a disorder and are intended to be a way of illustrating but not limiting the invention.

PHARMACOLOGICAL STUDIES Example: 1: Formulation having Agomelatine and Palmitoylethanolamide

[00132] Description of Manufacturing Process: The composition, disclosed in Table 1, was manufactured in four steps described below: TABLE 1 Ingredients mg per tab gm per 5000 tabs Agomelatine 12.50 62.50 Palmitoylethanolamide (PEA) 150.00 750.00 Micro crystalline cellulose 40.00 200.00 Croscarmellose sodium 22.50 112.50 Povidone K30 5.00 25.00 Polysorbate 80 1.00 5.00 Colloidal silica 1.00 5.00 Magnesium Stearate 2.00 10.00 Water* q.s. q.s. Total weight of IR tablet 234 mg 1170 g Wet granulation process for manufacture of immediate release tablets. [00133] Palmitoylethanolamide was sifted through a #140 mesh (US) sieve (less than 105 µιη) and ensure that there are no lumps in the powder. [00134] Separately, agomelatine and microcrystalline cellulose were charged in a suitable blender (Turbula mixer, twin shell blender or bin blender) after sifting the excipients through #40 mesh (US) sieve. The contents were mixed thoroughly for 5 minutes. [00135] The pre-sifted palmitoylethanolamide and agomelatine reactants were mixed and shaken thoroughly for 10 minutes.

[00136] In a separate vessel, Povidone K 30 was sifted through #80 mesh US sieve and dissolved in 80% of purified water at 30°C. The contents were stirred at slow speed. The Povidine reaction mixture was heated with 20% purified water to 60°C. Polysorbate 80 was added to Povidone solution and stirred slowly till the solution becomes clear by gentle mixing. [00137] The granulating fluid prepared above was added to palmitoylethanolamide and agomelatine and other excipients. The contents were granulated in a Rapid mixer granulator (RMG) by running the mixer and chopper at slow speed. The granules were checked to ensure there are no lumps. The granules were dried at 60°C till the moisture content of the granules is less than 2% and passed through a suitable mill (Fitz or Multi mill) with a #30 mesh (US) sieve. The contents were transferred to a blender, and sodium CMC was added. Colloidal Silica was passed through sieve no. #80 and was mixed with granules for 5 minutes. [00138] Magnesium stearate was passed through sieve no #80 and was added to granules. The reactants were stirred for another 2-3 minutes. The particle size distribution of the granules was controlled for the fine fraction to be not more than 25 to 30% to prevent potential flow issues. The fines are defined as particles sized < 140µιη (100 mesh US Standard) [00139] The tablets were prepared by compressing the granules in a rotary tablet machine with appropriate tooling and a compression weight of 234 mg.

Example 2 : Case Study A (PT #3342 DP) agomelatine and PEA [00140] Patient: The case study patient was 55-year-old single woman, with a history of five yearlong osteoarthritis and type two diabetes. Her glycemic control was achieved with diet and oral medication. Her symptoms included numbness and pain in the distal aspect of the calves and feet, which she said was much worse at night when she tried to sleep. Her pain was evaluated using the 11-point numeric rating scale (NRS-scale:0 indicating no pain, 10 indicating worst pain imagined). She scored her pain at 7/10 during the day (ranging from 5 to 8/10) and 9/10 at night (ranging from 7 to 10/10). The patient described her pain sensation "burning", "with someone jabbing pins". She also described it as electrical shocks and tingling.

[00141] The patient's occupational and personal history was taken, and indicated that she had been active in her retirement community, a member of several committees, politically active, and played golf several times weekly. However, because of the unrelenting pain, she could no longer do the things she enjoyed. She maintained satisfactory glycemic control (HbAlc, 6.7%). On physical examination, the patient's vital signs were normal, and no pronounced abnormalities involving the major organs were noted. Abnormalities of the peripheral nervous system, skin, and vascular supply for her distal lower extremities were observed. The skin of her feet was shinny and thin, with a bluish coloration, and her feet were cool to the physician's touch. Pulses in her feet were bilaterally diminished but symmetrical. Lower extremity strength testing was 5/5. Deep tendon reflexes were diminished at the ankles (1/4) relative to the knees (2/4) bilaterally.

[00142] The patient tried to control her recent "numbness/burning/tingling" pain by increasing the acetaminophen, which used to control her osteoarthritis pain, doses and was not relieved of her new pain. She tried to use over the counter capsaicin cream that was unsuccessfully as well. Because patient appeared depressed her mood was evaluated.

[00143] Diagnosis: The diagnosis of DPNP was made based on the physical examination of the patient, which revealed no other pronounced abnormalities, coupled with her description of bilateral burning pain and dysesthesia in her feet, abnormal skin appearance, and diminished pulses. [00144] Treatment: Over a two-week period, the patient was treated with gabapentin (from 100 mg to 600 mg/day) at bedtime. The gabapentin dose was reduced to 300 mg/day and duloxetine (30 mg/day) was added. The patient was told to take duloxetine in the morning. She was able to successfully increase the dose to the target dosage of 60 mg/d after 1 week, with her daytime pain level decreasing from 8/10 to 6/10.

[00145] To continue to improve her clinical condition and better control her pain, the patient's physician switched from gabapentin to palmitoylethanolamide (PEA) 300 mg/day. After fourteen days of combination treatment with palmitoylethanolamide (PEA) and duloxetine, her pain intensity was showing improvements and decreased from 6/10 to 4/10. The patient was asked to discontinue duloxetine and replaced with agomelatine, 25 mg/day. After two days, the patient called to tell us excitingly, she was able sleep and her pain was so much better. The pain score measured after 14 days to read at 3/10-4/10. But her general condition and mood had improved significantly. She was able to play out door games. However she still complained of some mild tingling and electrical shock type sensations. The palmitoylethanolamide (PEA) dose increased to 600 mg/day and reduced agomelatine to 12.5 mg/day. Once stabilized with PEA and agomelatine, her pain intensity during the day was 2/10 with intensity during the night of 3/10. With these final changes, she was able to resume her favorite sports.

EXAMPLE 3: Case Study B (PT #3349 FS) [00146] Patients: Three patients aged 45 years old (patient 1), 53 years old patient 2) and 51 (patient 3) years old all diagnosed with fibromyalgia syndrome were recruited for the study. The same physician diagnosed all three subjects with primary fibromyalgia, and those patients with associated rheumatic or other medical disorders that contributed to the symptoms of fibromyalgia were excluded at screening phase. Each of the patients had widespread pain present for at least 3 months and pain in at least 11 of 18 specific tender point sites), had an average pain score > 4 on an 11-point numeric rating scale (NRS; 0 = "no pain" to 10 = "worst possible pain") during the baseline assessment. None of them had history of substance abuse in the last year or history of psychosis. They had not used skeletal muscle relaxants, antidepressants or PEA, opioid narcotics, and anti-Parkinson's disease medications > 7 days before their screening visit. Every one of them had been on either pregabalin or gabapentin treatment prior to the study.

[00147] Treatment Method: The patients were asked to discontinue the pregabalin and a washout period maintained. During the wash out period, each of the patents underwent physiotherapy as rescue treatment. After one week of washout period, subjects received 12.5 mg agomelatine and 300 mg tablets of PEA (BID) and were titrated. Patients were instructed to maintain their normal daily routine and not to alter exercise regimens. The pain was measured using the 11-point NRS with respect the single primary endpoint was mean pain score from patients' daily pain diaries. Each day on awakening, patients rated their pain during the previous 24 hours. The patients were treated for a period of six weeks after wash out period. The pain and sleep quality scores were recorded and followed up every week. There after the patients were followed up once every month for three more visits.

[00148] Baseline characteristics: The baseline pain scores for patient 1, patient 2, and patient

3 were 7.45, 7.7, and 7.23 respectively. Similarly the baseline sleep quality scores for patient 1, patient 2, and patient 3 were 6.85, 6.99, and 7.07 respectively.

