US 20110269.727A1 (19) United States (12) Patent Application Publication (10) Pub. No.: US 2011/0269727 A1 Toledan0 (43) Pub. Date: Nov. 3, 2011

(54) COMPOSITION TO REDUCE ALLODYNIC A6IP 29/00 (2006.01) BACKPAN AND RELATED METHOD OF A6II 3/54 (2006.01) USE A6IP II/4 (2006.01) (52) U.S. Cl...... 514/171; 514/227.2: 514/249; (76) Inventor: Annette C. Toledano, North 514/282; 514/331 Miami, FL (US) (57) ABSTRACT (21) Appl. No.: 12/824,367 The invention relates to a pharmaceutical composition to (22) Filed: Jun. 28, 2010 reduce back pain comprising two compounds: an opioid antagonist and a direct-acting alpha 2 adrenegic agonist. The Related U.S. Application Data Opioid antagonist is selected from the group consisting of (60) 29,Provisional 2010, provisionalapplication applicationNo. 61,343,489, No. filed61/395,772, on Apr. RE"R"RE". E. E. E. p . Ically p i. C filed on May 17, 2010. Irect-acting alpna 4 aarenegic agonist is selected Irom a group consisting of Apraclonidine, Brimonidine, Clonidine, O O Detomidine, Dexmedetomidine, Guanabenz, Guanfacine, Publication Classification Lofexidine, Medetomidine, Romifidine, Tizanidine, Toloni (51) Int. Cl. dine, Xylazine and Fadolmidine. In one embodiment, the A6 IK3I/56 (2006.01) composition may include naltrexone (or its pharmaceutically A6 IK 3/498 (2006.01) acceptable salt) as the opioid antagonist and clonidine hydro A6 IK 3/439 (2006.01) chloride (or its pharmaceutically acceptable salt) as the A6 IK 3L/45 (2006.01) direct-acting alpha 2 adrenegic agonist. It is preferred naltr A6IP 2L/02 (2006.01) exone be administered with a second agent Such as an anti A6IP 25/24 (2006.01) tussive, expectorant, decongestant, orantihistamine. The dos A6IP 25/08 (2006.01) age of naltrexone may range between 0.25 mg to 15 mg, while A6IP II/O (2006.01) the dosage of clonidine hydrochloride ranges between 0.0125 A6IP II/02 (2006.01) mg and 0.3 mg. US 2011/0269.727 A1 Nov. 3, 2011

COMPOSITION TO REDUCE ALLODYNC role of the dorsal ramus in patients that have no radiographic BACKPAN AND RELATED METHOD OF abnormalities. The management goals when treating back USE pain are to achieve maximal reduction in pain intensity as rapidly as possible; to restore the individual’s ability to func CROSS-REFERENCE TO RELATED tion in everyday activities; to help the patient cope with APPLICATION residual pain; to assess for side-effects of therapy; and to facilitate the patient's passage through the legal and Socio 0001. The application seeks priority to U.S. Provisional economic impediments to recovery. For many, the goal is to Application Ser. No. 61/343,489 entitled “Methods For keep the painto a manageable level to progress with rehabili Treating Pain By Composition of Naltrexone/Clonidine At tation, which then can lead to long term pain relief. Also, for Any Dose Combination' filed on Apr. 29, 2010 and U.S. Some people the goal is to use non-Surgical therapies to man Provisional Application Ser. No. 61/395,772 entitled “Phar age the pain and avoid major Surgery, while for others Surgery maceutical Combinations for Alleviation of Back Pain also may be the quickest way to feel better. called Spinal Pain” filed on May 17, 2010, the contents of 0008 While only a minority of individuals suffering from which are hereby both incorporated by reference in their back pain resort to Surgery, there are only limited options for entirety. offering relief from chronic back pain. Heat therapy is one 0002 This invention is directed to a pharmaceutical com option for short term relief, as well as alternative cold com position of two compounds to alleviate back pain. More spe pression therapy proximate to the location of pain. Alterna cifically, the composition teaches combination of a low dose tive treatments such as message therapy, acupressure and Opioid antagonist, Naltrexone, and an alpha two adrenergic pressure point message have also been used. Some pharma receptor agonist, Clonidine, to reduce back pain. ceuticals have shown usefulness in treating back pain, includ ing muscle relaxants, non-steroidal anti-inflammatory drugs, BACKGROUND OF THE INVENTION analgesics and Opioid agonists. 