This application is a continuation-in-part of U.S. patent application Ser. No. 13/211,101 filed Aug. 16, 2011 and also claims the benefit of priority to U.S. Provisional Application No. 61/475,908, filed Apr. 15, 2011, each of which is incorporated herein by reference in its entirety.
FIELD OF THE INVENTION
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The field of the invention is chronic pain management, and more specifically to administration of specific low doses of human chorionic gonadotropin (HCG).
An ongoing and pervasive problem in the medical community is treating patients with chronic pain syndromes. It is well recognized today that chronic pain is fundamentally different from acute pain, also referred to as nociceptive pain, which pain results from a mechanical, chemical, metabolic or inflammatory insult.
It has been recognized by some that since the mechanisms and pathways for chronic and acute pain are physiologically different, they require different approaches for treatment. Unfortunately, many in the medical community continue to treat patients suffering from chronic pain syndromes with agents designed to address acute nociceptive pain pathways. Such methods are often fraught with toxicity and dependence issues, and in the end are generally unsatisfactory in ending pain and/or improving quality of life. A new diagnostic paradigm and treatment protocol is therefore needed to address chronic pain.
Central sensitization is a newly recognized diagnostic entity that underlies a broad range of phenotypic syndromes, including various chronic pain and mood disorders. As used herein, central sensitization means an abnormal state of functioning of the neurons and circuitry of the central pain intensity, perception and modulation systems; due to synaptic, chemical, functional and/or structural changes, in which pain is no longer coupled, as acute nociceptive pain is, to particular peripheral stimuli. Instead, the central nervous system (CNS) initiates, maintains and contributes to the generation of pain hypersesensitivity and perception, absent a peripheral stimulus. As used herein, therefore chronic pain and central sensitization represent an overlapping constellation of diagnostic conditions and syndromes.
The present inventors consider the following to be a non-exhaustive listing of conditions associated with (causative or resulting from) central sensitization, each of which is thought to be applicable to humans or other vertebrates.
1. Autonomic neuropathies
2. Chronic back pain
3. Chronic joint pain associated metabolic neuropathy
4. Chronic joint pain associated with inflammation
6. Irritable bowel syndrome
8. Neuropathic pain
10. Post Herpetic neuralgia
12. Post Traumatic Stress Disorder Pain Syndrome
11. Post surgical pain syndromes
13. Rheumatoid, arthritic, psoriatic and other chronic arthropathies
14. Spinal nerve compression syndromes associated with neoplasia and/or disc herniation
15. Trigeminal neuralgia
16. Vulvodynia syndrome
Central sensitization is currently thought to be established via a well characterized constellation of cellular changes termed, neuroplasticity. Neuroplasticity consists of the physical remodeling of neuronal and microglial cytoarchitecture; such as changes in synaptic gap junctions, membrane excitability shifts due to ion channel modulation, and gene transcription. Neuroplasticity changes can be bi-directional. In other words, appropriately functioning cells can undergo remodeling that results in a dysfunctional operating state creating the ‘disease states’ of chronic pain and mood disorders. Conversely, these neuroplasticity mediated dysfunctional changes can be reversed with a return to ‘normal’ functioning, which can correspond clinically to a resolution of a ‘disease’ state.
Central sensitization involves, in part, shifts in gene transcription involved in nociception and pain modulation. Huber, et al has clearly shown this phenomenon occurring at specific HCG concentration levels in endometriotic tissue (1). Some of the specific genes identified in this study were genes encoding for G-protein coupled receptor (GPCR) function (2). See:
1. Huber A, Hudelist G, Knofler N, Saleh L, Huber J C, Singer C F. Effect of highly purified human chorionic gonadotropin preparations on the gene expression signature of stromal cells derived from endometriotic lesions: potential mechanisms for the therapeutic effect of human chorionic gonadotropin in vivo. October 2007 Fertility and Sterility Vol. 88, No. Suppl 2.
2. Foukes T, Wood J N. Pain Genes. PLoS Genetics. July 2008 (4)7:e1000086.
These and all other extrinsic materials discussed herein are incorporated by reference in their entirety. Where a definition or use of a term in an incorporated reference is inconsistent or contrary to the definition of that term provided herein, the definition of that term provided herein applies and the definition of that term in the reference does not apply.
