MX2008004197A - Milnacipran for the long-term treatment of fibromyalgia syndrome - Google Patents

Abstract

The present invention is directed to methods for providing long-term treatment of fibromyalgia syndrome (FMS) by administering a dual re-uptake inhibitor to a patient with FMS. More particularly, the present invention is directed to the long-term treatment of FMS by administering a norepinephrine-serotonin reuptake inhibitor (NSRI) to a patient with FMS.

Description

M ILNACIPRAN FOR LONG-TERM TREATMENT OF FIBROMYALGIA SYNDROME FIELD OF THE INVENTION The present invention relates to the long-term treatment of fibromyalgia and its symptoms by administration to the patient suffering from fibromyalgia from a dual inhibitor of serotonin and norepinephrine. Particularly, the present invention is directed to the long-term treatment of fibromyalgia and its symptoms by the administration of dual serotonin and norepinephrine reuptake inhibitors that inhibit the reuptake of norepinephrine to a degree greater than or equal to that in the which inhibits the reabsorption of serotonin. BACKGROUND OF THE INVENTION Fibromyalgia, also known as fibromyalgia syndrome (FMS) is a common systemic rheumatological disorder that is estimated to affect 2% to 4% of the population, second in prevalence among rheumatologic conditions after osteoarthritis. Wolfe et al. , Arthritis Rheum. 1990; 33 (2): 1 60-1 72; Wolfe et al. , Arthritis Rheum. nineteen ninety five; 38 (1); 1 9-28. Fibromyalgia is associated with a reduction in pain threshold, usually identified by an increase in pressure sensitivity throughout the body, and is often accompanied by fatigue, sleep disturbances and tension upon awakening. Other common symptoms include headache, migraines, variable bowel habits, abdominal pain diffuse and urinary frequency. The criterion for the diagnosis of fibromyalgia requires not only the history of general pain, but also the finding of sensitivity when performing physical examinations (points of sensitivity). In order to complete the established criteria for fibromyalgia established in 1 990 by the American College of Rheumatology (ACR), an individual must have general pain in all four quadrants of the body, as well as axial skeleton, and the presence of 1 1 of the 1 8 sensitivity points at the time of the exam. Wolfe et al. , Arthritis Rheum. 1990; 33 (2): 1 60-1 72. While there have been some suggestions that FMS may represent a form of somatization disorder, there is increasing evidence and acceptance that FMS is a medical problem, which reflects a perception generalized increase in increase, to sensory stimuli. It is believed that the abnormality is originated within the central nervous system (CNS) instead of in the peripheral areas and the term of the physiopathological defect is called "central sensitization". Caluw DJ and Chrousos GP, Neuroimmunomodulation 1997; 4 (3): 1 34-1 53, Yunas MB, J Rheumatol. 1992; 1 9 (6): 846-850; Bradley et al. , Curr Rheumatol Rep. 2000; 2 (2): 141 -1 48; Simas Rw, Am J Med Sci. 1,998; 31 5 (6): 346-350. Patients with FMS commonly suffer from both allodynia (noticeable pain from a non-painful stimulus such as mild contact) and hyperalgesia (increase in the pain process in which a painful stimulus is magnified and felt with greater intensity of what a normal volunteer would perceive). Mountz et. Al, Arthritis & Rheumatism 1 995; 38 (7): 926-938; Arroyo JF and Cohen ML, J Rheumatol. 1993 20 (11): 925-1 931. In this aspect there are many parallels in the clinical presentation and in the fundamental mechanisms proposed with neuropathic pain, such as diabetic neuropathy and trigeminal neuralgia. Sindrup SH and TS Jensen, Pain 1999; (3): 389-400; Wolf CJ, Nature 1983; 306 (5944): 686-688; Wolf CJ and RJ Mannion, Lancet 1 999; (91 68): 1 959-1 964. As a result, FMS is treated today, mainly within this medical model. It is frequently diagnosed in primary care settings and almost half of the office visits are to internal medicine and family medicine (1 998 National Survey of Ambulatory Medical Care). Visits to rheumatologists consist of 1 6% of visits to offices in relation to patients with FMS. The remaining visits are carried out to a variety of tertiary care providers, including pain centers, physical medicine specialists and psychiatrists. Individuals with fibromyalgia suffer from a variety of symptoms, including a high incidence of noncardiac chest pain, heartburn, palpitations and irritable bowel syndrome. Wolfe, et al. , Arthitris Rheum. 1990; 33 (2): 1 60-1 72; Mukerji et al. , Angiology 1995; 46 (5): 425-430. Although the physiological basis of these symptoms remains uncertain, the increasing evidence suggests that Autonomic nervous system dysfunction is common in fibromyalgia and related diseases. Clauw DJ and Chrousos GP, Neuroimmunomodulation 1997; 4 (3): 134-153; Freeman R and Komaroff AL, Am J Med. 1997; 102 (4): 357-364. Prospective studies of randomly selected individuals with fibromyalgia have detected objective evidence in relation to the dysfunction of several visceral organs, including the incidence in 75% of echocardiographic evidence of the mitral valve, an incidence of 40% to 70% of incidence of poor esophageal motility and decreased inspiratory and expiratory static pressures in lung function analysis. Lurie et al. , Scand J Rehab Med. 1990, 22 (3): 151-155; Pellegrino et al. , Arch Phys Med Rehab. 1989, 70 (7): 541-543. The study of fibromyalgia has recently emerged as a significant area of research different from the study of other chronic pain conditions. A significant body of literature at this time supports the use of tricyclic antidepressants for FMS, and there are several other controlled studies in which the efficacy of other therapeutic agents is evaluated. However, the interpretation of the test information is complicated by factors such as the lack of an accepted binary definition of "responder" versus "non-responder", as is now commonly used in tests of other rheumatological conditions, such as arthritis. rheumatoid Felson et al., Arthritis Rheum. 1993; 36 (6): 729-740; Felson DT, J Rheumatol. 1993; 20 (3): 581-534.