0003 Back pain represents one of the most common and 0009. Accordingly, there is a need in the art of treating chronic physical ailments. In the United States, acute back back pain for an alternative pharmaceutical composition that pain (also referred to as “lumbago') is the fifth most common reduces the symptoms of back pain effectively for longer reason for physician visits. In fact, nine often adults experi periods of time and is not a narcotic compound. ence back pain at Some point in their life, and five out often working adults report back pain every year. SUMMARY OF THE INVENTION 0004 Observational studies suggest two conditions to 0010. The present invention offers an alternative pharma which back pain has been attributed. The first is lumbar disc ceutical composition which reduces the symptoms of back herniation and degenerative disc disease, where the underly pain. The composition includes two compounds: an Opioid ing mechanisms causing the pain remain unknown. Studies antagonist and a direct-acting alpha 2 adrenegic agonist. The Suggest that for as many as 85 percent of cases, no physiologi Opioid antagonist is selected from the group consisting of cal cause can be shown. There are several potential sources alvimopan, nalmefene, naloxone, naltrexone, methylnaltrex and causes of back pain. However, the diagnosis of specific one, nalorphine, and pharmaceutically acceptable salt. The tissues of the spine as the cause of pain presents problems. direct-acting alpha 2 adrenegic agonist is selected from a This is because symptoms arising from different spinal tis group consisting of Apraclonidine, Brimonidine, Clonidine, sues can feel very similar and is difficult to differentiate Detomidine, Dexmedetomidine, Guanabenz, Guanfacine, without the use of invasive diagnostic intervention proce Lofexidine, Medetomidine, Romifidine, Tizanidine, Toloni dures, such as local anesthetic blocks. dine, Xylazine and Fadolmidine. 0005 One potential source of back pain is attributed to 0011. In one embodiment, the composition may include skeletal muscle in the back. Causes this type of back pain maltrexone (or its pharmaceutically acceptable salt) as the include muscle strains, spasm, and imbalances. However, opioid antagonist, and clonidine hydrochloride (or its phar imaging studies do not support the notion of muscle tissue maceutically acceptable salt) as the direct-acting alpha 2 damage in many back pain cases, and the neurophysiology of adrenegic agonist. It is preferred that naltrexone be adminis muscle spasm and imbalances are not well understood. tered in low doses, along with a second pharmaceutical agent 0006 Another potential source of low back pain is the such as annon steroidal anti inflammatory drug (NSAID) of synovial joints of the spine (e.g., Zygapophysial joints). These all chemical groups, including COX-2 selective inhibitors have been identified as the primary source of the pain in (coxibs), Steroidal anti inflammatory drugs, Tricyclic antide approximately one third of people with chronic low back pressants (TCAS), Selective serotonin reuptake inhibitors pain, and in most people with neck pain following whiplash. (SSRIs), Serotonin-norepinephrine reuptake inhibitors (SN However, the cause of Zygapophysial joint pain is not fully RIs), Anticonvulsants, muscle relaxant, drug with NMDA understood. Capsule tissue damage has been proposed in antagonist properties, Tetrahydrocannabinol derivatives, people with neck pain following whiplash. In people with antitussive, an expectorant, a decongestant, or an antihista spinal pain stemming from Zygapophysial joints, one theory mine. The dosage of naltrexone may range between 0.25 mg is that intra-articular tissue Such as invaginations of their to 15 mg, while the dosage of clonidine hydrochloride ranges synovial membranes and fibro-adipose meniscoids (that usu between 0.0125 and 0.3 mg. ally act as a cushion to help the bones move over each other 0012. The invention is further directed to a method for Smoothly) may become displaced, pinched or trapped, and reducing back pain. The first step includes administering a consequently give rise to nociception. first compound which includes an opioid antagonist. The 0007 New attention has been focused on non-discogenic second step includes taking a second compound which back pain, where patients have normal or near-normal MRI includes a direct-acting alpha 2 adrenegic agonist. As and CT scans. One of the newer investigations looks into the described above, the opioid antagonist can be a low dose of US 2011/0269.727 A1 Nov. 3, 2011