Pain, in general, represents a hyper-excitatory state of neuronal tissue associated with an increase in action potential firing. Action potential generation is the result of increased amplitude and/or frequency of electrical signaling. This is created by the cellular integration of changes in molecular signaling, ion gradients and gene expression resulting in the perception of acute or chronic discomfort.
Pain transmission and modulation through the central nervous system network of neurons and support glial cells (microglia and astrocytes) is largely under the control of a large family of cellular receptors known as G protein-coupled receptors (GPCRs). The function of these complex transmembrane receptors is to transduce extracellular stimuli into intracellular signaling including gene transcription. GPCRs modulate and/or mediate virtually all physiologic processes in eukaryotic organisms, including acute and chronic pain. An estimated 90% of all known GPCRs are expressed in the central nervous system. 80% of the currently proposed GPCR families have a known role in modulation of pain. Similarly, most of the identified genes associated with pain modulation are GPCR related genes. Stone L S, Molliver D C. In search of analgesia: Emerging role of GPCRs in pain. Molecular Interventions. 2009 (9):5; 234-251. The LH/HCG receptor is a GPCR. Id.
The LH/HCG receptor complex specifically has been specifically shown to complex with the Gαi/o group resulting in modulation of neurotransmission. Hu L, Wada k, Mores N, Krsmanovic L Z, Catt K J. Essential role of G protein-gated inwardly rectifying potassium channels in gonadotropin-induced regulation of GnRH neuronal firing and pulsatile neurosecretion. Jour Biol Chem. 2006:281(35); 25231-25240.
Gαi/o proteins mediate the widespread inhibitory effects of many neurotransmitters and they mediate the effects of almost all analgesic GCPR agonists. Stone L S, Molliver D C. In search of analgesia: Emerging role of GPCRs in pain. Molecular Interventions. 2009 (9):5; 234-251.
Due to the multiplicity of pathways involved in establishing central sensitization, chronic pain is a complex phenomenon that can be difficult to treat with single-pathway-active-agent therapy. See Latremoliere A, Woolf C J. Central sensitization: A generator of pain hypersensitivity by central neural plasticity. J Pain. 2009 September; 10(9): 895-926.
This may explain why there remains a critical dearth of effective medical interventions to treat chronic pain disorders. Traditional pharmaceutical approaches generally deal with a single involved pathway, which tends to yield less than ideal results and is often associated with significant toxicity. For example, the treatment options most commonly investigated to date consist of centrally acting drugs. These include ketamine, dextromethorphan, gabapentin, pregabalin, duloxetine, milnacipran, lamotrigene; and not all of these have reached human trials at this time. Each has demonstrated a poor therapeutic index in trials.
Thus, there is still a need for apparatus, systems, and methods for treating chronic pain, and more generally central sensitization that approaches this disorder in a pleiotropic fashion.
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OF THE INVENTION
The inventive subject matter provides apparatus, systems, and methods in which a gonadotropin is administered within a surprisingly effective narrow range for the purpose of treating chronic pain or other central sensitization sequelae in a pleiotropic manner.
In one aspect, contemplated methods involve communicating with a subject, person, non-human animal, or other recipient to determine whether that recipient suffers from chronic pain, and then facilitating the recipient's taking of at least one of human chorionic gonadotropin (HCG), a pharmaceutically active HCG analogue, and a pharmaceutically active metabolite of the HCG or analogue. Preferably, the dosage is selected to provide, or be equivalent to, a human subcutaneous dosage of between 120 IU/day and 170 IU/day of HCG. More preferably, the dosage is selected to provide, or be equivalent to, a human subcutaneous dosage of between 140 IU/day and 160 IU/day of HCG.
Contemplated manners of communication include procuring a written and/or oral symptom history, performing physical examination, referring for laboratory tests and other studies, and especially focusing on whether the recipient has one or more of fibromyalgia, irritable bowel syndrome, chronic back pain, chronic arthropathy, inflammatory pain, post herpetic neuralgia, trigeminal neuralgia, neuropathic pain, vulvodynia and migraine. Such communication can be performed synchronously between a health care professional and the recipient, as for example in a doctor's office or over the phone, and/or asynchronously, as for example using physical mail, electronic mail, and so forth. It is also contemplated to conduct a physical test that aids in distinguishing between nociceptive pain and central sensitization that the recipient may have.
