Classifications

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  • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
  • A61K31/5685—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone having an oxo group in position 17, e.g. androsterone
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  • A61K31/568—Compounds containing cyclopenta[a]hydrophenanthrene ring systems; Derivatives thereof, e.g. steroids not substituted in position 17 beta by a carbon atom, e.g. estrane, estradiol substituted in positions 10 and 13 by a chain having at least one carbon atom, e.g. androstanes, e.g. testosterone
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  • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
  • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
  • G01N33/5005—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells
  • G01N33/5094—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving human or animal cells for blood cell populations
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  • G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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  • G01N2333/46—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans from vertebrates
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Definitions

• the invention relates to the administration of a pain-reducing androgen to a human subject in a safe and effective way.
• the invention relates to a method of reducing unresolvable chronic or acute pain (hereafter called either chronic pain or pain) in a human subject with androgen deficiency symptoms (as defined elsewhere herein) comprising administering a composition comprising a pain-reducing amount of an androgen to a human subject, wherein the subject's androgen serum levels are restored to safe levels within the reference range, such that pain is reduced safely and effectively, as discussed in paragraphs
• the invention also relates to the administration of a pain-threshold-increasing androgen to a human subject in a safe and effective way in patients both with and without unresolved pain.
• the invention further relates to a method of increasing the pain threshold of an human subject with androgen deficiency symptoms, as defined paragraphs [0008], [0029]- [0033], and [0041], comprising administering a composition comprising a pain threshold- increasing amount of an androgen to a human subject, wherein the subject's androgen serum levels are restored to safe levels within the appropriate reference range so that the subject's pain threshold is increased safely and effectively.
• the usage of androgens to treat unresolvable pain, or low threshold pain is unique.
• the present invention relates to pain due to chronic inflammatory pain states, and to the formulation of treatment strategies thereof.
• Such chronic pain states have been seen as the focus for developing the many different treatments for chronic pain. Therefore, conceptualization of most all treatment strategies has revolved around understanding the causes of pain for each of these pain states, each being instructive as an example for the best approaches to therapy.
• the present invention focuses on a different approach to this population by seeing their pain as caused by a variety of biologic stressors, derived from either the environment and/or genetic predisposition, that deplete androgen levels and induce androgen deficient states.
• Current standard practice pain therapies for treating unresolvable pain do not include the androgen sex steroid hormone class of drugs. The same approach applies to treatment of patients with a low threshold of pain.
• the androgen as described for all embodiments of the invention, is an androgen with biologic activity, also called “bioactive androgen” or “androgen.” It can be administered by a variety of means, including, but not limited to, transdermal or transmucosal administration, oral administration, time release capsule, by injection, and by suppository.
• the androgen can be administered on a daily basis.
• the androgen can be administered to the subject over any period of time wherein the subject's pain is alleviated and/or the subject's pain threshold increased in a safe and efficacious manner.
• the androgen can be
• the androgen can be any period of time to a subject without pain, wherein the subject's pain threshold is increased in a safe and efficacious manner.
• the androgen can be any period of time to a subject without pain, wherein the subject's pain threshold is increased in a safe and efficacious manner.
• Some of the more well-known therapeutics for pain involve the usage of: 1) the non-steroidal anti-inflammatory drugs or NSAID analgesics; 2) the morphine-related opioid analgesic class of drugs, such as oxycodone and hydromorphone; and 3) the usage of anti-depressants, for example the Serotonin- Norepinephrine Reuptake Inhibitor (SNRI) and Selective Serotonin Reuptake Inhibitor (SSRI) classes of drugs including duloxetine, sertraline, venlafaxine, and fluoxetine, the tricyclic class of antidepressants; and cognitive behavioral therapy.
• SNRI Serotonin- Norepinephrine Reuptake Inhibitor
• SSRI Selective Serotonin Reuptake Inhibitor
• all of these approaches suffer from either a lack of efficacy and/or unintended side effects that are frequently worse than the benefits.
• the NSAID class of analgesics when used for chronic pain over a period of time, can cause significant GI tract irritation.
• opioid or morphine related class of drugs recent data indicate that chronic usage can even be responsible for and induce pain by itself (Mao, J., "Opioid-induced Abnormal Pain Sensitivity," Current Pain and Headache Reports, 2006, 10:67-70).
• side effects for opiates include nausea and vomiting, confusion, compromised immune function, subnormal testosterone levels in males leading to osteoporosis, addiction, lack of efficacy over time (tolerance), and constipation.
• antidepressants are well known in the clinical realm as having sexual dysfunction side effects, including arousal disorder, ejaculation failure and difficulty achieving orgasm, as well as an FDA mandated black box warning for increased risk of suicidality.