[00149] Results: All three patients reported improvement in sleep after two days and pain relief after three days of treatment. Their general condition and mood had improved significantly after one week of treatment. The patient's pain scores and sleep quality scores were monitored over a period ten weeks. The scores were at least 30% less that the baseline scores every week during the entire treatment period. Table 2 and Figures 1 and 2 illustrate the results. TABLE 2

TREATMENT ARM Patient 1 Patient 2 Patient 3 Average Age (Years) 45.3 53.1 51.2 Duration of FMS Prior to Baseline 7.70 7.10 6.90 Body Mass Index (BMI) 31.20 30.50 32.30 Number of Painful Tender Points 18.00 17.00 18.00 Baseline Pain Score (NRS) 7.45 7.70 7.23 Baseline Sleep Quality Score 6.85 6.99 7.07 End of Treatment Pain Score (NRS) 3,10 2.87 3.31 End of Treatment Sleep Quality Score 3.70 3.95 3.80

[00150] The end of treatment pain scores (week 6) for patient 1, patient 2, and patient 3 were 3.10, 2.87, and 3.31 respectively. Similarly, the end of treatment sleep quality scores for patient

1, patient 2 and patient 3.70 were 3.95, and 3.80 respectively. The patients indicated they were able to sleep much faster and longer because of new treatment. Their general conditions and their pain were improved.

[00151] The patients were followed up for a period of additional three months after six weeks of treatment period. The patients were able to resume their normal route work after four-six weeks of treatment with significant improvement in pain relief and sleep quality scores.

[00152] The above studies show that the oral administration of palmitoylethanolamide (PEA) in combination with agomelatine was consistently beneficial in treating patients with pain and pain related disorders. Example 4 : Bilayer Pharmaceutical Composition [00153] The combination formulation shown in Example 4 is for illustration. TABLE 3 Modified release layer Ingredients mg per tab mg per tab Pregabalin 300.00 300.00 Ethylcellulose 48.00 48.00 Hydrogenated castor oil 25.00 25.00 Magnesium Stearate 2.00 2.00 Total weight of Modified release layer 375 mg 375 mg

Immediate release layer Agomelatine 25.00 12.50 Mannitol 61.80 74.30 Maize starch 18.00 18.00 Povidone K30 9.00 9.00 Sodium Starch glycolate 12.00 12.00 Stearic acid 2.60 2.60 Silica colloidal anhydrous 0.30 0.30 Magnesium Stearate 1.30 1.30 Water* q.s. q.s. Total weight of Immediate release layer 130 mg 130 mg

Coating (Non functional) Gm/Ltr Gm/Ltr HPMC (2910 - 15 cps viscosity grade) 20.16 20.16 PEG 8000 6.72 6.72 PEG 400 6.72 6.72 Titanium dioxide (micronized) 6.72 6.72 Water* 1 Liter 1 Liter

[00154] Description of Manufacturing Process: The composition was manufactured in four steps described below:

Step I: Granulation of the modified release layer [00155] Pregabalin and 50% of the ethyl cellulose were passed through sieve no. #40 and agglomerates were removed. The materials were mixed in a blender (Turbula mixer, twin shell V blender or bin blender) for 10-15 minutes. The Hydrogenated castor oil was melted, at 90°C, in a jacketed rapid mixer granulator (RMG) and the pregabalin-ethyl cellulose blend was added and granulated. The granulated materials were mixed continuously with gradual cooling to room temperature. The resulting granules were sized through a 1.5 mm screen to break the agglomerates. The screened granules were transferred to a blender and mixed with the remaining quantity of Ethyl cellulose for 5 minutes in a V shaped blender.

[00156] To the above blend, Magnesium stearate (passed through sieve no.# 60) was added and mixed for 4 minutes. Particle size distribution of the granules was controlled for the fine fraction to be not more than 25 to 30%. (Fines are defined as particles sized < 140µιη (100 mesh US standard).)

Step II: Wet granulation of the immediate release layer. [00157] Agomelatine, Maize starch and Mannitol were charged in a suitable blender (Turbula mixer, twin shell blender or bin blender) after sifting the excipients through #40 mesh (US) sieve. The contents were mixed for 5-10 minutes. [00158] In a separate vessel, Povidone K 30 (sift through #80 mesh US sieve) was charged and dissolved in sufficient quantity of water to form the granulating fluid. The granulating fluid was added and mixed with the agomelatine, starch and mannitol mixture and granulated in a Rapid mixer granulator (RMG) to prepare granules. [00159] The granules were dried at 60°C until the moisture content of the granules is less than

2% and passed through a suitable mill (Fitz or Multi mill) with a 1.5 mm sieve. The granules were transferred to a blender, to which Sodium Starch Glycolate, Stearic acid and Magnesium stearate (passed through sieve no. #60) were added, and mixed thoroughly for 5 minutes. Silicon dioxide (passed through sieve no #80) was added to the granules and thoroughly mixed for 5 minutes. The particle size distribution of the granules is controlled for the fine fraction to be not more than 25 to 30% so that there are no flow issues. (Fines are defined as particles sized < 140µιη (100 mesh US standard).)

Step III: Compression on a bilayer press [00160] The tablets were compressed using a bilayer press and compression tooling. The immediate release material prepared in step II (agomelatine layer) was loaded into one hopper of the bilayer press, and the modified release material prepared in step I (pregabalin layer) was loaded into the second hopper of the bilayer press.

[00161] The MR release layer was adjusted target weight of 375 mg and the IR layer was at target weight of 130 mg. The average tablet hardness after compression was achieved 25 to 30 kp. Step IV: Coating layer for tablets [00162] A suitable container was charged with 80 ml of purified water and heated to about 60°C - 70°C. HPMC, 20.16 g was added into the heated water, with gentle stirring. After the polymer is wetted, 80 ml of cold water was added immediately. The dispersion was stirred until it becomes homogenous. Polyethylene 8000, 6.72 g, was dissolved in 100 ml of water and added to the HPMC dispersion. This was followed by addition of PEG400, 6.72 g, and stirring for an additional five minutes. The pigment, micronized titanium dioxide, 6.72 g, was added to this polymer solution, with constant stirring. The dispersion was homogenized to achieve particle size reduction of the pigment. The volume was increased by addition 336 mL of cold water. The core tablets were loaded onto a coating pan. The coating dispersion was applied to provide a weight gain of about 2.5 to 4.0% w/w. The coating dispersion was agitated during the coating process. The coating is a non-active material and is provided only for the purpose of providing a protective layer and for ease of swallowing. [00163] A person skilled in the art can prepare additional dosage forms using techniques known in the art.

Example 5: Pharmacological Studies with agomelatine and pregabalin [00164] Procedure: The procedure used to determine and compare the effect of the disclosed compositions, for which there is a good correlation with human efficacy for the treatment of pain, is the procedure for the measurement of allodynia according to the Chung Model (Quantitative Assessment of Tactile Allodynia in the Rat Paw, J. Neurosci. Meth., 1994, 53, 55- 63, Chaplan, S.R., Bach, F.W., Pogrel, J.W., Chung, J.M. and Yaksh, T.L., and An Experimental Model for Peripheral Neuropathy Produced by Segmental Spinal Nerve Ligation in the Rat, Pain, 1992, 50, 355-363, Kim, S.H. and Chung, J.M.,). The anti-allodynic effect of the composition of the present invention in the Chung Model is expressed in Maximum Possible Effect (% MPE). These documents are hereby incorporated by reference and form part of the disclosure.

[00165] Animals: Pathogen-free, male albino Sprague-Dawley rats, 150 g to 200 g, were supplied by Charles River Laboratories and maintained on a 12-hours light/dark cycle (lights on at 06:00 hours) in a climate-controlled room with food and water available ad libitum.

[00166] Animal Surgical Preparation: The rats were anesthetized with isoflurane inhalant anesthesia. Ligatures were applied to the left L5/L6 spinal nerves of the animals. Animals developed tactile allodynia at the ipsilateral paw. Three to four weeks after the operation the tactile allodynia threshold baseline (withdrawal threshold) was measured on the ipsilateral and contralateral hind paw by an electronic von Frey anaesthesiometer.