Contemplated manners of facilitating the recipient's taking of the drug(s) include administering the drug(s), issuing a prescription for the drug(s), suggesting use of the drug(s), as in a book or article, and/or providing the recipient (directly or indirectly) with contact information for a supply of the drug(s). It is contemplated that one or more of the drugs could be self-administered by the recipient.
The drug(s) are preferably taken as a monotherapy for the central sensitization, but could be combined with other drugs and/or non-drug treatments, including for example, lifestyle changes such as elimination diet, and anti-inflammatory diet. It is preferred that the drug(s) is/are taken in the absence of concurrent opioid pain treatment, and in the absence of concurrent treatment with another gonadotropic substance.
In some instances, a clinician or other provider may have been administering or recommending HCG for some other purpose, or in some other dosage, not realizing that HCG can be effective to ameliorate chronic pain or central sensitization as claimed herein. In such instances it is contemplated that the provider receive information that HCG may have a peak effect on central sensitization between 120 IU/day and 170 IU/day, inclusive, and can thereafter administer or recommend HCG, a pharmaceutically active HCG analogue, or a pharmaceutically active metabolite of the HCG or analogue as claimed herein.
It is contemplated that a kit could include (a) a supply of a drug selected from the group consisting of at least one of HCG, a pharmaceutically active HCG analogue, and a pharmaceutically active metabolite of the HCG or analogue, (b) a delivery device and (c) a label that identifies at least one of chronic pain and central sensitization as an indication for the drug.
In some aspects of preferred embodiments, the label identifies a daily dosage regimen at or equivalent to a subcutaneous dosage of human chorionic gonadotropin (HCG) between 120 IU/day and 170 IU/day, inclusive, with respect to chronic pain relief. In other aspects of some preferred embodiments, the label identifies a daily dosage regimen at or equivalent to a subcutaneous dosage of human chorionic gonadotropin (HCG) between 140 IU/day and 160 IU/day, inclusive, with respect to chronic pain relief.
In yet other aspects of preferred embodiments, a kit can include a vial or cartridge with at least first chamber having a lyophilized preparation of the drug that is suitable for injection when mixed with a diluent contained in a second chamber of the cartridge. Alternatively, the drug could be provided in a stabilized liquid form. The drug could be disposed in an auto-inject or a dial up dosing pen equipped with a cartridge with at least first and second chamber for HCG formulation storage and delivery. Alternatively or additionally, a kit could include a container that includes the drug in an orally available composition or as an aerosolized nasal spray. The kit could also consist of a sub-dermal pellet and device for placement of said pellet for a timed release of HCG formulation.
A provider need not actively communicate with the recipient, but could determine in some other manner that the recipient might suffer from a central sensitization disorder. For example, the step of determining could comprise initiating a plurality of testing procedures that includes: (a) at least one test selected from a first group consisting of dynamic tactile allodynia, secondary punctate/pressure hyperalgesia, temporal summation, and sensory after effects, and (b) at least one other test selected from a second group consisting of SMAC 25, fMRI, Neuro-Endocrine profile (neurotransmitters and hormones), CSF study (substance P, glutamate, NGF, BDNF), cytokines profile, genetic polymorphism profile, food allergy panel, and heavy metals analysis panel.
In other aspects, the step of determining comprises (i) determining that the subject may suffer from central sensitization due to a trauma, and (ii) providing the subject with access to the drug peritraumatically. In yet other aspects of some preferred embodiments, the trauma is a surgery, and the drug is administered perioperatively.
Various objects, features, aspects, and advantages of the inventive subject matter will become more apparent from the following detailed description of preferred embodiments, along with the accompanying drawing figures in which like numerals represent like components.
BRIEF DESCRIPTION OF THE DRAWING
FIG. 1 is a schematic of one preferred embodiment of a method of interacting with a person.
FIG. 2 is a perspective view of one preferred embodiment of a kit that includes a supply of a drug, a delivery device and a label.
FIG. 3 is a perspective view of delivery device as an auto-inject dosing pen.
FIG. 4 is a perspective view of a delivery device as a dial-up dosing pen.
FIG. 5 is a schematic of one preferred embodiment of a method of treating a subject.