Additionally, there is no consensus regarding several aspects of the test design, including the designation of appropriate points. However, there is a generalized agreement which states that the measurement and characterization of the patient's pain are very important for determining the effectiveness of the agent in the FMS; Evaluation of fatigue, sleep, depression, physical ability function and general well-being help to further illuminate the general effectiveness of the agent. A wide range of medications have been used outside of their therapeutic indication in patients with FMS with varying levels of success. Buskila D. Baillieres Best Pract Res Clin Rheumatol. 1999; 13 (3): 479-485; Leventhal LJ, Ann Intern Med. 1999; 131 (11): 850-858; Lautenschlager J, Scand J Rheumatol Suppl. 2000: 113: 32-36. While antidepressants are the basis of several treatments, other agents such as anticonvulsants, anti-spasticity agents, anxiolytics, sedatives and opiates have been used. Additionally, a large number of patients use anti-inflammatory drugs without steroids and acetaminophen (Wolfe et al., Arthritis Rheum, 1997; 40 (9): 1571-1579), even though peripheral inflammation has not been demonstrated (Clauw DJ and Chrousos GP, Neuroimmunomodulation 1997; 4 (3): 134-153), and several studies have failed to confirm the effectiveness of analgesics in FMS. Goldeberg et al., Arthritis Rheum. 1986; 29 (11): 1371-1377; Yunus et al., J Rheumatol. 1989; 16 (4): 527-532; Wolfe et al., Arthritis Rheum. 2000; 43 (2): 378-385; Russell et al., Arthritis Rheum. 1991; 34 (5): 552-560; Jaw-Stroke et al., Pain 1996; 65 (2-3): 221-225. These agents, however, provide an element of protection against other generators of peripheral pain, such as osteoarthritis. Antidepressants of all varieties represent a common form of therapy for many chronic pain states, including FMS. Sindrup SH and Jensen TS, Pain 1999; 83 (3): 389-400; Buskila D, Baillieres Best Pract Res Clin Rheumatol. 1999; (3): 479-485; Leventhal LJ, Ann Intern Med. 1999; 131 (11): 850-858; Lautenschlager J, Scand J Rheumatol Suppl. 2000; 113: 32-36; Bennett RM, J Functional Syndroms 2001; 1 (1): 79-92. The majority of antidepressants that are in the direct market or indirectly increase the levels of 5-HT and / or NE in the CNS. Mono-amine levels are increased either by inhibiting absorption (by blocking transport proteins) or by interfering with the decomposition of mono-amines (by inhibiting monoamine oxidase enzymes) when released into the synaptic cleft. Tricyclic antidepressants (TCA) The TCAs most commonly used for the treatment of FMS include amitriptyline, doxepin and cyclobenzaprine. Buskila D, Baillieres Best Pract Res Clin Rheumatol. 1999; 13 (3): 479-485; Lautenschlager J, Scand J Rheumatol Suppl. 2000; 113: 32-36; Bennett RM, J Functional Syndromes 2001; 1 (1): 79-92., While cyclobenzapine is commonly cataloged as a muscle relaxant, instead of an antidepressant, it shares structural and pharmacological similarities with the TCA. Although its sedative qualities frequently can nullify its usefulness in other applications. Kobayashi et al., Eur J Pharmacol. nineteen ninety six; 311 (1): 29-35. The TCA block the absorption of both 5-HT and NE, but favor blocking the reabsorption of the NE, and it can be interpreted that the efficacy of the TCA supports the primacy of NE as an agonist for the analgesic activity. However, the additional anti-cholinergic, antihistaminergic and a-adrenergic receptor blocking activities of TCAs impart a wide variety of undesirable side effects, which often compromise their tolerance and clinical acceptance. Kent JM, Lancet 2000; 355 (9297): 911-918. TCAs have shown moderate efficacy for the treatment of pain conditions from neuropathy, such as neuralgia and painful diabetic neuropathy. Max et al., Neurology 1988; 38 (9): 1427-1432; Max et al., N Eng J Med. 1992; 326 (19): 1250-1256; Watson et al., Neurology 1982; 3286): 671-673; Watson et al., Pain 1992; 48 (1) 29-36. Multiple studies of ACTs with respect to FMS treatment support use for this syndrome as well, and ACTs have often been used as positive controls against which new agents have been compared. Max et al., N Eng J Med. 1992; 326 (19: 1250-1256; Watson et al., Pain 1992; 48 (1): 29-36; Hannonen et al., Br J Rheumatol. 1998: 37 (12): 1279-1286; Goldenberg et al., Arthritis &Rheumatism 1996; 39 (11): 1852-1859.