Preparation of the Composition Doses of agomelatine and pregabalin [00167] The dosing materials were all prepared in the vehicle, a suspension of 0.9% NaCl in distilled water; drug weights were calculated as the free base. The agomelatine solution was prepared first, and the appropriate volume of this solution was added to an amount of the pregabalin to give the final dosing suspension. Drug weights were calculated as the free base, and the ratios used were based on the respective ED 0 values. The necessary doses for each ratio were prepared separately and dosed orally in a volume of 10 mL/kg per rat. [00168] Animal dosing: The Chung Model rats were all dosed orally with the composition comprising a combination of agomelatine and pregabalin (calculated as the base) or the composition of each agent separately dissolved in distilled water or dissolved in a suspension of 0.9% NaCl in distilled water. The dosing volume was 5 mL/kg. After the tests and baseline measurements, the rats were incubated with various doses of agomelatine alone, pregabalin drug alone, combined doses of agomelatine and pregabalin or vehicle such as distilled water or a suspension of 0.9%> NaCl in distilled water by the intravenous (i.v.) route (application volume 5 ml/kg). Animals were randomly assigned to groups of 10 for each test dose and vehicle (0.9 % NaCl solution) and tactile withdrawal thresholds were tested 0.5 hours before administration and on several time points (0.5, 1 and 3 hours) after intravenous administration. Ipsilateral and contralateral hind paws were tested. [00169] Measurement: The median of the withdrawal threshold for each animal at a given time is calculated from five individual stimulations. Withdrawal thresholds of the injured paws are expressed as % MPE (Maximum possible effect) comparing pre-drug threshold of Chung- Animals (= 0 % MPE) and control threshold of sham-animals (100 % MPE). A cut-off is set at 100 % MPE. The effect of each compound and vehicle is calculated for each testing time point as inter-individual % MPE value. Data (anti-allodynic efficacy (% MPE), ipsilateral, paw withdrawal threshold (g), ipsilateral and contralateral) were analyzed by means of a two-factor analysis of variance (ANOVA) with repeated measures. In case of a significant treatment effect, post hoc analysis with Bonferroni adjustment was performed. Results were considered statistically significant if P < 0.05. ED50 values and 95 % confidence intervals (95 % CI) were determined for the anti-allodynic efficacy (% MPE) at the time of the peak effect for each drug by regression analysis.

[00170] The analysis of the results was carried out via statistical comparison of the theoretical additive EDso-value with the experimentally determined EDso-value of a so-called fixed ratio combination (As per Statistical analysis of drug-drug and site-site interactions with isobolograms; Life Sci. 1989; 45: 947-61 Tallarida, R.J., Porreca, F., and Cowan, A.). [00171] Results: The three formulations, Agomelatine alone, an antiepileptic (pregabalin) alone, and the combination of Agomelatine and an antiepileptic (pregabalin) showed a dose dependent increase in the withdrawal threshold of the ipsilateral hind paw. [00172] Agomelatine (0.1, 3.16 and 5 mg/kg) and pregabalin (0.1, 3.16 and 10 mg/kg i.v.) show a dose dependent increase in the withdrawal threshold of the ipsilateral hind paw. Agomelatine and an antiepileptic (pregabalin) composition show a potency difference, which amounts to a factor 2.5 based on the ED50 values 30 minutes after administration. Combinations in a fixed ratio of 1 : 2.5 (agomelatine : pregabalin) were tested in doses of 0.01 mg/kg + 0.25 mg/kg; 0.03 mg/kg + 0.75 mg/kg, 0.09 mg/kg + 2.5 mg/kg i.v. Agomelatine + pregabalin, respectively. The results are illustrated in Table 4. TABLE 4

[00173] The experimental ED50 value (95 % confidence interval) of the combination is below the theoretical additive ED50 value (95 % confidence interval) of the combination and is statistically significant (p<0.001) as compared to the additive value. Thus, the interaction of agomelatine and pregabalin is synergistic.

Example 6: Pharmacological Studies for Treatment of Fibromyalgia An Exploratory study to test the tolerability and safety of the Pregabalin and Agomelatine combination in the treatment of patients with Fibromyalgia was conducted. The double blind design study was conducted to assess the efficacy and safety of the disclosed compositions, compared with a placebo for the pain relief associated with fibromyalgia. The measured change from baseline to end of treatment with respect the single primary endpoint provided a mean pain score from patients' daily pain diaries, as measured by the 11-point Numerical Rating Scale (NRS). Each day on awakening, patients rated their pain during the previous 24 hours.

[00174] The 3 to 30-day screening phase was followed by a 1-week, single blind, placebo lead-in baseline phase begun at visit 2. Subjects were provided a placebo for 1 week to obtain an evaluation of the baseline variables, including safety measures. At visit 3, the patients were randomized to 1 of 4 treatment groups: 1) pregabalin, 2) agomelatine, 3) a combination of agomelatine and pregabalin, or 4) placebo, in a 1:1:1:1 ratio. Assignment to treatment groups was determined by a computer-generated random sequence using an interactive voice response system. The treatment phase was a double blind for 12 weeks. The patients were evaluated

Weeks 1, 2, 5, 9, 13 (termination), and 13 (follow up). [00175] The level of drug(s) administered to the patients was determined by titration. The number of placebo capsules was similarly adjusted to maintain the blinding.

[00176] Sample Size: A total of about 98 patients were enrolled from 132 screened. The design ensured that drugs were administered to at least 15 patients in each of four clinical arms so that at least 10-12 patients completed treatments in each arm.

[00177] The patients were both female or male and at least 18 years of age old. All met the ACR criteria for primary fibromyalgia, had widespread pain for at least 3 months and pain in at least 11 of 18 specific tender point sites, and an average pain score > 4 on an 11-point numeric rating scale (NRS; 0 = "no pain" to 10 = "worst possible pain") during the baseline assessment. All patients reported a score > 40 mm on the 100-mm numeric rating scale (NRS) at visits 1 (screening) and 2 (the placebo lead-in phase).

[00178] The patients were instructed to maintain their normal daily routine and not to alter exercise regimens, and they were allowed to continue stable (e.g., for > 30 days prior to screening) non-pharmacologic therapy, such as physical therapy, massage, chiropractic care, and psychological therapy, through the course of the trial.

[00179] Patients with associated pain from traumatic injury, rheumatic disease or other medical disorders that contributed to the symptoms of fibromyalgia were excluded. [00180] The patients were treated once daily with one of: 1) Pregabalin (300 mg); 2) Agomelatine (25 mg); 3) a combination of Agomelatine (25 mg) and Pregabalin (300 mg); and 4) a placebo.

Measurement Methods [00181] Primary Measures: The change in pain levels, from baseline to end of treatment, with respect the single primary endpoint was the mean pain score, taken from the patients' daily pain diaries, as measured using the 11-point NRS. Each day on awakening, patients rated their pain during the previous 24 hours. The proportion of responders, defined as patients with a > 30% reduction in mean pain score from baseline to endpoint, was determined as a supplemental measure of the primary efficacy measure, as was weekly mean pain score.

[00182] Patients rated their sleep quality on the 11-point non-restorative sleep (NRS) scale (0 = "best possible sleep" to 10 = "worst possible sleep") included in their daily diaries. The Medical Outcomes Study (MOS)-Sleep Scale was administered as an additional measure of sleep. Functioning was assessed using the Short-Form 36 (SF-36) Health Survey, the Sheehan Disability Scale (SDS), and the Fibromyalgia Health Assessment Questionnaire (F-HAQ). The Short-Form McGill Pain Questionnaire (SF-MPQ) served as an additional measure of pain, while the Multidimensional Assessment of Fatigue (MAF) was used to evaluate fatigue and the degree to which it interferes with daily activities. Finally, mood disturbances were evaluated via the Hospital Anxiety and Depression Scale (HADS). Most of these secondary efficacy measures, with the exception of the daily sleep diary, were performed at baseline, termination, and at 2 additional time points during the trial (Weeks 5 and 9).

[00183] The clinical laboratory evaluations were performed at baseline, Week 5, and upon termination. Adverse events (AE) were recorded at each trial visit irrespective whether volunteered by patients or observed by the clinicians. A physical examination, full neurologic examination, and a 12- lead ECF were completed at baseline and termination. [00184] Secondary Measures: Two secondary methods for evaluating pain were also employed:

[00185] FIQ-Total Scores, administered at the termination visit, was used as additional primary endpoints to evaluate the efficacy of pregabalin for meeting the management of FM, and [00186] The Patient Global Impression of Improvement (PGI-Improvement) scale, ranging from 1 (very much better) to 7 (very much worse).

[00187] Results

[00188] Patient Characteristics: The treatment groups, Table 5, were well balanced in demographic and baseline characteristics. In all 133 patients were screened as potential study participants and 98 among them were randomized and received study medication. The reasons for not randomizing patients were either because the patient didn't meet the criteria (42%) or dropped out (30%>) the patients couldn't participate in the trial because of logistical reasons (12%). TABLE 5

[00189] Of the 98 patients who received study medication, 31 (3 1%>) withdrew from the trial during the double-blind treatment phase. The key reasons were missing medications, non- recording of scoring and deviations from time of administration, etc., protocol deviations, rescue medication use, and compliance. Twenty-one percent (21%>), withdrew due to an adverse event, eighteen percent (18%>) due to lack of efficacy, and forty-eight percent (48%>) for other reasons. Of the patients who withdrew due to lack of efficacy, the greatest number of such withdrawals were in the placebo group (3 patients; 50%> of the all patients who discontinued) followed by the agomelatine treatment group (2 patients; 33% of the all patients who discontinued). No patient withdrew from the combination group due to lack of efficacy. Similarly, of the 9 patients who withdrew due to an AE, the greatest number were in the agomelatine and pregabalin treatment groups (3 patients; 33% of all AE related withdrawals in each group,) versus 2 patients (22%) who received placebo and 1 ( 11%) in the combination treatment arm.