maltrexone in the range of 0.25 mg to 15 mg, while the direct cytes infiltrate the spinal cord, for example, because of injury, acting alpha 2 adrenegic agonist is a dose of clonidine hydro and release TNF-alpha and other pro-inflammatory mol chloride ranging between 0.0125 and 0.3 mg. The method ecules 15 TNF-alpha then binds to the TNF receptors further contemplates administering a dosage of both compo expressed on nociceptors, activating the MAPK/NF-kappa B sitions once during the daytime, with a second administration pathways. This leads to the production of more TNF-alpha, its proximate to bedtime to maximize the results. release, and binding to the receptors on the cells that released it (autocrine signaling). DETAILED DESCRIPTION OF THE INVENTION 0020. This mechanism also explains the perpetuation of 0013 The present invention will now be described more sensitization and thus allodynia. TNF-alpha might also fully hereinafter with reference to the accompanying draw increase the number of AMPA receptors, and decrease the ings, in which preferred embodiments of the invention are numbers of GABA receptors on the membrane of nocicep shown. This invention may, however, be embodied in many tors, both of which could change the nociceptors in a way that different forms and should not be construed as limited to the allows for their easier activation. Another outcome of the embodiments set forth herein. Rather, these embodiments are increased TNF-alpha is the release of PGE2, with a mecha provided so that this disclosure will be thorough and com nism and effect similar to the ones in the thalamus. plete, and willfully convey the scope of the invention to those 0021 Based upon this, the invention first teaches use of an skilled in the art. opioid antagonist in order to sensitize nociceptive neurons to 0014. The Pharmaceutical Composition in turn lower the sensation of back pain. Specifically, the 0015 This invention is directed to a pharmaceutical com invention contemplates several forms of opioid antagonist position of two compounds which help alleviate and reduce selected from a group consisting of alvimopan, nalmefene, the systems commonly associated with back pain. The spe naloxone, naltrexone, methylmaltrexone, nalorphine, and cific focus of the present invention is the treatment of back pharmaceutically acceptable salt. pain, which is a type of alloynia. Allodynia means “other 0022 Low dose naltrexone and its pharmaceutically pain, and is defined as pain due to a stimulus which does not acceptable salt are contemplated as the primary choice for the normally provoke pain. opioid antagonist. Currently, low dose naltrexone is used in 0016. Different cell types have been linked to allodynia. drug/alcohol rehabilitation purposes, as well as treating cer Recent reports that microglia in the thalamus might contrib tain immunologically-related disorders, including HIV/ ute to allodynia by changing the properties of the secondary AIDS and multiple sclerosis. Naltrexone has also been shown nociceptors. The same effect is achieved in the spinal cord by to have positive results in the treatment of fibromyalgia, the recruitment of immune system cells such as monocytes/ autoimmune diseases such as rheumatoid arthritis, ankylos macrophages and T lymphocytes. There is a strong body of ing spondylitis, Crohn's disease, ulcerative colitis, Hashimo evidence that the so called sensitization of the central nervous to's thyroiditis, and certain central nervous system disorders. system contributes to the appearance of allodynia. Sensitiza 0023. Here, the invention contemplates use of naltrexone tion refers to the increased response of neurons following hydrochloride