Selective Serotonin Reuptake Inhibitors (SSRIs) SSRIs have revolutionized the treatment of depression due to their improved side-effect profile, which is secondary to the more selective inhibition of resorption. SSRI agents such as fluoxetine, sertraline and citolopram have been evaluated in randomized placebo-controlled trials in FMS. Goldenberg et al., Arthritis & Rheumatism 1996; 39 (11): 1852-1859; Wolfe et al., Scand J Rheum. 1994; 23 (5): 255-259; Anderberg et al., Eur J Pain 2000; 4 (1): 27-35; Norregaard et al., Pain 1995; 61 (3): 445-449. However, the results of these tests have been somewhat inconsistent, leaving a great debate regarding the relative efficacy of SSRIs, especially in comparison with ACTs. Two placebo-controlled citalopram tests, the most specific for 5-HT SSRIs, in patients with FMS, were both convincingly negative. Anderberg et al., Eur J Pain, 2000; 4 (1): 27-35; Norregaard et al., Pain 1995; 61 (3): 445-449. This suggests that serotonergic improvement alone is not sufficient to deliver analgesia in a chronic pain setting. In fact, based on the collected evidence collected to date, SSRIs, as a class, are generally less effective than ACTs in chronic pain states (Max et al., N Engl J Med. 1992; 326 (19): 1250-1256; Ansari A, Harv Rev Psych 2000; 7 (5): 257-277; Atkinson et al., Pain 1999; 83 (2): 137-145; Jung et al., J Gen Intern Med. 1997; 12 (6): 384-389), although there are certain exceptions (Saper et al., Headache 2001; 41 (5): 465-474). Dual reabsorption inhibitors Dual reabsorption inhibitors (DRI) are pharmacologically similar to TCAs (such as amitriptyline and doxepin), demonstrating activity in both 5-HT and reabsorption of N E. Sánchez C and Hytell J. Cel Mol Neurobiol. 1999; 1 9 (4): 467-489. Fortunately, these new agents generally do not possess significant activity in other responder systems, resulting in reduced side effects and increased tolerance against ACTs. Therefore, this category of antidepressants may have significant potential for the treatment of FMS and / or other conditions of chronic pain. DRIs that are commercially available in the United States include venlafaxine and duloxetine. An amount of DRI is in clinical development; these include milnacipran, bicifadine, viloxazine, LY-1 1 3821, sep-2271 62, ad-337, and desvenlafaxine succinate (DVS-233). An open-label study of venlafaxine (EFEXOR®) in 1 5 patients with FMS has been revealed. Dwight et al. , Psychosomatics 1 998; 39 (1): 1 4-1 7. Of the 1 1 patients who completed the study, 6 patients obtained a positive response to venlafaxine, which was defined as 50% or more improvement in two different measures of pain general . Insomnia was the most reported side effect, requiring adjacent medical therapy in 3 of the 1 1 patients who completed the study.