• Other common side effects for anti-depressants include nausea, insomnia, dizziness, tremor, and decreased libido.
• the sex steroid hormones are normally considered to be important in the clinic for sexual health, but have never been used in routine practice or as standard therapy in the clinic to reduce chronic pain. Androgens, estrogens and progestins, or their agonists and antagonists, are used by reproductive endocrinologists within the clinic to treat sexual disorders. The use of these hormones are not normally thought of outside the context of sexual function such as reproduction and secondary sex traits. However, more recently, it has been recognized that estrogens, for example, are important in the health of men for bone plate formation (Smith et al, The New England Journal of Medicine, 1994, 331 : 1056-1061 ; Ohlsson and Vandenput, European J.
• the instant invention relates to the importance of healthy serum levels of testosterone for non-reproductive neuroendocrine health for reducing pain and/or increasing pain threshold, and to foster feelings of well-being.
• the sex hormones in particular estrogens, progestins, and now testosterone, can be correlated to subjective feelings of well-being and quality of life. In fact, either too high or too low levels of the sex steroid hormones, including testosterone, result in a loss of feeling of well-being.
• testosterone can have an effect on dopamine, serotonin, N-methyl-D-aspartic acid (NMDA), and enkephalinergics, all of which contribute to feelings of well-being and modulation of mood.
• NMDA N-methyl-D-aspartic acid
• the best way to evaluate testosterone deficiency in the clinic is to look for clinical symptoms of too-low androgen levels in a human subject whose blood serum levels are in the lower half of the reference range.
• Clinical symptoms of androgen insufficiency may include, but are not limited to, loss of libido, bouts of impotence, chronic fatigue, insomnia, hot flushes, sweating, alopecia or hair loss, mood change, mood swings, nervousness, loss of feelings of well-being, anemia such as that caused by insufficient erythropoietin production, impaired memory, inability to concentrate, Alzheimer's Disease (patients with androgen insufficiency have a higher risk), andropause (low production of androgens), night sweats, anovulatory menstrual cycles, amenorrhea, menorrhagia, menometrorragia, metrorrhagia, oligomenorrhea, polymenorrhea, decrease in muscle mass, osteoporosis, compression fractures, and obesity (unhealthy fat to muscle ratios) (see paragraph [0041]).
• disorders such as diabetes, hypertension, Klinefelter' s, Wilson-
• Acute vs. chronic pain is a sensation that is normally triggered in the nervous system to alert an individual about possible injury and the need to respond to the situation.
• Chronic pain is different.
• Chronic pain usually inflammatory in nature, has been defined by the National Institute for Neurological Disorders and Stroke as persistent pain, which can last as long as six months or more.
• pain signals keep firing in the nervous system for weeks, months, even years.
• pain as unresolvable chronic or acute inflammatory pain, or an abnormally low pain threshold due to stress/distress on/within the individual that is unresolvable.
• chronic pain There are numerous conditions that are accompanied with, or caused by pain, some of which involve chronic pain.
• pain There are also numerous theories relating to the treatment of chronic pain.
• the importance of receptors in the body and how some neurotransmitters function is being studied (See, e.g., Millan, 2000, Prog. Neurobiol. 66:255-474), although effective treatment of pain in the clinic remains problematic.
• Stress on an individual can be resolved (“eustress "), but when stress is unresolvable by the individual (“distress "). it can be the basis of unresolvable pain. It is known that chronic pain can be the result of a wide variety of stressor conditions and stressor states, including disease, surgery, various types of trauma and/or physical distress. Emotional distress such as grief, and pathologic states within the immune system, nervous system, endocrine system, and other biologic systems can also act as stressor states that contribute to pain. Such stress can lead to unresolvable pain in both females and males. Selye defines stress as a "nonspecific response of the body to any demand.
• a stressor is an agent that produces stress at any time.” (Selye, CMA Journal, 1976, 1 15:53-56 at 53). Selye's "general adaptation syndrome” recognizes three phases in an individual's resistance to stress: the initial alarm, resistance to that alarm, and if not resolved, exhaustion. Further, Selye coined the term “eustress” in which the individual responds to a stressor such that adaptation and coping responses resolve the stress, as opposed to "distress” in which the individual's stress response fails to be resolved. However, it is not well understood why, despite cognitive behavior modification training, for example, some individuals are able to adapt so much better than others, or why an individual who has previously been able to adapt can no longer do so.
• the individual can adapt to the stress such that the stress is resolved, while in other situations the individual cannot adapt, and the stress on the individual remains unresolved.