in crystalline or amorphous form with a dosage repetitive stimulation. ranging between 0.25 mg to 15 mg. Such dosage can be 0017. In addition to repeated activity, the increased levels combined with a second pharmaceutical agent selected from of certain compounds lead to sensitization, as well. The work a group consisting of annon steroidal anti inflammatory drug of many researchers has led to the elucidation of pathways (NSAID) of all chemical groups, including COX-2 selective that can result in neuronal sensitization both in the thalamus inhibitor(coxibs), Steroidal anti inflammatory drugs, Tricy and dorsal horns. Both pathways depend on the production of clic antidepressants (TCAs), Selective serotonin reuptake chemokines and other molecules important in the inflamma inhibitors (SSRIs), Serotonin-norepinephrine reuptake tory response. inhibitors (SNRIs), Anticonvulsants, muscle relaxant, drug 0018. A very important molecule in the thalamus appears with NMDA antagonist properties, Tetrahydrocannabinol to be cysteine-cysteine chemokine ligand 21 (CCL21). The derivatives, antitussive, an expectorant, a decongestant, oran concentration of this chemokine is increased in the Ventral antihistamine. posterolateral nucleus of the thalamus where secondary noci 0024 Apart from opioidantagonist, the invention contem ceptive neurons make connections with other neurons. The plates administration of a direct-acting alpha 2 adrenegic source of CCL21 is not exactly known, but two possibilities agonist as a second compound to reliefback pain. The direct exist. First, it might be made in primary nociceptive neurons acting alpha 2 adrenegic agonist is selected from a group and transported up to the thalamus. Most likely, neurons consisting of Apraclonidine, Brimonidine, Clonidine, Deto intrinsic to the Ventral posterolateral nucleus make at least midine, Dexmedetomidine, GuanabenZ, Guanfacine, Lofexi some of it. In any case, CCL21 binds to C-C chemokine dine, Medetomidine, Romifidine, Tizanidine, Tolonidine, receptor type 7 and chemokine receptor CXCR3 receptors on Xylazine and Fadolmidine. The invention specifically con microglia in the thalamus. The physiologic response to the templates clonidine hydrochloride or its pharmaceutically binding is probably the production of prostaglandin E2 acceptable salt as the direct-acting alpha 2 adrenegic agonist. (PGE2) by cyclooxygenase 2 (COX-2). Activated microglia More specifically, the dosage of clonidine hydrochloride making PGE2 can then sensitize nociceptive neurons as ranges contemplated between 0.0125 and 0.3 mg. manifested by their lowered threshold to pain. 0025) Clonidine is a drug commonly used to treat high 0019. The mechanism responsible for sensitization of the blood pressure has been shown to effectively treat neuro central nervous system at the level of the spinal cord is dif pathic pain, is FDA-approved for administration via epidural ferent from the one in the thalamus. Tumor necrosis factor (an injection given in the lower back), and is the third most alpha (TNF-alpha) and its receptor are the molecules that commonly prescribed drug for chronic intrathecal (an injec seem to be responsible for the sensitization of neurons in the tion into the cerebrospinal fluid) use in people with chronic dorsal horns of the spinal cord. Macrophages and lympho pa1n. US 2011/0269.727 A1 Nov. 3, 2011

0026. Accordingly, the invention teaches a pharmaceuti an affected areas for 30 minutes to 45 minutes. The "O-10 cal compound to reduce back pain with a single unit dosage of numeric pain intensity Scale' was administered before and a low dose quantity of naltrexone (or its pharmaceutically 30-60 minutes after administration of composition orally. The acceptable salt) and a quantity of clonidine hydrochloride (or control group responded to the "O-10 numeric pain intensity its pharmaceutically acceptable salt). The dosage of these two scale” before and immediately after physical therapy to one primary pharmaceutical compounds can be orally through aca. pill, through a liquid or transdermal gel, or through injection 0033. The results of this pilot study showing the