U.S. Patent No. 6, 602, 911 describes the uses of milnacipran for the treatment of FMS and its symptoms, the entire description is incorporated herein by reference. Opioids Opioids exert their anti-nocioreceptive effects at various locations within the ascending and descending channels of pain. Duale et al., Neuroreport 2001; 12 (10): 2091-2096; Besse et al., Brain Res. 1990; 521 (1-2): 15-22; Fields et al., Nature 1983; 306 (5944): 684-686; Yaksh et al., Proc Nati Acad Sci USA 1999; 96 (14): 7680-7686. Concerns related to the use of opioids for use in conditions of chronic pain have been widely discussed and debated. Bennett RM, J Functional Syndromes 2001; 1 (1): 79-92. However, opioids are used to some degree in the clinical management of FMS, especially when other analgesics have failed to provide sufficient improvement. Bennett RM, Mayo Clin Proc. 1999; 74 (4): 385-398. Most patients affected by fibromyalgia syndrome suffer from the symptoms for years. (Carette et al., Arthritis &Rheumatism 1994; 37 (1): 32-40, 32-33, 39). Carette et al. Reported the results of the clinical study in which amitriptyline (tricyclic antidepressant), cyclobenzaprine (a muscle relaxant structurally similar to the tricyclic antidepressant) and placebo were administered to subjects suffering from fibromyalgia syndrome (Carette). et al. , Arthritis & Rheumatism 1994; 37 (1): 32-40. After one month, 21% of the subjects of amitriptyline, 1 2% of the subjects of the cyclobenzaprine, and 0% of the subjects of the placebo obtained significant clinical improvement. At three months, there was no difference between any of the treatment or placebo groups. At six months, no long-term effect could be demonstrated due to a placebo response higher than expected, 19% improvement with placebos. Therefore, the need for an effective long-term treatment for the fibromyalgia syndrome and its symptoms. SUMMARY OF THE INVENTION No compound, while having benefits for the short-term treatment of fibromyalgia and its symptoms, has been shown to provide a lasting effect in a manner that effectively provides a long-term treatment for fibromyalgia and its symptoms. Surprisingly according to the methods of the present invention, the administration of a dual serotonin and norepinephrine absorption inhibitor provides a patient suffering from fibromyalgia syndrome with an effective and long-term treatment of fibromyalgia and its symptoms. The double-blind, randomized, placebo-controlled clinical study reported here first in Example 1 described below unexpectedly demonstrated that DRI can be effectively used in the long term (at least three months) for the treatment of fibromyalgia and its symptoms in the case of patients who suffer from fibromyalgia. Additionally, the results of this clinical study surprisingly demonstrate that DRI can effectively provide long-term treatment of FMS and its symptoms for at least six months. Therefore, the present invention provides methods for the long-term treatment of fibromyalgia syndrome in patients who require it, by administering DRI for at least three months. In some applications, the DRI is a compound that inhibits the reuptake of norepinephrine in greater quantity or equal to the reuptake of serotonin (NSRI). In example applications the NSRI is the milnacipran. For example, in accordance with the methods of the present invention, long-term treatment of FMS and its symptoms can be provided to a patient suffering from FMS by administration of 25 mg per day to 400 mg per day. . In example applications, milnacipran can be administered in doses of 1000 mg per day for the long-term treatment of FMS and its symptoms in patients suffering from FMS. In example modalities, milnacipran can be administered in doses of 200 mg per day for the long-term treatment of FMS and its symptoms in patients suffering from FMS. Brief description of the figures Figure 1 is a chronogram of the clinical study described in example 1. Figure 2 is a bar graph illustrating the percentage of responders at three months and six months for the placebo, milnacipran 1 00 mg / day and milnacipran 200 mg / day for the groups described in example 1. DETAILED DESCRIPTION OF THE INVENTION As used herein, the term "subject" or "patient" includes humans and non-human mammals. As used herein, "treatment" or "effective treatment" means alleviating, delaying, reducing, reversing, improving or preventing at least one symptom of fibromyalgia. The term "dual resorption inhibitors" refers to a well-recognized type of antidepressant compound that selectively inhibits the reabsorption of both norepinephrines and serotonin.

"Norepinephrine-Serotonin Reuptake Inhibitor" (NSRI) e "Serotonin-norepinephrine reuptake inhibitor" (NSRI) refer to subclasses of DRI. The DRI compounds that block the reuptake of norepinephrine are preferably referred to as NSRIs.