[00190] Baseline characteristics: Demographic and baseline characteristics of the randomized subjects were similar across treatment groups. Most patients were female (90%>), and between 18 and 64 years of age (80%), with a mean age of 58.5 years (range 33 to 82). The majority of women were postmenopausal (65%). The pain scores were similar at the baseline for all groups. Most patients in the study had been symptomatic with FM for more than 6 years, with a mean duration of 7.5 years.

[00191] The mean baseline values for efficacy measures (Table 6) reflected known characteristics of patients with FM, namely, high levels of baseline pain (mean pain score 7.4), mean sleep quality of 6.87, sleep disturbance (MOS-Sleep Disturbance score 65.1), and fatigue (MAF global fatigue index 37.7). The FIQ-Total Score (Mean score 66.1) and Mean Short- Form McGill Pain Questionnaire scores (Mean Score 73.2) did not change between screening and randomization. TABLE 6

EFFICACY MEASURE (RANGE), n-98 or as noted Mean (SD)

Mean pain score (0-10) 7.42 (1.3) Mean sleep quality score (0-10) 6.7 (1.7) Hospital Anxiety and Depression Scale Anxiety score (0-2 1) 10.1 (4.2) Depression score (0-2 1) 8.1 (4.0)

Fibromyalgia Impact Questionnaire (total, 0-100; items 0-10) Total 66.1 (11.4) Physical function 4.2 (2.1) Feel good 8.3 (1.9) Work missed 3.8 (3.4) Do job 7.1 (2.2) FIQ pain 7.7 (1.6) Fatigue, n = 742 8.8 (1.8) Rested, n = 95 8.7 (1.9) Stiffness, n = 97 8.5 (1.6) Anxiety, n = 97 4.9 (2.8) Depression, n = 97 4.9 (2.8) TABLE 6 (Cont.) SF-36 (each domain, 0-100) General health perception, n = 96 44.1 (23.6) Physical functioning 45.1 (19.8) Physical role limitations 37.2 (18.5) Emotional role limitations 63.7 (29.5) Social functioning 49.2 (23.6) Mental health 58.3 (23.1) Bodily pain 27.2 (14.6) Vitality 23.2 (16.3) Physical component score, n = 97 31.8 (7.1) Mental component score, n = 97 40.1 (11.5) Sheehan Disability Scale (total, 0-30; items, 0-10) Work, n = 96 6.1 (2.3) Social life, n = 97 5.5 (1.7) Family/home, n = 95 6.6 (2.8) Total score, n = 97 15.5 (5.5) Medical Outcomes Study Sleep Scale (items, 0-100, unless noted otherwise) Sleep disturbance, n = 95 65.1 (19.3) Snoring, n = 97 55.6 (26.9) Awaken short of breath or with headache, n = 97 38.7 (29.1) Quantity of sleep, (hours /night) n = 97 5.7 (1.3) Optimal sleep, (%) n = 97 14.90% Sleep adequacy, n = 97 20.1 (19.0) Somnolence, n = 97 52.8 (22.2) Sleep problem index, n = 97 67.0 (15.2) Fibromyalgia Health Assessment Questionnaire (all items 0-3) Dressing, n = 95 0.59 (0.55) Stand up from chair, n = 95 1.1 1(0.65) Washing, n = 95 0.47 (0.47) Reach overhead, n = 93 1.05 (0.77) Bending, n = 94 0.98 (0.58) Run errands, n = 93 0.91 (0.46) Get in and out of car, n = 93 0.81 (0.44) Do chores, n = 94 1.51 (0.77) F-HAQ total score, n = 94 0.96 (0.66) Short-Form McGill Pain Questionnaire Sensory (0-33) 20.1 (5.4) Affective, (0-12) 5.6 (1.9) Total (0-45) 25.1 (7.7) Visual analog scale (0-100) 73.2 (6.6) Present pain intensity, (0-5) 3.4 (0.7) TABLE 6 (Cont.) Multidimensional Assessment of Fatigue (index, 1-50) Global fatigue index 37.7 (6.2)

[00192] Finally, the baseline Hospital Anxiety and Depression Scale ratings; mean anxiety (10.1) and depression (8.1) scores, were in the mild category (both scales range from 0 to 21, and the mild category is 8-10). The size and distribution of the primary analysis population between treatment groups did not provide sufficient statistical power to evaluate the minor variations at baseline.

Efficacy [00193] The proportions of patients classified as responders (> 30% decrease in mean pain score) rates were higher than the placebo response rate for all three groups-Agomelatine (38%), Pregabalin (43%) and the combination (45%) groups. [00194] The patients in the treatment groups Agomelatine alone, Pregabalin alone, and the combination group, showed statistically significant improvement in endpoint mean pain score compared with patients receiving placebo (Table 7), demonstrating that treatment with pregabalin and the combination with pregabalin and agomelatine provided symptomatic relief of pain. TABLE 7

[00195] The change in mean pain score from baseline to endpoint between pregabalin and placebo was -0.47 (p = 0.0451) for the Pregabalin alone group and 0.35 for the agomelatine and placebo group (p = 0.0456). However, the mean pain scores in the pregabalin group were not significantly superior to those in the placebo group at Weeks 2, 4, 7, and 10 and the agomelatine group at Weeks,2, 3 and 7. [00196] The change in mean pain score from baseline to endpoint between combination and placebo groups were -0.89 (p = 0.0075) for the investigative drug group. The patients in the combination group showed statistically significant improvement versus placebo at every weekly time point, (except week 8) throughout the trial duration (See Figure 3).

[00197] The efficacy for the management of FM, were evaluated for agomelatine, pregabalin, and for combination, compared with placebo. The PGIC response rates for patients in agomelatine, pregabalin and combination were significant compared with the patients in placebo group (p= p.044, p = 0.048, and p = 0.0105 for agomelatine, pregabalin and combination groups, respectively).

[00198] The PGIC measures are listed in Table 8 and Figure 4. Overall, the percentage of patients reporting at least minimal improvement in PGIC at endpoint 58% for agomelatine, 65% for pregabalin and 72% for combination, compared with 47% in the placebo group.

[00199] The percentage of patients reporting at least "much improved" on the PGIC at endpoint was 38% for agomelatine, 39% for pregabalin and 48% for combination, compared with 26%o in the placebo group (Figure 5).

TABLE 8

[00200] The FIQ-Total Score at endpoint was the third outcome used to assess efficacy. All patients improved from baseline, greater improvement was observed in patients using agomelatine, pregabalin, and the combination groups.

TABLE 9 [00201] Among the secondary efficacy measures, all three treatment groups, agomelatine, pregabalin and combination dosages were associated with statistically significant improvement in sleep quality at endpoint (Table 10) and at each week beginning at Week 1 (all p values < 0.001). The improvement in sleep quality with agomelatine and the combination was significantly faster and better than with placebo and pregabalin treated patient groups (Figure 6).

TABLE 10

MEDICAL OUTCOMES STUDY SCALE [00202] The Medical Outcomes Study Scale is adopted from the methodology as disclosed in "Evaluation of the reliability and validity of the Medical Outcomes Study sleep scale in patients with painful diabetic peripheral neuropathy during an international clinical trial", Muriel Viala-

Danten et al, Health and Quality of Life Outcomes 2008, 6:1 13 doi: 10.1 186/1477-7525-6-1 13, was used as an additional measure of efficacy. The MOS-Sleep is a 12-point measurement developed using patients with chronic illness; it is divided into 6 dimensions evaluating "sleep disturbance," "snoring," "sleep awakening short of breath or with headache," "sleep adequacy," "somnolence," and "quantity of sleep/optimal sleep". A sleep problems index summarizing information across 9 items of the MOS-Sleep scored as outlined below. [00203] All three groups- agomelatine, pregabalin and the combination treatment groups showed significant improvement in the MOS-Sleep Disturbance (all p values < 0.0034) and Sleep Problem Index (all p values < 0.0174) at endpoint.