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In FIG. 1 a schematic of a method of interacting with a person is shown. The method includes the steps of: (i) communicating with the person in a manner that aids in determining whether the person might suffer from chronic pain; and (ii) facilitating the person discontinuously taking a drug at or equivalent to a subcutaneous dosage of human chorionic gonadotropin (HCG) between 120 IU/day and 170 IU/day, inclusive, with respect to chronic pain relief, for an express purpose of ameliorating the chronic pain, wherein the drug is selected from the group consisting of at least one of HCG, a pharmaceutically active HCG analogue, and a pharmaceutically active metabolite of the HCG or analogue.
As used herein, the term human chorionic gonadotropin (HCG) means a compound in a pharmaceutical composition of matter obtained from at least one of the following sources: purified urine of pregnant and/or post-menopausal women (uHCG); purified bacterial, yeast, plant and/or mammalian cell cultures utilizing recombinant DNA hybridization techniques (rHCG).
As used herein, the term pharmaceutically active HCG analogue means a compound that, with respect to amelioration of chronic pain or other sequelae of central sensitization, has either (i) has at least a partial biological activity of HCG (e.g., mutant, truncated form, chemically modified), or (ii) can bind to HCG receptors, either an agonist or neutral ligand. As used herein the term “analogues” includes prodrugs of HCG.
As used herein, a “prodrug” means a modification of a contemplated compound, wherein the modified compound exhibits less pharmacological activity (as compared to the contemplated compound) and wherein the modified compound is converted within a target cell (e.g., hepatic-cell) or target organ/anatomic structure (e.g., spinal cord) back into the contemplated form. For example, conversion of contemplated compounds into prodrugs may be useful where the active drug is too toxic for safe systemic administration, or where the contemplated compound is poorly absorbed by the digestive tract or other compartment or cell, or where the body breaks down the contemplated compound before reaching its target. Thus, it should be recognized that the compounds according to the inventive subject matter can be modified in numerous manners, and especially preferred modifications include those that improve one or more pharmacokinetic and/or pharmacodynamic parameter. For example, one or more substituents may be added or replaced to achieve a higher area under the curve (AUC) of HCV in serum.
As used herein, the term pharmaceutically active metabolite means any compound resulting from in vivo metabolism of HCG or an HCG analogue (for example, via proteolytic digest, glycosylation, hydroxylation, phosphorylation, sulfuration, etc), where the metabolite is effective with respect to amelioration of chronic pain or other sequelae of central sensitization.
Unless the context dictates the contrary, all ranges set forth herein should be interpreted as being inclusive of their endpoints, and open-ended ranges should be interpreted to include commercially practical values. Similarly, all lists of values should be considered as inclusive of intermediate values unless the context indicates the contrary.
The step of communicating can comprise obtaining medical and diagnostic data, including procuring from the person at least one of a written and an oral symptom history, performing physical examination; and referring for tests and imaging studies. The symptom history can be used to assist in determining whether the person has at least one of fibromyalgia, irritable bowel syndrome, chronic arthropathy, inflammatory pain, neuropathic pain, chronic back pain, post herpetic neuralgia, trigeminal neuralgia, vulvodynia and migraine.
The step of communicating can be performed either synchronously between a health care professional and the person, or alternatively, asynchronously between a health care professional and the person using physical mail or electronic communication.
The step of facilitating can comprise issuing a prescription for use of the drug by the person. In addition, the step of facilitating can comprise providing the person with contact information from which the person can procure a supply of the drug.
The dosage is preferably at or equivalent to a subcutaneous dosage of between 140 IU/day and 160 IU/day, inclusive, with respect to chronic pain relief.
The method of FIG. 1 can further include the step of conducting and/or referring for a physical testing procedures that aids in distinguishing between nociceptive pain and central sensitization that the person may have.
The method can also include the step of assisting in procuring the drug for the person as a monotherapy for the central sensitization. In addition, the method can include the step of assisting in procuring a composition for the person in adjunct to the drug that facilitates coupling to the Gα, i/o, G-Protein Coupled Receptor (GPCR) subunits, facilitating and/or enhancing an analgesic effect.
It is also contemplated that one can perform the step of “facilitating” after receiving information that HCG may have a peak effect on central sensitization between 120 IU/day and 170 IU/day, inclusive.