While those that block the reuptake of norepinephrine are preferably referred to as NSRIs. The common compounds of DRI include, but are not limited to, the NSRI belafaxine and duloxetine and the NSRI bicifadine and milnacipran. The NSRI compounds are described in detail in U.S. Patent No. 6,602.91 1, the content of which is incorporated herein by reference in its entirety. According to some embodiments, the present invention provides methods of long-term treatment of the fibromyalgia in a patient who is given DRI for at least three months. In exemplary embodiments, the DRI compounds are NSRI. In other example modalities, the NSRI is milnacipran. In some applications, milnacipran can be administered as a hydrochloride salt: Z-2-aminomethyl-1-phenyl-N, N-diethylcyclopropanecarboxamide hydrochloride (chemical formula C? 5H23 Cl N2 O). In other embodiments, milnacipran can be administered as a mixture of dextro- and levorotatory enantiomers, for example as a mixture that includes more than one enantiomer or racemic mixture. In some embodiments, milnacipran can be administered in an enantiomerically pure form (e.g., as the pure dextrorotatory or pure levorotatory enantiomer). Unless otherwise indicated, milnacipran may include all stereoisomeric forms, mixtures of stereoisomeric forms, diastereomeric forms, and pharmaceutically acceptable salts thereof, including both enantiomerically pure forms of milnacipran, as well as mixtures of milnacipran enantiomers. Methods for separating and isolating the dextro- and levorotatory enantiomers of milnacipran and other NE 5-HT SNRI compounds are well known (see, for example, Grard et al., 2000, Electropohoresis 2000 21: 3028-3034). Pharmaceutical compositions suitable for use in the present invention include compositions in which the active ingredient is contained in a therapeutically or prophylactically effective amount, in an amount effective to achieve therapeutic and prophylactic benefits for the long-term treatment of FMS and its symptoms. Determining the effective amount is also within the capabilities of persons skilled in the art, specifically in light of the present disclosure. The therapeutic amounts of the DRI compounds commonly range from 1 μg to 1 g / day. The amount of the DRI compound administered to practice the methods of the invention, of course, will be dependent on the DRI, the subject to be treated, the severity of the affectation and the manner of administration. See, for example, U.S. Application No. 1 0 / 678,767, the content of which is incorporated herein by reference in its entirety. For example, therapeutically effective amounts can be determined from the data of the DRI compounds used in humans to treat depression. The therapeutically effective amount may be the same amount administered to treat the depression or may be a greater or lesser amount of the amount administered to treat the depression. For example, the amount of milnacipran administered to treat depression may be in the range of approximately 50 mg to approximately 400 mg per day. Thus, approximately 50 mg per day at 400 mg per day of milnacipran can be used for the long-term treatment of FMS and its symptoms. For example, for the treatment of FMS, CFS, or pain with milnacipran the dose range is commonly from 25 mg to 400 mg per day, commonly more than 1 00 mg to 250 mg per day. The dose can be administered once a day or several or multiple times a day. Therapeutically effective amounts for use in humans can be determined from animal models. For example, the dose for humans can be formulated to achieve circulatory concentration which has been found to be effective in animals. Useful models for pain in animals are well known in the art. For example, neuropathic pain models are described in ZELTSER et al. , 2000, Pain 89: 19-24; Bennett et al. , 1988, Pain 33: 87-107; Zeltzer et al. , 1990, Pain 43: 205-208; Kim et al. , 1992, Pain 50: 355-363; and Decoster et al. , 2000, Pain 87: 149-158. An animal model for inflammatory pain using Freund's complete adjuvant is described in Jasmin et al. , 1998, Pain 75: 367-382. The hyperalgesia model induced by stress described in Quintero et al. , 2000, Pharmacology, biochemistry and behavior 67: 449-458 can be used as an animal model of FMS and CFS. The route of administration of the pharmaceutical compositions of the present invention can be, for example, oral, enteral, intravenous and transmucosal (for example rectal). The preferred route of administration is oral. Pharmaceutical compositions suitable for oral administration may be presented in the form of tablets, capsules, pills, powders and granules or liquid solutions or dispersions. Each form will contain a predetermined amount of the compound of the invention as the active ingredient. The composition it can be prepared as a tablet using any pharmaceutical excipient known in the art for that purpose, and conventionally used for the preparation of solid pharmaceutical compositions. Examples of such excipients include, but are not limited to, starch, lactose, microcrystalline cellulose, and magnesium stearate. Compounds such as polyvinyl pyrrolidone can also be used in the composition of the present invention. Additionally, an active compound can be formulated as a controlled release preparation, such as tablets containing a hydrophilic or hydrophobic matrix. The pharmaceutical compositions of the present invention may be in the form of capsules formulated using conventional methods, for example by incorporating a mixture of active compounds and excipients into a hard gelatin capsule. Alternatively, a semisolid matrix of an active compound and a high molecular weight glycol can be formed and filled into hard gelatin capsules, or soft gelatin capsules can be filled with a solution of polyethylene glycol active compound or an oil dispersion. groceries. It is also possible to contemplate powder forms. Alternatively, oily vehicles can also be used as injectable formulations. Liquid forms for parenteral administration can additionally be formulated for administration by injection or continuous infusion. The routes accepted for Administration by injection are intravenous, intraperitoneal, intramuscular and subcutaneous. A typical composition for intravenous injections comprises a sterile isotonic aqueous solution or dispersion, including, for example, an active compound and dextrose or sodium chloride. Other examples of acceptable excipients are lactated Ringer's solutions for injections, lactated Ringer's solution for injections with dextrose, Normosol-M with dextrose, acylated Ringer's solution for injections. The injection formulation optionally may include co-solvents (for example polyethylene glycol and other agents (ethylenediaminetetraacetic acid, stabilizing agents (for example cyclodextrin) and / or antioxidants (for example sodium pyrosulfate) According to certain applications, the DRI may be administered in conjunction with other active compounds for the long-term treatment of fibromyalgia syndrome., the active compounds that can be administered include antidepressants, analgesics, muscle relaxants, anorectics, stimulants, antiepileptic drugs, beta blockers and sedatives / hypnotics. Some examples of compounds that can be administered in conjunction with the DRI include, but are not limited to, modafinil, gabapentin, pregabalin, XP13512, pramipexole, 1 -DOPA, amphetamine, tizanidine, clonidine, tramadol, morphine, tricyclic antidepressants, codeine, cambamazepine. , sibutramine, valium, trazodone, caffeine, nicergoline, bifemelano, propranolol, atenolol, and combinations of them. In certain examples, the DRI can be milnacipran and may be coadministered with an alpha-2-delta ligand such as, for example, pregabalin. As used herein, co-administration includes the simultaneous administration of the compounds in the same dosage form, simultaneous administration in the form of separate doses and separate