[00204] Improvement was also observed on the MOS-Sleep Quantity subscale for all three groups, agomelatine, pregabalin, and the combination treatment groups, was statistically significant versus placebo (all p values < 0.0217). It was trending better with agomelatine and combination. While all groups improved on MOS-Sleep Somnolence at endpoint, placebo had the greatest improvement, resulting in statistically significant differences in favor of placebo versus the combination groups. [00205] Treatment with agomelatine and the combination was associated with a reduction in sleep latency from week 2 onward. The difference between treatments was significant on all evaluations. Rapid eye movement latency was increased with pregabalin group compared with agomelatine and combination treatment groups, with significant between-group differences at every visit. Agomelatine and the combination preserved the number of sleep cycles, whereas there was no change with pregabalin group significant between-group differences at every visit. [00206] Most of the remaining secondary measures were generally in the direction of greater improvement with agomelatine, pregabalin and combination treatments.

[00207] A summary of the global fatigue index scores of the MAF showed improvement in combination treated patients than with agomelatine and pregabalin. [00208] The data provided show that an agomelatine and pregabalin combination is beneficial for FM patients affected by pain and associated sleep disturbance.

Example 7: Pharmacological Case Study, Epilepsy and Depression STUDY DESIGN: Open Label Study. STUDY PERIOD: - Twelve Weeks [00209] Patient History: The study recruited a 30-year-old male patient who had a long history of suffering from primary generalized epilepsy. The patient's history revealed he had no personality disorder, schizophrenia, schizoaffective, bipolar- or an organic mental disorder. His generalized tonic-clonic seizures began 7 years ago. The patient had a complete neurologic workup, with some of the tests repeated several times. He normally experiences 1-2 seizures per week.

[00210] The subject had been treated, over the previous five years, with a variety of antiepileptic drugs including lamotrigine (Lamictal), carbamazepine (Tegretol), topiramate (Topamax), oxcarbazepine (Trileptal), zonisamide (Zonegran) and gabapentin (Neurontin). In addition, he had augmentation therapy that included venlafaxine, citalopram, valproic acid, lithium, olanzapine, quetiapine, and buspirone. None of the psychopharmacological and psychotherapeutic interventions were effective in providing remission. [00211] Since diagnosis, the patient has not been very motivated. He did not complete graduate school; has worked only part time at a bookstore, still lives at home, and is uninterested in a relationship or in marriage. His parents fear that he will not be able to support himself independently in the future. Lately, he does not leave home because he is afraid of having a seizure.

[00212] When the patient was presented, he continued to be in a severely depressed and epileptic state. The diagnosis based on clinical history was that the patient was suffering from epilepsy with comormid depression.

[00213] Method: Seven days before the agomelatine and pregabalin combination treatment, all of other medications were stopped, to allow for a washout period. The patient underwent routine medical examination and tests. He was in good health, except for high blood pressure (R 150/90 mm Hg). His lab tests indicated the foliowing-BMI: 25.1, cholesterol: 8.2 mmol/1, triglycerides: 2.2 mmol/1, g-GT: 97 U/I, and there were no pathological issues found in MRI, EEG, ECF and radiographic tests. The patient received an administration of Agomelatine 25 mg once daily and pregabalin 75 mg (BID) for two weeks.

[00214] Results: After three days of treatment with pregabalin and agomelatine combination, the patient reported of feeling less depressed, was exhibiting no more signs of sadness or anxiety. The patient's mood continued to improve over the next several days. During the two-week treatment period there was no incident of seizures. [00215] After two weeks of initial treatment and follow up, the dosage of pregabalin was reduced to 50 mg BID keeping agomelatine dosage at 25mg. The revised treatment continued for four weeks. The patient returned for second follow up. There were no incidents of seizures or depression moments.

[00216] After the second follow up visit, the agomelatine dosage was reduced to 12.5 mg and pregabalin was retained at 50 mg (BID). The patient was monitored for additional eight weeks.

[00217] During the third follow up visit, the patient reported no instance of seizure and had resumed his normal work.

[00218] Conclusions: It was found the combination of agomelatine and pregabalin to be effective in treating depression-epilepsy comorbid condition. The combination had a strong and rapid antiepileptic and antidepressant effect. In addition, it was found that the combination provided sustainable relief, safe and free of any significant side effects. This suggests that a combination of agomelatine and pregabalin can be a valuable treatment option for patients with epilepsy comorbid depression conditions. Example 8: Pharmacological Studies-Neuropathic Pain [00219] An Efficacy Study of Agomelatine and Pregabalin combination, Compared with Concurrent Placebo and Positive Controls of Agomelatine and Pregabalin monotherapies in Subjects With Neuropathic Pain Associated With Diabetic Peripheral Neuropathy (DPN). [00220] Objectives: Primary objective: Change in pain score from beginning of treatment to end of treatment with respect to the mean 24-hour average pain intensity score based on the 11- point Numeric Rating Scale [Time Frame: 12 Week study]. [00221] Secondary objective: To test patient tolerability and safety of the combination for the treatment of patients with Neuropathic Pain associated with Diabetic Peripheral Neuropathy (DPN). [00222] Study Design: This was a two-center, interventional, randomized, parallel assignment, double blind design to study the efficacy and safety of the combination compared to concurrent controls with Placebo, Agomelatine alone and Pregabalin alone in patients with Neuropathic Pain associated with Diabetic Peripheral Neuropathy (DPN).

[00223] Sample Size: The screening was completed on 94 patients. A total of 63 patients in four clinical arms were enrolled and randomized to achieve at least ten patients in each arm at two centers. 45 patients completed the full treatment. [00224] Inclusion Criteria: The following inclusion criteria were used for patient selection for this study. Prior to randomization, subjects eligible for enrollment in the study must meet all of the following criteria: 1. Outpatient subjects aged 18 years or older. 2. A female subject is eligible to enter and participate in the study if she: a. Is of non-childbearing potential; or b. Is of child-bearing potential, is not lactating and has a negative pregnancy test <7 days prior to study treatment initiation and agrees to use one of the sponsor specified highly effective methods for avoiding pregnancy. 3. A documented medical diagnosis of Type 1 or Type 2 diabetes mellitus including: 4. Stable glycemic control for three months prior to randomization (diabetic regimens may be changed after randomization to maintain glycemic control) as defined: a. Insulin: <25% change of their routine insulin dose to maintain glycemic Control; and b. Oral anti-diabetic agents: <50% change of their routine oral dose to maintain glycemic control. A glycosylated hemoglobin (HbAlc) concentration < 9% at the time of randomization. Subjects with HbAlc concentration of 9 to 11% maybe eligible if, in the opinion of the investigator, attempts have been made by the subject to improve diabetic control but these attempts have failed. Note: Subjects who achieve stable glycemic control and meet HbAlc criteria through diet control are eligible. Distal symmetric chronic sensorimotor painful polyneuropathy (DPN) as defined by: a. Signs including: i. Bilateral reduced or absent reflexes at the ankles; and ii. Bilateral impaired vibration, pinprick, fine touch or temperature perception in the distal lower extremities. b. Symptoms including: i. Persistent distal burning or dull pain in the feet; ii. Persistent proximal aching pain in the legs; iii. Paroxysmal electric, shooting, stabbing pain; iv. Dysasthesias; and v. Evoked pain. A history of pain for at least 24 months and no greater than five years attributed to DPN (Note this requirement refers to duration of pain, not the duration of polyneuropathy) . A baseline 24-hour average daily pain intensity score >4.0 as measured on a 10 point pain intensity numerical rating numeric rating scale. The Baseline score is the calculated mean of the daily scores during the 7 days prior to randomization. (The subject must record at least four assessments of the 24-hour average daily pain intensity score during the seven-day Baseline Period. The investigators have the discretion to recruit patients with a baseline score of up to 3.5 as exceptions.) 9. The subject must be able to provide written informed consent prior to participation in the study. The contents and process of obtaining informed consent will be in accordance with all applicable regulatory requirements. [00225] Exclusion Criteria: The following criteria were used for excluding patients during patient selection for this study. Subjects meeting any of the following criteria must be excluded from the study: 1. The patient has other chronic pain conditions not associated with distal symmetric chronic sensorimotor painful polyneuropathy. However, the subject will not be excluded if: a. The pain condition is located at a different region of the body; b. The pain intensity of this condition is not greater than the pain intensity of the distal symmetric chronic sensorimotor painful polyneuropathy; or c. The subject can assess their DPN independently of their other pain condition. 2. Other causes of neuropathy or lower extremity pain, which may include, but not be limited to: a. Lower extremity pain of any severity caused by: mononeuropathy, osteoarthritis of the ankle or foot, gout, bursitis, or fasciitis; b. Diffuse peripheral neuropathy caused by: alcoholism, malignancy, human immunodeficiency virus (HIV), syphilis, drug abuse, peripheral ischemia, B-12 deficiency, hypothyroidism, liver disease, chemotherapy or radiation therapy; c. Focal neuropathy in the lower extremities including nerve entrapment or local trauma; d. Acute or chronic inflammatory polyradiculopathy; or e. Depression. 3. Focal or multifocal diabetic neuropathies including: a. Mono-neuropathies of the cranial nerve, trunk and limb; b. Entrapment or asymmetric lower limb motor neuropathy (amyotrophy); c. Multiple sclerosis or other conditions associated with central neuropathic pain; and d. Pain associated with distal limb ischemia including intermittent claudication. However subjects will not be excluded if amyotrophic pain has resolved more than one year prior to enrolment. The current pain should be due to distal symmetric chronic sensorimotor painful polyneuropathy. Is unable to discontinue: a. Users of skeletal muscle relaxants, antidepressants, antiepileptic drugs, corticosteroids, benzodiazepines, opioid narcotics, and anti-Parkinson's disease medications > 7 days before their screening visitor; or b. Non-drug therapies or procedures (i.e. nerve blocks, trans cutaneous electrical nerve stimulation [TENS]) for the relief of pain of DPN for the required washout period and throughout the duration of the study. Has any of the following medical conditions, laboratory abnormalities or disorders: a. Hepatic impairment defined as alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 2x upper limit of normal (ULN) or alkaline phosphatase or bilirubin > 1.5x ULN; b. Chronic hepatitis B or C with a positive Hepatitis B surface antigen (HBsAg) or Hepatitis C Core Antigen Antibody (Hep C antibody); c. Impaired renal function defined as either creatinine clearance < 60 mL/min (estimation of creatinine clearance by Cockroft and Gault Method) or renal dysfunction requiring hemodialysis; d. Corrected QT (QTc) interval >450 msec (based on single or average QTc value of triplicate electrocardiograms (ECGs) obtained over a brief recording period); e. QTc interval >480 msec for patients with Bundle Branch Block; f. Uncontrolled hypertension at screen (sitting systolic blood pressure [SBP] >160 mmHg and/or sitting diastolic blood pressure [DBP] >90 mmHg; g. A current diagnosis of active epilepsy or any active seizure disorder requiring chronic therapy with antiepileptic drug(s); or h. A medical condition or disorder that would interfere with the action, absorption, distribution, metabolism, or excretion of opioid or Lyrica (pregabalin), or, in the investigator's judgment:

6. Is considered to be clinically significant and could pose a safety concern; 7. Could interfere with the accurate assessment of safety or efficacy; or

8. Could potentially affect a subject's safety or study outcome.

Administration and Scoring

[00226] The patients were treated once daily with one of 1) Pregabalin (300 mg); 2) Agomelatine (25 mg); 3) a combination of Agomelatine (25 mg) and Pregabalin (300 mg); and 4) a placebo.

[00227] The first two weeks were for screening and to establish a baseline period. The baseline score and first drug administration were at To and continued every day for ten weeks. The pain scores were recorded by the patients daily in their daily pain dairies. The weekly pain scores were assessed on T0 (week 2) thru T 10 (week 12).

Efficacy Parameters: [00228] The primary efficacy measure was the mean Numeric Rating Scale from daily pain diaries ( 11-point numeric rating scale). The secondary efficacy measures included weekly NRS and proportion of responders (patients achieving >20% reduction in the mean Numeric Rating Scale compared those from comparator drugs.

Safety Parameters: [00229] Adverse events (AEs) and vital signs were monitored during the study. Safety evaluations also included laboratory measurements, physical examinations, and neurological exams, including Screening:

a. Vital signs every 2 weeks; b. Clinical laboratory parameters every 2 weeks; and c. Adverse events.

Statistical Methods: [00230] A p value of < 0.05 was considered as significant between the combination arm and comparator arms. SPSS 10.0 was used for the statistical analysis. RESULTS:

[00231] Patient Characteristics: The treatment groups, Table 11, were well balanced in demographic and baseline characteristics. The pain scores were similar at the baseline for all groups. The size and distribution of the primary analysis population between treatment groups didn't provide sufficient statistical power to evaluate the minor variations at baseline. There were 22 patients who were not eligible for the trail because - they did not meet the inclusion criteria (n=5), declined to participate (n=5) or for other reasons, e.g., lack of proper consent form, other medication, etc (n=12). [00232] From the allocated patients, three patients in agomelatine, two on combination treatment arm, two in placebo and two in pregabalin arms were not administered drugs because of administrative/logistical reasons. Fifteen patients (two in agomelatine, four in combination, seven in placebo and two in pregabalin treatment arms) dropped out of study either because follow up or discontinuation of medications. The reasons for discontinuations from study were similar between treatment groups. The key reasons are missing medications, non-recording of scoring and deviations from time of administration etc. Protocol deviations, rescue medication use, and compliance in both treatment groups were also similar between treatment groups.

[00233] The NRS scale, a simple numbered scale with 0= no pain and 10= worst possible pain, was used to measure the efficacy parameters. The patients were trained to mark on the scale that correlated what they think was best representation of intensity of pain. To use the Numeric Rating Scale, the patient was asked to choose the number between 0 (no pain) and 10 (worst possible pain) that best describes the intensity of pain felt by them. TABLE 11

Efficacy Results: [00234] The findings from both the primary global assessments of efficacy and secondary evaluations indicate that the use of Agomelatine 25 mg + Pregabalin CR 300 mg (combination) /day to treat neuropathic pain in results in a trend toward highly improved pain relief from baseline to the end of 10 weeks of treatment when compared with the placebo and with positive controls Agomelatine 25 mg, Pregabalin CR 300 mg and placebo. [00235] Pharmacokinetics was not assessed in this study. The pain relief from the treatment with the combination was faster and more efficient compared the comparator drugs. Table 12 illustrates the efficacy analysis from the study. The mean pain scores are plotted against T (Figure 7).

[00236] The mean of T0 (week 2) was the baseline score, the mean of T4, T and T (week 6, week 7 and week 8) NRS scores were taken as intermediate period pain score, T10 (week 12) as the Final data point for summary plotting. There was no difference in the changes among female and male patient populations. The proportion of responders (patients achieving >20% reduction in NRS score for the combination compared those from comparator drugs) was about 75%. TABLE 12

Drug/T To T T T3 T T T T7 T8 T Tio

Agomelatine 7.1 6.35 6.3 6.1 6.0 5.92 5.81 65.71 5.65 5.55 5.0405

Pregabalin 7.2 1 6.09 5.51 5.42 5.3 2 5.2 1 5.18 5.12 5.1 5.1 5

Combination 7.15 5.51 5.22 5.1 5 5.04 4.85 4.75 4.72 4.65 4.63 4.51

Placebo 6.95 6.61 6.55 6.55 6.52 6.61 6.62 6.51 6.7 6.65 6.7

[00237] The treatment with agomelatine, pregabalin, and a combination thereof showed statistical significance compared to pain scores from placebo treated patients (p<0.05). More importantly the pain scores changes from the combination treated patients shows statistically significance compared positive controls agomelatine alone and pregabalin alone (p<0.05) (Table 13).

TABLE 13

Safety Results: [00238] The combination was well tolerated for the treatment of neuropathic pain in the patient population studied as per the protocol. The incidences and types of AEs reported were typical for a patient population with neuropathic pain and similar between treatment groups. There were no deaths.

[00239] The results in Table 14 show the number (%) of patients who had at least 1 adverse event in any category and total numbers of adverse events during the treatment period (safety analysis population). TABLE 14

[00240] The common adverse events, in the combination and agomelatine treatment arms, were nausea and constipation while it was dizziness in the pregabalin treatment arm. The most commonly occurring AE, nausea had a higher incidence in the placebo treatment group (40%), than in the treatment groups (20%). The investigators in this study rated the majority of AEs as mild or moderate in intensity; none of the AEs rated as severe were judged to be causally related to the study drug by the investigators. There were no clinically important changes in vital signs, physical exams, and laboratory values, including 24-hour HbAlC, for patients in any of treatment groups. [00241] Additional Evaluation; An additional Efficacy Study was conducted to assess whether it was possible to either reduce dosage of at least drug (18 mg Agomelatine and 250 mg Pregabalin CR) and whether administration of pregabalin as BID (25 mg Agomelatine and 125 mg Pregabalin BID) will have any bearing on the extent of pain relief compared to once daily administration of 25 mg Agomelatine and 300 mg Pregabalin CR combination. The study was conducted as per above protocol except for dosage and mode of Pregabalin administration. The results are shown in Figure 8.