• the result is a state of eustress.
• the result is a state of distress and a lack of feeling of well-being, resulting in pain and/or illness.
• Part of the problem is our poor understanding of how the various neuroendocrine and immunologic pathways modulate our responses to stress, and promote or fail to promote eustress and feelings of well-being in an individual.
• the instant invention encompasses the use of androgen therapy to enable stress to be processed and pain to be decreased.
• Treatment for chronic inflammatory pain includes some of the same treatments for acute pain, including opioids, non- opioid analgesics, and anti-inflammatory drugs. Treatment of chronic pain can also include additional approaches, such as, antidepressants, acupuncture, local electrical stimulation, and brain stimulation, as well as surgery. Some physicians use placebos, which in some cases has resulted in a lessening or elimination of pain.
• Psychotherapy, relaxation, and medication therapies, biofeedback, and behavior modification may also be employed to treat chronic pain.
• Sex steroid hormones can be important for pain processing.
• androgens can be important for pain processing.
• both androgens and estrogens play a role in pain sensation in animal models, although this has not been adequately studied or approved in humans for chronic pain.
• gender can have an impact on the sensation of pain.
• testosterone decreases the production of sex hormone binding globulin (SHBG), while estradiol increases SHBG production.
• SHBG acts to sequester sex steroid hormones away from the bioavailable pool, preventing entry of sex steroid hormones across the blood-brain barrier (BBB) into the central nervous system.
• BBB blood-brain barrier
• Gonadal or sex steroid hormones down-regulate inflammatory cell responses.
• ovariectomy of animals results in a reversal of thymic involution, restoration of thymic cellularity and thymic output, and an increased T cell repertoire (in both diversity and numbers) in the periphery (Perisic M. et al., "Role of ovarian hormones in age- associated thymic involution revisited," Immunobiology, 2010, 215(4):275-293).
• rescue of gonadectomy with exogenous hormone by injection of gonadal steroid hormones into animals decreases the numbers of thymocytes and T cells in the periphery (Zoller A.L. et al., "Murine pregnancy leads to reduced proliferation of maternal thymocytes and decreased thymic emigration," Immunology, 2007 121(2):207-215).
• Hormone replacement therapy in women has focused on estrogens and progestins, but not on androgens.
• the Women's Health Initiative (WHI) clinical trial whose aim was to prospectively evaluate the risks and benefits of orally administered combination hormone replacement therapy in healthy women using estrogens and medroxyprogesterone acetate, was relatively recently halted (Fletcher, S. W., et al, J. Amer. Med. Assoc., 2002, 288: 366-368).
• ESTRATEST ® prescribed to women for hot flashes when they failed to get relief from estrogen replacement therapy, was taken off the market because Solvay never demonstrated efficacy to the FDA.
• the FDA's new regulation system Drug Efficacy Study and Implementation, DESI required additional studies on ESTRATEST® to prove drug efficacy, which forced
• Androgen therapy is effective asainst muscle wasting, for example in AIDS, but has not been approved to treat chronic inflammatory pain states.
• Most clinical trials evaluating sex hormone replacement therapy have focused on estrogens and progestins in women.
• Testosterone replacement therapy in individuals who may be testosterone deficient is now beginning to be addressed using transdermal delivery systems. For example, disease states in which there is loss of muscle mass may be treated with transdermal testosterone
• Androgens can be useful for modulatin the sensation of pain and distress; thus, androgen therapy can be used to treat unresolvable chronic inflammatory pain states or their associated states of distress.
• the present invention relates to chronic pain states, and to the formulation of treatment strategies thereof.
• the basis of the invention resides in the treatment with testosterone of chronic pain due to stressor states that affect males and females, said stressor states having a significant impact on pain sensation in such patients because of causing an androgen deficient state or symptoms of androgen deficiency ("distress").
• stress an androgen deficient state or symptoms of androgen deficiency
• FIGS. 3A-3B show the hypothesized metabolic pathway for testosterone in relation to nociception in the central nervous system.
• Substance P which is, in effect, a signal for pain or stress in the CNS. Pain or stress also causes serotonin levels to drop, thus reducing feelings of well- being.
• Substance P stimulates aromatase within the spinal cord nociceptive relay neurons.
• This Substance P regulation of aromatase is mediated by protein kinases and phosphoprotein phosphatases which can act quickly and in a complex way to allow the body to respond appropriately to pain and stress.
• Testosterone as the substrate for aromatase, can cross the blood-brain barrier much more readily than estrogens (the transit of sex steroid hormones across the blood-brain barrier (BBB) is highly regulated by sex hormone binding globulin as well as aromatase enzymology), thus allowing aromatase in the spinal cord nociceptive relay neuron to convert testosterone to 17-beta estradiol within the central nervous system.