administration of compounds. For example, milnacipran can be administered simultaneously with valium, where milnacipran and valium are formulated in the same tablet. Alternatively, milnacipran can be administered simultaneously with valium, where both milnacipran and valium are present in two separate tablets. In another alternative, milnacipran can be administered first, followed by administration of valium, or vice versa. Mono therapy with milnacipran for the treatment of fibromyalgia has been previously described in a Phase I I trial with 125 fibromyalgia patients. See, for example, United States Application No. 10 / 678,767, the content of which is incorporated herein by reference in its entirety. In this study, milnacipran was administered once or twice a day in a staged dose regimen, with a maximum dose of 200 mg / day. The study showed that milnacipran provided effective and acute (short-term) therapy for FMS symptoms. In particular, the doses of milnacipran 2 times a day (BID) and 1 time a day (QD) were effective in an approximately equal degree for fatigue, mood, general well-being and motor skills. The dosing twice a day was better tolerated than the QD dosing and was more effective in the treatment of pain than the QD dosing. The global impression of patient change (PGIC) showed that more than 70% of those who completed both milnacipran treatments reported an improvement in their general condition, while only 10% reported that it worsened. In contrast, 40% of the placebo patients who completed the test rated themselves as worse off at the end. The differences between placebo and milnacipran in the PGIC were statistically significant both in terms of comparison of the values at the end, as well as in the binary base improvement / no improvement. Milnacipran was well tolerated in Phase I of the study. There were no deaths or serious adverse events (AE) associated with treatment with milnacipran and most of the reported AEs were categorized as medium or moderate in severity. The frequently reported AE was nausea, reported (1 or more times) by 33% of patients treated with milnacipran; the remaining AEs were reported in less than 9% of patients treated with milnacipran. The higher incidence of nausea, abdominal pain, headache, and certain other AEs, in the 200 MG QD treatment group suggests that higher doses taken once a day are not tolerated as well as divided lower dosages administered twice daily. day. Information on dizziness, postural vertigo, hot flashes (and flushing), and palpitations was also greater in the group of QD treatment, which suggests that maximum drug levels can be a determining factor in the generation of various adverse factors. Consistent with the results of the previous tests, 7% of patients experienced mild increases in ALT and / or AST (= 2 times the upper limit of normal), without concomitant increases in bilirubin or alkaline phosphatase. Elevation of liver enzymes produced adverse events in only 2% of patients treated with milnacipran (ie, 2 out of 7 patients with enzyme elevations reported the adverse event of "elevation in SGOT" or "elevation in SGPT"). An increase of 4 to 8 heartbeats per minute was noted in patients treated with milnacipran, which is consistent with the results of the previously performed milnacipran test. Mean systolic and diastolic blood pressures in the groups treated with milnacipran showed only slight increases between 1.5 to 3.4 mm Hg for supine systolic pressures (-1.1 to 2.7 mm Hg in the placebo group), and 2.6 a 3.7 mm Hg for supine diastolic pressures (-3.5 to 1.2 mm Hg in the placebo group) 2% of patients treated with milnacipran BID experienced an exacerbation of hypertension; both patients had pre-existing hypertension and were receiving medical treatment for hypertension. One patient withdrew early from the trial due to an exacerbation of hypertension. The potential of orthostatic effects related to Treatment was also documented during the previous tests, and 6 (6%) of patients treated with milnacipran during FMS tests reported adverse orthostatic / postural vertigo events, with early discontinuation of a patient due to moderate postural vertigo. The vital signs information revealed that 4% of patients with placebo and 7% of patients with milnacipran experienced one or two visits with reduction of 20 mm Hg or more in systolic blood pressure after being incorporated for one minute. Therefore, Phase II trials demonstrated that treatment with milnacipran was an acute (short-term) effective therapy for the pain symptom in FMS and milnacipran dosed once or twice a day had verifiable beneficial effects in a variety of symptoms of FMS, including fatigue (measured in the FIQ, pain (multiple measures), quality of life (multiple measures), and potentially in the mood (Beck instrument). It has not been previously shown that the milnacipran or any Another active agent is effective long-term (more than 3 months) for the treatment of FMS and its symptoms.The clinical study described in example 1 below provides the first and surprising report of the effective long-term treatment of FMS using the NSRI The following examples are merely illustrative of the present invention and should not be considered as limiting the The scope of the invention is in no way, since various variations and equivalents that are included in the present invention will be apparent to qualified persons in this field to read the present disclosure. Examples Example 1. A randomized, double-blind, placebo-controlled study in multiple centers of milnacipran for the treatment of fibromyalgia. The main objective of this study was to demonstrate the clinical and statistical safety and efficacy of milnacipran in the treatment of fibromyalgia syndrome. The main result was a composite responder analysis evaluating the response rate at weeks 14 and 15, and a secondary analysis evaluating the response rate at weeks 26 and 27. Other objectives of this study were: 1. To compare the clinical and statistical efficacy of 1000 mg / day and 200 mg / day of milnacipran in the treatment of fibromyalgia syndrome based on each component of the composite responder analysis, as well as in an additional number of secondary points including fatigue, sleep, mood and perception. 2. Establish and compare the safety profiles of 1 00 and 200 mg of milnacipran administered daily in patients with MS F. Methodology This was a three-arm, placebo-controlled study. double blind, randomized, in multiple centers, for which 888 patients were recruited who fulfilled the criteria of the ACR 1990 for the fibromyalgia syndrome, as well as with the admission criteria more detailed in the protocol. Patients registered symptoms at baseline during the first two weeks after eliminating antidepressants, benzodiazepine, and certain other drugs that could potentially interfere with efficacy measurements. The patients were randomly selected to receive placebo, 100 mg / day of milnacipran or 200 mg / day of milnacipran in a ratio of 1: 1: 2. All random medications (placebo and milnacipran) were administered as divided doses (BID). The doses were administered in a regimen of dose escalation detailed below. Step 1: 12.5 mg 1 day (12.5 mg pm) Step 2: 25 mg 2 days (12.5 mg am, 12.5 mg pm) Step 3: 50 mg 4 days (25 mg am, 25 mg pm) Step 4: 100 mg 7 days (50 mg a, 50 mg p.m.) Step 5: 200 mg 7 days (100 mg a, 100 mg p.m.) All patients were scheduled to receive a total of 24 weeks of milnacipran or placebo after 3 weeks of steps of stepped dose increase, for a total of 27 weeks of exposure to milnacipran or placebo. Patients were asked to complete an electronic journal as well as other paper evaluations of conformity with what is described in the program of evaluations of the study. Data on adverse events, physical examinations, concomitant medication, vital signs and clinical laboratory data were collected as detailed in the study's evaluation program.