Example 9: Pharmacological Example of Agomelatine and Opioid (Tapentadol) [00242] A Efficacy Study of Tapentadol + Agomelatine, Compared With Concurrent Placebo and Positive Controls Tapentadol monotherapy, agomelatine mono therapy, in Subjects With Neuropathic Pain Associated With Diabetic Peripheral Neuropathy (DPN) [00243] The primary efficacy was measured with the change from baseline to end of treatment with respect to the mean 24-hour average pain intensity score based on a 10-point VAS [Time Frame: 1 Weeks].

[00244] A total of 28 patients were screened to achieve targeted patient size of about 5 patients in each of the four arms- agomelatine, tapentadol, placebo and the combination of tapentadol and agomelatine. [00245] Change in pain score and severity of toxicity over time was assessed by Friedman's test or Cochrane's Q where appropriate. A p value of < 0.05 was considered as significant between combination arm and the comparator arms. SPSS 10.0 was used for the statistical analysis. The results are shown in Table 15.

TABLE 15 ARM/PERIOD Baseline Intermediate Final Tapentadol 5.8±0.66 4.31±0.0.21 4.03±0.17 Agomelatine 4.4±0.44 4.1 1±0.12 4.10±0.43 Combination 5.33±0.33 3.57±0.48 2.99±0.53 Placebo 4.88±0.33 4.66±0.21 4.94±0.82 Baseline; Week 0-2, Intermediate: Week 6-12 and Final: Week 18 or Last Visit.

Example 10: Pharmacological Example of Agomelatine and NSAID (Naproxen)

[00246] The study involved 15 patients were suffering from chronic back pain for at least six months. The patients with neuropathic pain, osteoarthritis, rheumatoid arthritis, fibromyalgia, musculoskeletal pain migraines, dental pain, abdominal pains (from chronic pancreatitis, kidney stones, etc.) and ischemic pain from vascular disease were. Patients with history of addiction (alcohol or drugs) were excluded from the trials. The patients were selected from screening 26 patients and were randomly assigned to three groups- Agomelatine, Naproxen and Combination groups.

[00247] The patients were administered for one week either agomelatine 25 mg, naproxen 250 mg or a combination of 25 mg agomelatine and 250 mg of naproxen. Placebo capsules were administered to mask the drugs. Patients were trained record the pain scores on 11- point Numeric Rating Scale (NRS) in their pain dairies. Data are expressed as means ± SD. Differences in NRS were analyzed with use of the unpaired Student t test and differences in pain score reductions between the two groups were analyzed with use of the Mann-Whitney U test for the median difference. Similar statistical tests were used for between group comparisons of other outcome variables as appropriate. A two tailed P value of less than. 0.5 was considered to demonstrate statistical significance. SAS software was used for the statistical analysis. The results are illustrated in Table 16.

TABLE 16

[00248] The abbreviations used herein have their conventional meaning within the chemical and biological arts. The disclosures of each and every patent, patent application, and publication cited herein are expressly incorporated herein by reference in their entirety into this disclosure. In the case of any inconsistencies, the present disclosure, including any definitions therein will prevail. Illustrative embodiments of this disclosure are discussed and reference has been made to possible variations within the scope of this disclosure. These and other variations and modifications in the disclosure will be apparent to those skilled in the art without departing from the scope of the disclosure, and it should be understood that this disclosure and the claims shown below are not limited to the illustrative embodiments set forth herein.

[00249] It is also noted that compounds having formula I, disclosed herein, have been shown to be useful in treating pain and pain related disorders in the following applications: U.S.

Provisional Application No.: 61/551,376, filed on October 25, 201 1; U.S. Provisional Application No.: 61/660,765, filed on June 17, 2012; U.S. Provisional Application No.: 61/619,405, filed on April 2, 2012; U.S. Provisional Application No.: 61/665,296, filed on June 27, 2012; and PCT application no.: , filed concurrently herewith, (attorney docket no 111-P-043WO01). Claims:

1. A pharmaceutical composition comprising a therapeutically effective amount of a naphtha lene compound having formula I :

I wherein R1 is substituted or unsubstituted (Ci-Ce)alkyl; R2 is hydrogen or substituted or unsubstituted (Ci-C )alkyl; and R is hydrogen, substituted or

unsubstituted (Ci-C )alkyl, or substituted or unsubstituted (C3 -Cio)cycloalkyl,

substituted or unsubstituted (C -Cio)aryl, substituted or unsubstituted (C7 -C 16)- arylalkyl, substituted or unsubstituted (Cs-C^heteroaryl, substituted or unsubstituted

(C6-C2i)heteroarylalkyl, substituted or unsubstituted heterocyclic group or substituted

or unsubstituted (C6-Ci )heterocycloalkyl group; wherein the substituents for the alkyl, aryl, cycloalkyl, or heterocyclic groups include (Ci-C )alkyl, fluoro, chloro, or bromo; and a therapeutically effective amount of a second active agent, wherein the second active agent is; a) an antiepileptic drug; b) a peroxisome proliferator-activated receptors (PPAR) agonist; or c) an opioid; or d) an NSAID; and optionally at least one pharmaceutically acceptable carrier; or a pharmaceutically acceptable salt, isomer, or polymorph thereof, wherein the compositions are useful for treating useful for treating pain or pain related disorders. The pharmaceutical composition of claim 1, wherein the naphthalene compound has formula I-A :

I-A wherein, R1 is methyl, ethyl, n-propyl, or 1-methylethyl (isopropyl), and R3 is methyl, ethyl, n-propyl, 1-methylethyl (isopropyl), n-butyl, isobutyl, n-pentyl, t-butyl (1,1-dimethylethyl), or phenyl; or a pharmaceutically acceptable salt, isomer, or polymorph thereof.

3. The pharmaceutical composition of claim 1 or 2, wherein R1 is methyl; and R is methyl, ethyl, isopropyl, isobutyl or phenyl.

4. The pharmaceutical composition of any preceding claim, wherein the compound of formula I is agomelatine.

5. The pharmaceutical composition of any preceding claim, wherein the amount of a compound of formula I is from about 0.1 mg to about 1500 mg.

6. The pharmaceutical composition of claim 6, wherein the amount of a compound of formula I is from about 1 to about 100 mg.

7. The pharmaceutical composition of claim 7, wherein the amount of a compound of formula I is from about 1 to about 50 mg.

8. The pharmaceutical composition of any of claims 1-7, wherein the antiepileptic drug is aminobutyric acid, baclofen, beclamide, barbexaclone, brivaracetam, clonazepam, carbamazepine, ethotoin, ethadione, ethosuximide, eslicarbazepine, felbamate, fosphenytoin, gabapentin, gabapentin enacarbil, lamotrigine, levetiracetam, lacosamide, mephenytoin, methylphenobarbital, metharbital, mesuximide, oxcarbazepine, phenytoin, phenobarbital, primidone, paramethadione, phenacemide, pheneturide, phensuximide, pregabalin, progabide rufinamide, selectracetam, stiripentol, sultiame, topiramate, trimethadione, tiagabine, valproic acid, amino(diphenylhydantoin) valeric acid, valpromide, vigabatrin, or zonisamide or a combination thereof.

9. The pharmaceutical composition of claim 8, wherein the antiepileptic drug is pregabalin, gabapentin, gabapentin enacarbil, topiramate or baclofen.

10. The pharmaceutical composition of claim 9, wherein the antiepileptic drug is pregabalin, or gabapentin.

11. The pharmaceutical composition of any of claims 8-10, wherein the compound of formula I, and the antiepileptic drug of are present as a salt formed from the two drugs.

12. The pharmaceutical composition of any of claims 1-7, wherein the peroxisome proliferator-activated receptor agonist is palmitoylethanolamide, anandamide, stearoyl ethanolamine, oleoylethanolamine, fenofibrate, bezafibrate, ciprofibrate, clofibrate, gemfibrozil, ureido-fibrate-5 (UF-5) or a combination thereof.

13. The pharmaceutical composition of claim 12, wherein the peroxisome proliferator- activated receptor agonist is palmitoylethanolamide.

14. The pharmaceutical composition of claim 13, wherein one of, the compound of formula I, or palmitoylethanolamide is present in controlled-release form.

