US 20110259786A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0259786 A1 Roberts et al. (43) Pub. Date: Oct. 27, 2011 (54) DROXDOPA AND PHARMACEUTICAL Publication Classification COMPOSITION THEREOF FOR THE TREATMENT OF FIBROMYALGA (51) Int. Cl. B65D 69/00 (2006.01) (76) Inventors: Michael J. Roberts, Charlotte, NC (52) U.S. Cl. ........................................................ 2O6/570 (US); Simon Pedder, Fort Mill, SC (US) (57) ABSTRACT (21) Appl. No.: 13/174,827 The present invention provides methods of treating fibromy algia or other diseases or conditions causing widespread pain (22) Filed: Jul. 1, 2011 and/or fatigue. In particular, the invention provides pharma ceutical compositions comprising droxidopa alone, or in Related U.S. Application Data combination with one or more further active agents, that can be used in the inventive methods. The methods of treatment (62) Division of application No. 12/044,680, filed on Mar. can comprise treating, preventing, reducing, or eliminating a 7, 2008, now Pat. No. 8,008,285. variety of symptoms recognized as indicative of fibromyal (60) Provisional application No. 60/894,030, filed on Mar. gia. Such as chronic pain, allodynia, hyperalgesia, fatigue, 9, 2007. sleep disturbance, and depression. Patent Application Publication Oct. 27, 2011 Sheet 2 of 2 US 2011/0259786 A1 Lo cN CN cN N - CN ve (Snou) eu US 2011/0259786 A1 Oct. 27, 2011 DROXDOPA AND PHARMACEUTICAL physically. Many fibromyalgia patients also have an associ COMPOSITION THEREOF FOR THE ated sleep disorder that prevents deep, restful, restorative TREATMENT OF FIBROMYALGA sleep. Studies have documented specific and distinctive abnormalities in the stage 4 deep sleep of fibromyalgia CROSS-REFERENCE TO RELATED patients. During sleep, individuals with fibromyalgia are con APPLICATION stantly interrupted by bursts of awake-like brain activity lim iting the amount of time they spend in deep sleep. Additional 0001. The present application is a division of U.S. Patent symptoms associated with fibromyalgia can include the fol application Ser. No. 12/044,680, filed Mar. 7, 2008, which lowing: irritable bowel and bladder, headaches and claims priority to U.S. Provisional Patent Application No. migraines, restless legs syndrome (periodic limb movement 607894,030, filed Mar. 9, 2007, the disclosures of which are disorder), impaired memory and concentration, skin sensi incorporated herein by reference in their entireties. tivities and rashes, dry eyes and mouth, anxiety, depression, ringing in the ears, dizziness, hypotension, vision problems, FIELD OF THE INVENTION Raynaud's Syndrome, neurological symptoms, and impaired 0002 The present application is directed to the use of coordination, as well as other symptoms. droxidopa, alone or in combination with one or more addi 0007 Currently there are no known diagnostic tests spe tional components, for the treatment of Central Sensitivity cific to fibromyalgia. Accordingly, diagnosis generally arises Syndromes, such as fibromyalgia. from evaluation of patient histories, self-reported symptoms, physical examination, and an accurate manual “tender point' BACKGROUND examination based on the standardized criteria from the 0003 Droxidopa is a known synthetic amino acid precur American College of Rheumatology (ACR). As defined by sor of norepinephrine that is converted directly to norepi ACR guidelines, FMS involves the presence of pain for over nephrine via the action of dopa decarboxylase (DDC). Droxi three months duration in all four quadrants of the body, as dopa is generally used to treat orthostatic hypotension (OH) well as along the spine. In addition, pain is elicited by palpa and can be categorized as an antiparkinsonian agent; how tion in at least 11 out of 18 “tender points'. It is estimated that ever, multiple pharmacological activities have been observed it takes an average of five years for a fibromyalgia patient to with droxidopa, including the following: (1) it is directly get an accurate diagnosis, and many fibromyalgia symptoms converted to 1-norepinephrine by the action of the aromatic overlap with those of other conditions. Moreover, the pres L-amino acid decarboxylase which is widely distributed in a ence of comorbidities (such as rheumatoid arthritis or lupus) living body, and thus has an effect of replenishing norepi does not rule out a fibromyalgia diagnosis. nephrine; (2) it has limited permeability through the blood 0008. The etiology and pathophysiology of fibromyalgia brain barrier into the brain; (3) it specifically recovers nore are unknown; however, it is generally believed to include pinephrine activated nerve functions which have decreased in central nervous system involvement. Most researchers agree the central and peripheral