Patients who successfully completed this double blind test were eligible to participate in an open trial for 1-5 additional weeks of therapy. A study schedule is provided in Figure 1. Safety Assessments: The safety of milnacipran was evaluated by analyzing the frequency and intensity of adverse events, changes in vital signs, as well as changes in the physical examination and in the clinical laboratory data collected during the study period. Efficacy: In addition to the requirement to comply with the electronic diary of the owner patient, the following evaluations were obtained: a. Primary variables: Global impression of change of the patient (PGI C) and the questionnaire of impact on fibromyalgia (F IQ); b. Psychological exploration on the line: M. I .N. I c. Miscellaneous status evaluations: periodically, in accordance with what is described in the evaluation program: BDI dream quality scale and ASEX; Y d. FMS status evaluations: patient pain in 24 hours and 7 days on the visual analogue scale (VAS), and the SF-36 questionnaire, multi-capacity self-report questionnaire (SMOC, cognitive function), the multidimensional questionnaire for the health assessment (M DHAQ) and the multidimensional inventory of fatigue (FM I). Daily assessments include current pain (in the morning, daily randomly and reports in the afternoon); daily pain (morning report), medications taken (afternoon report), general pain in the previous week (weekly report), general fatigue in the previous week (weekly report), and the degree to which the pain prevented the patient take care of himself (weekly report). The primary outcome of this study was a responder analysis composed of the 3 domains of interest, evaluated at 24 weeks as a primary analysis and at 12 weeks as a secondary analysis. The domains measured were: 1. Pain (measured by an electronic journal as a pain response score calculated for average weekly scores, 2. Global patients (measured by PG CI, scale 1-7), and 3. Physical function, (measured by FIQ-PF). For the primary analysis, the pain domain score was determined by a calculation that compared the average of the weeks of treatment 14 and 1 5 with the two weeks taken from the base and the treatment weeks 26 and 27 with the baseline for him secondary analysis. The last observation was made later if neither in week 14 nor in week 1 5 (or in weeks 26/27) was available the pain score reported by the patient to compare with the base values. The binary response rate for placebo is expected (based on the final composite result) in the present study is in the range of 10-1 3%, with a response rate of milnacipran in the arm or active arms expected in the range of 27-29% based on ITT / LOCF. Based on these assumed response rates, it was calculated that 125 randomly selected patients (250 for high dose groups) would be the maximum sample size required (90% intensity). Secondary analyzes included the total area under the pain intensity curve, and the pain reported by the patient weekly in the clinic visits, as well as the FMS status evaluations and the QOL measurements. Results: A responder was defined as a subject who experienced a reduction greater than 30% of pain, starting from the base, and improvements of the PIGC. At three months, the percentage of responders was: 35.44% (56/1 58) in the placebo group; 53.33% (72/1 35) (p = 0.001) in the group with milnacipran 1 00 mg per day, and 55.00% (1 43/260) (p <0.001) in the group with milnacipran 200 mg per day. At six months the percentage of responders was: 32.86% (46/1 40) in the group with placebo; 49.59% (60/1 21) (p = 0.002) in the group with milnacipran 1 00 mg per day, and 51.74% (1 19/230) (p <0.001) in the group with milnacipran 200 mg per day . See table No. 1 for the summary of the results in the population that was tried and table No. 2 for the summary of the last observation made after (LOCF), base observation made after (BOCF) and populations that completed the study (OC) The LOCF is an analysis in which observations are made at the last point for patients who withdrew. The LOCF analysis handles the information performed as observed data in the last point. The BOCF is an analysis that requires the patient to remain active in the test so that the response is evaluated. If a patient withdraws from the test for any reason, it is categorized as non-respondent, regardless of their overall and pain scores at the time of withdrawal. Table 1 Analysis of responders for the treatment of pain of fibromyalgia during the weeks of treatment 14-1 5 and 26-27 (cases observed) in the population that was tried to treat Table 2 These results surprisingly establish that continuous administration of milnacipran (daily administration for at least 3 months) to subjects suffering from fibromyalgia provides long-term relief (at least 3 months) of fibromyalgia and its symptoms. Additionally, these results surprisingly establish that continuous administration of low doses of milnacipran (eg, 100 mg / day) is almost as effective as continuous administration of high doses of milnacipran (eg, 200 mg / day) for the long-term treatment of fibromyalgia and its symptoms. Figure 2. While the invention has been illustrated and described by reference to exemplary embodiments of the invention, said reference does not imply or limit the invention, and such limitation should not be inferred. The invention is susceptible to considerable modification, alteration and equivalents in form and function, which will occur to those skilled in the art who have the benefit of this disclosure. The embodiments of the invention illustrated and described are examples only, and are exhaustive of the scope of the invention. Consequently, it is intended that the invention be limited only by the spirit and scope of the appended claims, granting wide recognition to its equivalent in all aspects. All references cited herein are incorporated by reference in their entirety.