15. The pharmaceutical composition of any of claims 1-7, wherein the opioid drug is alfentanil, allylprodine, alphaprodine, anileridine, benzylmorphine, bezitramide, buprenorphine, butorphanol, clonitazene, codeine, desomorphine, dextromethorphan, dextromoramide, dezocine, diampromide, diamorphone, dihydrocodeine, dihydromorphine, dimenoxadol, dimepheptanol, dimethylthiambutene, dioxaphetyl butyrate, dipipanone, eptazocine, ethoheptazine, ethylmethylthiambutene, ethylmorphine, etonitazene, faxeladol, fentanyl, heroin, hydrocodone, hydromorphone, hydroxypethidine, isomethadone, ketobemidone, levorphanol, levophenacylmorphan, lofentanil, meperidine, meptazinol, metazocine, methadone, metopon, morphine, myrophine, narceine, nicomorphine, norlevorphanol, normethadone, nalorphine, nalbuphene, normorphine, norpipanone, opium, oxycodone, oxymorphone, papaveretum, pentazocine, phenadoxone, phenomorphan, phenazocine, phenoperidine, piminodine, piritramide, propheptazine, promedol, properidine, propoxyphene, sufentanil, tilidine, tapentadol, axamadol, or, tramadol, mixtures thereof, or salts thereof.

16. The pharmaceutical composition of claim 15, wherein the opioid is morphine, codeine, oxycodone, hydrocodone, dextromethorphan, dihydrocodeine, propoxyphene, fentanyl, tapentadol, tramadol, or mixtures thereof.

17. The pharmaceutical composition of claim 16, wherein the opioid is morphine, oxycodone, tramadol, tapentadol or a mixture thereof.

18. The pharmaceutical composition of claim 1, wherein the NSAID is Celecoxib, Diclofenac, Difiunisal, Etodolac, Fenoprofen, Flurbirofen, Ibuprofen, Indomethacin, Ketoprofen, Ketorolac, Mefenamic acid, Meloxicam, Nabumetone, Naproxen, Oxaprozin, Piroxicam, Sulindac and Tolmetin or their pharmaceutically equivalent salts or mixtures thereof

19. The pharmaceutical composition of any preceding claim, wherein the carrier comprises at least one adjuvant, preservative, antioxidant, thickening agent, chelating agent, antifungal agent, antibacterial agent, isotonic agent, flavoring agent, sweetening agent, anti-foaming agent, colorant, diluent, moistening agent, parietal cell activator, or a combination of thereof.

20. The pharmaceutical composition of any preceding claim, wherein the composition is suitable for oral, buccal, intravenous, intra-arterial, intra-peritoneal, intra-dermal, transdermal, intrathecal, intramuscular, intranasal, transmucosal, subcutaneous, or rectal administration.

21. A method for treating pain or pain related disorders in a patient in need thereof comprising administering an effective amount of a pharmaceutical composition according to any of claims 1-20.

22. The method of any of claims 21, wherein the pain is selected from fibromyalgia, inflammatory pain, neuropathic pain, acute pain, chronic pain, visceral pain, migraine pain, irritable bowel syndrome pain, inflammatory bowel disease (IBD) pain, or cancer pain. 23. The method of claim 22, wherein the compound having formula I, and the second active agent are administered simultaneously or sequentially to the mammal; wherein the compound having formula I can be administered either before or after the second active agent and administered to the mammal either by the same or a different pathway of administration.

24. The method of claims 20-23, wherein the mammal is a human.

25. The method of any preceding claim, wherein the disorder is pain or a pain disorder.

26. The method of any preceding claim, wherein the amount of agomelatine is from about 1 mg to about 250 mg.

27. The method of claim 26, wherein the amount of agomelatine is from about 5 to about 100 mg.

28. The method of claim 27, wherein the amount of agomelatine is from about 10 to about 30 mg.

29. A pharmaceutical composition of any of claims 1-28, for use in a method for preparing a medicament for the prevention or treatment of treatment of pain and pain related disorders in a mammal, comprising administering to said mammal an effective amount of said pharmaceutical composition.

30. The pharmaceutical composition of claims 29, where the medicament optionally comprises a liquid carrier or solid carrier.

31. A pharmaceutical composition having the formula of any of claims 1-20, for use in a method for prevention or treatment of a pathological condition or symptom in a mammal, wherein the condition is pain, and relief from the condition is desired; and where the medicament optionally comprises a liquid carrier, comprising administering to said mammal an effective amount of said composition.

32. Use of a composition of any of claims 1-20, to prepare a medicament for use in the prevention or treatment of pain or a pain related disorder.

INTERNATIONAL SEARCH REPORT International application No. PCT/US 12/61922

A . CLASSIFICATION O F SUBJECT MATTER IPC(8) - A01 N 37/1 8 ; A61 K 31/1 6 (2013.01 ) USPC - 5 14/61 3 According to International Patent Classification (IPC) or to both national classification and IPC

B . FIELDS SEARCHED ~ Minimum documentation searched (classification system followed by classification symbols) USPC: 514/613

Documentation searched other than minimum documentation to the extent that such documents are included in the fields searched USPC: 514/481 , 514/563, 514/682 (see search terms below)

Electronic data base consulted during the international search (name of data base and, where practicable, search terms used) PubWest, Google Scholar naphthaline, amide, antiepileptic, peroxisome proiiferator-activated receptor, opioid, NSAID, agomelatine, pain

C . DOCUMENTS CONSIDERED TO BE RELEVANT

Category* Citation of document, with indication, where appropriate, of the relevant passages Relevant to claim No.

X US 201 1/01 59048 A 1 (Crain et al.) 30 June 201 1 (30.06.2001) abstract; para [0028], [0035], 1-3 and 18 [0043], [0047], [0053], [0062]; claims 29, 33

A US 5,1 94,614 A (Andrieux et al.) 16 March 1993 (16.03.1993) entire document 1-3 and 18

A US 5,225,442 A (Andrieux et al.) 06 July 1993 (06.07.1993) entire document 1-3 and 18

I I Further documents are listed in the continuation of Box C . □ Special categories of cited documents: T" later document published after the international filing date or priority A" document defining the general state of the art which is not considered date and not in conflict with the application but cited to understand to be of particular relevance the principle or theory underlying the invention E" earlier application or patent but published on or after the international X" document of particular relevance; the claimed invention cannot be filing date considered novel or cannot be considered to involve an inventive " document which may throw doubts on priority claim(s) or which is step when the document is taken alone cited to establish the publication date of another citation or other Y" document of particular relevance; the claimed invention cannot be special reason (as specified) considered to involve an inventive step when the document is O" document referring to an oral disclosure, use, exhibition or other combined with one or more other such documents, such combination means being obvious to a person skilled in the art P" document published prior to the international filing date but later than &" document member of the same patent family

Date of the actual completion of the international search Date of mailing of the international search report 22 February 2013 (22.02.2013) 2 2 MAR 2013

Name and mailing address of the ISA/US Authorized officer: Mail Stop PCT, Attn: ISA/US, Commissioner for Patents Lee W. Young P.O. Box 1450, Alexandria, Virginia 22313-1450 PCT Helpdesk: 571-272-4300 · Facsimile No. 571-273-3201 PCTOSP: 571-272-7774 Form PCT ISA 2 10 (second sheet) (July 2009) INTERNATIONAL SEARCH REPORT International application No. PCT/US 12/61922

Box No. II Observations where certain claims were found unsearchable (Continuation of item 2 of first sheet)

This international search report has not been established in respect of certain claims under Article 17(2)(a) for the following reasons

Claims Nos.: because they relate to subject matter not required to be searched by this Authority, namely:

Claims Nos.: because they relate to parts of the international application that do not comply with the prescribed requirements to such extent that no meaningful international search can be carried out, specifically:

Claims Nos.: 4-1 7 and 19-32 because they are dependent claims and are not drafted in accordance with the second and third sentences of Rule 6.4(a).

Box No. ΠΙ Observations where unity of invention is lacking (Continuation of item 3 of first sheet)

This International Searching Authority found multiple inventions in this international application, as follows:

As all required additional search fees were timely paid by the applicant, this international search report covers all searchable claims.

As all searchable claims could be searched without effort justifying additional fees, this Authority did not invite payment of additional fees.

As only some of the required additional search fees were timely paid by the applicant, this international search report covers only those claims for which fees were paid, specifically claims Nos.:

No required additional search fees were timely paid by the applicant. Consequently, this international search report is restricted to the invention first mentioned in the claims; it is covered by claims Nos.:

The additional search fees were accompanied by the applicant's protest and, where applicable, the payment of a protest fee. □ The additional search fees were accompanied by the applicant's protest but the applicable protest fee was not paid within the time limit specified in the invitation. □ No protest accompanied the payment of additional search fees. Form PCT SA 210 (continuati on of first sheet (2)) (July 2009)