improved via Syringe. For more immediate results, treatment can be mood and reduced headaches of patients suffering from back performed by a professional through epidural. pain are illustrated by reference to Table 3: 0027 Method of Use 0028. The invention is further directed to a method for TABLE 3 reducing back pain. The first step of the method is to admin Cervical, Lumbarf Joint Mood ister a first compound which includes an opoid antagonist Average number of number number of number of selected from the group consisting of alvimopan, nalmefene, improvement patients of patients patients patients Headache naloxone, naltrexone, methylmaltrexone, nalorphine, and Study -4.75, 12 -4.33,12 -64 4.72f11 -54 pharmaceutically acceptable salt. The second step is to take a group. (15) second compound which includes a direct-acting alpha 2 Control -1.2.10 -0.81.11 -0.9 O4;S Of4 adrenegic agonist selected from the group consisting of Apra group, clonidine, Brimonidine, Clonidine, Detomidine, Dexmedeto physical midine, Guanabenz, Guanfacine, Lofexidine, Medetomidine, therapy. (15) Romifidine, Tizanidine, Tolonidine, Xylazine and Fadolmi dine. Specifically, the invention contemplates administering a 0034. The group that received the composition had a low dose of naltrexone in the range of 0.25 mg to 15 mg, and reduction of 4.75 points of the "O-10 Numerical Pain Intensity then later taking a dose of clonidine hydrochloride ranging Scale” in the cervical area, 4.3 point reduction in the lumbar between 0.0125 and 0.3 mg. area. 6 point reduction in joint (such as knee or hip joint)and 0029. The method can further include a regiment of taking 5 point reduction in headache. There was 4.72 improvement a dosage of both compounds in the morning/daytime, with a in mood (10 good mood). The group that received physical second administration proximate to bedtime. The ratio of therapy had a reduction of 0.81-1.2 points of "O-10Numerical maltreZone to clonidine dosage contemplated for the initial Pain Intensity Scale”. This finding has a P value of morning/daytime administration of the pharmaceutical <0.000001, extremely statistically significant difference ranges as illustrated by reference to Table 1: between group treated with composition and the group treated with physical therapy. TABLE 1. 0035. The composition treated group has done better than just being compared to placebo, it was compared to a treat Clonidine Hydrochloride Naltrexone Hydrochloride ment that is considered to be helpful. Although the peak 0.0125 mg 1 mg benefit of the composition is not until 3-4 hours after admin 0.025 mg 1 mg istration the results were obtained only 30-60 minutes after 0.025 mg 2 mg administration and there for under estimate the full effect of 0.025 mg 3 mg 0.05 mg 3 mg the composition on back pain. The effect of physical therapy is maximal immediately after treatment. There was 4.7 point improvement in mood comparing to 0.4 points in control. Similarly, the ratio of naltrexone to clonidine dosage contem Accordingly, the results are striking and reveal a high efficacy plated for the secondary nighttime administration of the phar of this invention. maceutical ranges illustrated by reference to Table 2: 1. A pharmaceutical formulation to reduce back pain, the TABLE 2 formulation comprising: a first compound which includes an opioid antagonist; and Clonidine Hydrochloride Naltrexone Hydrochloride a second compound which includes a direct-acting alpha 2 O.OS 1 mg adrenegic agonist. O.1 1 mg 2. The formulation of claim 1, wherein the opioid antago O.2 1 mg nist is selected from a group consisting of alvimopan, nalmefene, naloxone, naltrexone, methylmaltrexone, nalor 0030 Pilot Study phine, and pharmaceutically acceptable salt. 0031. In a pilot study fifteen patients with a diagnosis of 3. The formulation of claim 1, wherein the opioid antago back pain of cervical and/or lumbar areas coexisting with nist is naltrexone or its pharmaceutically acceptable salt. ?without headache or osteoarthritic joint pain (hip or knee) 4. The formulation of claim 1, wherein the opioid antago were studied. A control group of 15 patients received