Claims (10)

1 . A method for providing long-term treatment of fibromyalgia syndrome in a patient who requires it by administering a dual reabsorption inhibitor (DRI) to the patient for at least three months.

2. The method of claim 1, further characterized in that the DRI is a norepinephrine-serotin reuptake inhibitor (NSRI).

3. The method of claim 2, further characterized in that the NSRI is milnacipran.

4. The method of claim 3, further characterized in that milnacipran is administered in a dose of between about 25 mg / day and about 400 mg / day.

5. The method of claim 4, further characterized in that milnacipran is administered in a dose of about 200 mg / day.

6. The method of claim 4, further characterized in that milnacipran is administered in a dose of approximately 1000 mg / day. The method of claim 1, further characterized in that the DRI is administered for at least six months. 8. A method for the treatment of fibromyalgia and its symptoms in a patient suffering from fibromyalgia, which comprises: to. Administer approximately 200 mg / day of milnacipran to the patient for the treatment of acute pain; b. Decrease the dose of milnacipran to approximately 100 mg / day when acute pain has been treated; and c. Administer approximately 100 mg / day of milnacipran to the patient for at least three months for the long-term treatment of fibromyalgia and its symptoms. The method of any of claims 1 to 8, which includes co-administering a second active compound, wherein the second active compound is selected from the group consisting of an antidepressant, an analgesic, a muscle relaxant, an anorectic, a stimulant , an antiepileptic drug, a beta blocker, a sedative, a hypnotic and combinations thereof. The method of claim 9, further characterized in that the second active compound is selected from the group consisting of modafinil, XP13512, gabapentin, pregabalin, pramipexole, 1 -DOPA, amphetamine, tizanidine, clonidine, tramadol, morphine, tricyclic antidepressants, codeine, carbamazepine, sibutramine, valium, trazodone, caffeine, nicergoline, bifemelan, propranolol, atenolol and combinations thereof. eleven . A method for providing long-term treatment of pain symptoms associated with fibromyalgia syndrome in a patient who requires it, the method comprises administering a dual reabsorption inhibitor (DRI) to the patient at least during three months. The method of claim 1, further characterized in that the DRI is a dual norepinephrine-serotin reuptake inhibitor (NSRI). 3. The method of claim 2, further characterized in that the NSRI is milnacipran. 4. The method of claim 3, further characterized in that the milnacipran is administered in a dose of between about 25 mg / day and about 400 mg / day. The method of claim 4, further characterized in that the milnacipran is administered in a dose of approximately 200 mg / day. 6. The method of claim 4, further characterized in that milnacipran is administered in a dose of approximately 1000 mg / day.

7. The method of claim 1, further characterized in that the DRI is administered for at least six months. 1

8. A method for the treatment of fibromyalgia and its symptoms in a patient suffering from fibromyalgia, which includes: a. Give the patient approximately 200 mg per day of milnacipran for the treatment of acute pain; b. Decrease the dose of milnacipran to approximately 1000 mg per day when acute pain has been treated; and c. Administer approximately 1000 mg per day of milnacipran to the patient for at least 3 months for the long-term treatment of fibromyalgia and its symptoms 1

9. The method of any of claims 1 to 18, which includes co-administering a second active compound, wherein the second active compound is selected from the group consisting of an antidepressant, an analgesic, a muscle relaxant, an anorectic, a stimulant, an antiepileptic drug, a beta-blocker, a sedative, a hypnotic and combinations thereof. The method of claim 19, further characterized in that the second active compound is selected from the group consisting of modafinil, XP13512, gabapentin, pregabalin, pramipexole, 1 -DOPA, amphetamine, tizanidine, clonidine, tramadol, morphine, tricyclic antidepressants, codeine , carbapine, sibutramlna, valium, trazodone, caffeine, nicergoline, bifemelano, propanolol, atenolol and combinations of them.