nervous system; and (4) it shows fibromyalgia is a disorder of central processing with neuroen various actions, as norepinephrine, via the adrenaline recep docrine/neurotransmitter dysregulation. Fibromyalgia tors in various tissues. patients often experience pain amplification due to abnormal 0004 Fibromyalgia—also referred to as fibromyalgia sensory processing in the central nervous system. Further syndrome (FMS)—is a chronic pain illness or condition char more, studies show multiple physiological abnormalities in acterized by a generalized heightened perception of sensory fibromyalgia patients, including: increased levels of Sub stimuli and manifested by widespreadaches, pain, and stiff stance P in the spinal cord; low levels of blood flow to the ness in muscles, fascia, and joints, as well as Soft tissue thalamus region of the brain; HPA axis hypofunction; low tenderness. The most common sites of pain include the neck, levels of serotonin and tryptophan; and abnormalities in back, shoulders, pelvic girdle, and hands, but any body part cytokine function. Recent studies indicate the possibility of a can be affected. Patients with fibromyalgia display abnor genetic susceptibility to fibromyalgia. malities in pain perception in the form of both allodynia (pain 0009 Treatment of fibromyalgia is often multi-faceted with innocuous stimulation) and hyperalgesia (increased sen and typically seeks to alleviate the associated symptoms sitivity to painful stimuli). Other symptoms typically include rather than treat the condition itself. Medications, such as general fatigue, sleep disturbances, and depression. analgesics, anti-inflammatories, and muscle relaxants can be 0005 Fibromyalgia is characterized by the presence of beneficial in reducing pain. Antidepressants may also be pre multiple tender points and a constellation of symptoms. The scribed. Complementary therapies include: physical therapy, pain of fibromyalgia is profound, widespread, and chronic therapeutic massage, myofascial release therapy, water and is known to migrate to all parts of the body with varying therapy, light aerobics, diet adjustments, acupressure, appli intensity. Fibromyalgia pain has been described as deep mus cation of heat or cold, acupuncture, yoga, relaxation exer cular aching, throbbing, twitching, stabbing and shooting cises, breathing techniques, aromatherapy, cognitive therapy, pain. Neurological complaints such as numbness, tingling, biofeedback, herbs, nutritional Supplements, and osteopathic and burning are often present and add to the discomfort of the or chiropractic manipulation. One or more of these may be patient. Pain severity and stiffness is often worse in the morn used. ing, and aggravating factors include cold/humid weather, 0010 Despite all of the above approaches for management non-restorative sleep, physical and mental fatigue, excessive offibromyalgia, there remains an ongoing search for effective physical activity, physical inactivity, anxiety, and stress. drug treatment of fibromyalgia. Multiple studies have been 0006 Fatigue associated with fibromyalgia can itself be performed around a wide variety of compounds, and Such debilitating, interfering with even the simplest daily activi studies are further referenced in U.S. Pat. No. 6,610,324, ties. At times, fibromyalgia-associated fatigue can leave the which is incorporated herein by reference. None of the pre patient with a limited ability to function both mentally and viously evaluated drugs have shown particularly useful for US 2011/0259786 A1 Oct. 27, 2011 long-term treatment of fibromyalgia beyond symptomatic tyline, nortriptyline, desipramine, traZodone, Venlafaxine, alleviation, and the need for effective drug treatment offibro dulloxetine, milnacipran, nefopam, bupropion, and combina myalgia persists. tions thereof. 0018. The invention also comprises methods of treating SUMMARY OF THE INVENTION fibromyalgia comprising administering droxidopa in combi 0011. The present invention provides pharmaceutical nation with one or more additional active agents having a compositions useful in the treatment of fibromyalgia or other complimentary activity to the activity of droxidopa. In one conditions falling under the umbrella of Central Sensitivity particular embodiment, the invention provides a method of Syndrome (CSS). The pharmaceutical compositions gener treating fibromyalgia comprising administering a pharma ally comprise droxidopa alone or in combination with one or ceutical composition comprising droxidopa and one or more more further pharmaceutically active compounds. DOPA decarboxylase inhibiting compounds. Preferably, the 0012. In one aspect, the invention provides a method of DOPA decarboxylase inhibiting compounds are selected treating fibromyalgia.