Equivalents of a subcutaneous dosage of HCG can include all suitable modes of administration, such as intramuscularly, subdermally, orally dissolving tab, sublingually as a liquid, transdermally, rectally, and via subdermal slow release pellets. U.S. Pat. No. 6,488,649 teaches suitable subdermal pellet implant devices.
The method shown in FIG. 1 can be used to treat numerous disorders related to chronic pain and central sensitization. For example: fibromyalgia, rheumatoid arthritis, osteoarthritis, chronic arthropathy, spinal nerve compression syndromes associated with neoplasia and/or disc herniation, chronic back pain, chronic joint pain of any etiology associated with inflammation and/or structural joint abnormalities, post herpetic neuralgia, trigeminal neuralgia, chronic metabolic neuropathy associated with chronic pain, migraine, inflammatory pain, post surgical pain syndromes, post traumatic stress disorder pain syndrome, irritable bowel syndrome, autonomic neuropathies, vulvodynia, and chronic pain syndrome associated with activation of central sensitization pathways.
It is also contemplated that the “person” can include humans, pets, and mammals.
FIG. 2 one preferred embodiment of a kit 200. Kit 200 includes a container 205. Container 205 is a delivery device that holds a drug 210 and has an exterior label 220.
Drug 210 is preferably selected from the group consisting of at least one of HCG (uHCG and/or rHCG), a pharmaceutically active HCG analogue, and a pharmaceutically active metabolite of the HCG or analogue. Drug 210 is a sublingual or an orally dissolving tablet. It is also contemplated that drug 210 could comprise other dosage forms.
It should be recognized that all formulations are deemed suitable for use herein and especially include parenteral and oral formulations. For example, for oral administration, contemplated compositions may be in the form of a tablet, orally dissolving tablet, capsule, suspension, or liquid. The pharmaceutical composition is preferably made in the form of a dosage unit containing a particular amount of the active ingredient. Examples of such dosage units are tablets, drops, or capsules. For parenteral formulation, the active ingredient can be administered by injection as a lyophilized or a stabilized liquid composition wherein, for example, saline, sucrose, maltose or water may be used as a suitable carrier. In especially preferred aspects, it is contemplated that the formulation is suitable for intrathecal administration, subdermal pellets, administration via aerosol, and for topical administration. Consequently, where the compound is formulated for intrathecal administration (e.g., in the treatment of spinal cord injury), it is preferred that the compound is prepared as an injectable solution, suspension, or emulsion. Alternatively, in contemplated formulations, contemplated compounds may be formulated for aerosol delivery (e.g., micropowderized, coated onto a dispersible carrier, dissolved in atomizable solvent, etc.) and slow-release pellets for subdermal implant. Furthermore, especially suitable formulations may be sterile aqueous solutions for topical spray or drop administration, or application as a tincture. In still further, suitable topical formulations may include creams, ointments, foams, lotions, emulsions, etc. It should be appreciated that the choice of the particular formulation and carrier will at least in part depend on the specific use and type of compound. There are numerous manners of drug formulation known in the art, and all of those are deemed suitable for use herein (see e.g., Pharmaceutical Preformulation and Formulation: A Practical Guide from Candidate Drug Selection to Commercial Dosage Form by Mark Gibson; Informa HealthCare, ISBN: 1574911201; or Advanced Drug Formulation Design to Optimize Therapeutic Outcomes by Robert O. Williams, David R. Taft, and Jason T. McConville; Informa HealthCare; ISBN: 1420043870).
Although age, gender and weight of a recipient of HCG treatment for chronic pain does not appear with current studies to affect the preferred therapeutic ranges, it is contemplated that the amount of therapeutically active compound that is administered and the dosage regimen for treating a disease condition with the compounds and/or compositions of this invention could depend on one of more of a variety of factors, including the age, weight, sex and medical condition of the subject, the severity of the disease, the route and frequency of administration, and the particular compound employed, and thus may vary widely.
Label 220 identifies at least one of chronic pain and central sensitization as an indication for the drug. Label 220 also identifies a daily dosage regimen at or equivalent to a subcutaneous dosage of human chorionic gonadotropin (HCG) between 120 IU/day and 170 IU/day, inclusive, with respect to chronic pain relief. Alternatively, label 220 could identify a daily dosage regimen at or equivalent to a subcutaneous dosage of human chorionic gonadotropin (HCG) between 140 IU/day and 160 IU/day, inclusive, with respect to chronic pain relief.