physical nist is naltrexone hydrochloride in crystalline or amorphous therapy. The test had patients rank their back pain based upon form. a “0-10 numeric pain intensity scale” where 10 represented 5. The formulation of claim 1, wherein the direct-acting intolerable pain. alpha 2 adrenegic agonist is selected from a group consisting 0032. The study group received a dose of the composition of Apraclonidine, Brimonidine, Clonidine, Detomidine, and the control group received physical therapy with follow Dexmedetomidine, Guanabenz, Guanfacine, Lofexidine, ing modalities: hot pack, electrical muscle stimulation, ultra Medetomidine, Romi?idine, Tizanidine, Tolonidine, Xyla Sound, manual electrical muscle stimulation and massage to Zine and Fadolmidine. US 2011/0269.727 A1 Nov. 3, 2011

6. The formulation of claim 1, wherein the direct-acting (b) taking a second compound which includes a direct alpha 2 adrenegic agonist is clonidine or its pharmaceutically acting alpha 2 adrenegic agonist. acceptable salt. 14. The method of claim 13, wherein the opioid antagonist 7. The formulation of claim 1, wherein the direct-acting is selected from a group consisting of alvimopan, nalmefene, alpha 2 adrenegic agonist is clonidine hydrochloride or its naloxone, naltrexone, methylmaltrexone, nalorphine, and pharmaceutically acceptable salt. pharmaceutically acceptable salt. 15. he method of claim 13, wherein the opioidantagonist is 8. The formulation of claim 1, wherein the opioid antago maltrexone or its pharmaceutically acceptable salt. nist is a quantity of naltrexone in combination with second 16. he method of claim 13, wherein the opioidantagonist is pharmaceutical agent selected from a group consisting of a maltrexone hydrochloride in crystalline or amorphous form. non steroidal anti inflammatory drug (NSAID) of all chemi 17. he method of claim 13, wherein the direct-acting alpha cal groups, including COX-2 selective inhibitor(coxibs).Ste 2 adrenegic agonist is selected from a group consisting of roidal anti inflammatory drugs, Tricyclic antidepressants Apraclonidine, Brimonidine, Clonidine, Detomidine, (TCAs), Selective serotonin reuptake inhibitors (SSRIs), Dexmedetomidine, Guanabenz, Guanfacine, Lofexidine, Serotonin-norepinephrine reuptake inhibitors (SNRIs), Anti Medetomidine, Romi?idine, Tizanidine, Tolonidine, Xyla convulsants, muscle relaxant, drug with NMDA antagonist Zine and Fadolmidine. properties, Tetrahydrocannabinol derivatives, an antitussive, 18. The method claim 13, wherein the direct-acting alpha2 an expectorant, a decongestant, or an antihistamine. adrenegic agonist is clonidine or its pharmaceutically accept 9. A formulation compound to reduce back pain, compris able salt. ing a single unit dosage of 19. The method of claim 13, wherein the opioid antagonist a quantity of naltrexone or its pharmaceutically acceptable is a quantity of naltrexone in combination with second phar salt; and maceutical agent selected from a group consisting of a non a quantity of clonidine hydrochloride or its pharmaceuti steroidal anti inflammatory drug (NSAID) of all chemical groups, including COX-2 selective inhibitor(coxibs), steroi cally acceptable salt. dal anti inflammatory drugs, Tricyclic antidepressants 10. The formulation of claim 9, wherein the dosage of (TCAs), Selective serotonin reuptake inhibitors (SSRIs), maltrexone ranges between 0.25 mg to 15 mg. Serotonin-norepinephrine reuptake inhibitors (SNRIs), Anti 11. The formulation of claim 9, wherein the dosage of convulsants, muscle relaxant, drug with NMDA antagonist maltrexone hydrochloride ranges between 0.25 mg to 15 mg. properties, Tetrahydrocannabinol derivatives, an antitussive, 12. he formulation of claim 9, wherein the dosage of cloni an expectorant, a decongestant, or an antihistamine. dine hydrochloride ranges between 0.0125 and 0.3 mg. 20. The method of claim 13, further including the step of 13. A method for reducing back pain, comprising the steps administering a dosage during the daytime, and then a second of: dosage proximate to bedtime. (a) administering a first compound which includes an opioid antagonist; and c c c c c