• BBB blood-brain barrier
• Enkephalins opioid peptides
• aromatase is also found in the brain and the periphery, allowing for these mechanisms to take place in both the CNS and the periphery in response to pain or stress. This Circle Hypothesis is discussed in greater detail below in paragraphs [0042]-[0046].
• the androgen used in the invention is a biologically active androgen.
• Biologically active androgens may be active in their native state, may be a precursor or pro-drug that is metabolized to a biologically active state upon ingestion by the subject.
• the biologically active androgen may be, but is not limited to, testosterone, androstenedione, androstendiol, dehydroepiandrosterone, danazol, fluoxymesterone,
• testosterone is frequently discussed as an exemplary androgen compound.
• Androgens bind not only to androgen receptors, but they also are able to act within cells via androgen receptor (AR) independent pathways to ameliorate and reverse the physiological consequences of low testosterone and resultant loss of feelings of well-being.
• the instant invention can act both at the AR level and the AR-independent level to reduce androgen deficiency symptoms.
• the treatments of the invention as primary therapies, can either replace or be used in combination with other pharmacological agents.
• Androgens can modulate pain. In animal models, pain appears to be reduced during pregnancy via opiate production, when testosterone concentrations are elevated.
• Androgens can improve clinical symptoms of non-inflammatory fibromyalgia patients (a counter-intuitive concept since androgens have historically been considered reproductive hormones rather than hormones that impact pain responses).
• the vast scientific literature on androgens and the sex steroid hormones in general relates to their ability to promote reproduction. And androgens in particular are notable for their role and abuse potential in promoting muscle strength.
• Clinical testing for chronic inflammatory pain patients is distinct from that for fibromyalgia patients. Further, there are different tests that can be performed by physicians, which can also give an indication regarding the etiology of certain conditions and a way of classifying the patient's condition. For example, a laboratory test known as the erythrocyte sedimentary rate, or "sed rate,” measures the rate at which a patient's red blood cells settle to the bottom of a tube or assay vessel over a prescribed period of time. This is a non-specific test that indicates the presence of an inflammatory process in a patient. Inflammatory responses are an indicator of immune system-derived mediators from white blood cells that signal pain to the nervous system. And it is the neurologist who normally treats chronic inflammatory pain states.
• Fibromyalgia is distinct from chronic inflammatory pain, in that fibromyalgia is a rheumatologic illness, and such patients have "sed rates" that are unchanged from “normal” sed rates. This indicates that fibromyalgia is caused by a very different process than what typifies the autoimmune or infectious disease states, for example, of chronic inflammatory pain. Further, for patients with chronic inflammatory pain, testosterone levels can be exhausted, and a low testosterone level can lead to a hyperinflammatory state, thus exacerbating the chronic inflammatory pain state.
• a fibromyalgia patient is likely to see a rheumatologist.
• these two distinct sets of doctors are uniquely versed in different treatments. For example, a rheumatologist who sees a large number of fibromyalgia patients would not look to the same treatments as a neurologist, the doctor most chronic inflammatory patients would see.
• the neurologist pain doctor is unlikely to review fibromyalgia treatments for methods of treating chronic inflammatory pain.
• the neurologist is likely to prescribe opioid analgesics, which will have the unintended consequence of actually lowering testosterone levels and exacerbating the pain.
• the instant invention relates to a method of reducing chronic inflammatory pain or state of distress in a human subject comprising diagnosing a human subject to have 1) any one of the following: a) elevated C-reactive protein, b) elevated erythrocyte sedimentation rate, c) any one of the following DSM-IV defined Disorders: Pain Disorder Associated With
• Psychological Factors 307.80 Pain Disorder Associated With Both Psychological Factors and a General Medical Condition 307.89, Dementia including Alzheimer's Type and Vascular Dementia 290, Alcohol-Related Disorders 291 , Drug Withdrawal and Psychotic Disorders 292, Mood, Anxiety, and Mental Disorders 293, Dementia, Cognitive, and Amnestic Disorders including Head Trauma 294, Mood Disorder 206.90; Anxiety Disorders 300, Male and Female sexual Disorders 302.70-302.74, 302.9; Alcohol and Drug Dependence Disorders 303, Alcohol, Drug, and Nicotine Abuse 305; Sleep Disorders 307.42; Acute Stress Disorder 308, Adjustment Disorders, including Post Traumatic Stress Disorder 309, Personality Disorders 310; Depressive Disorders 31 1 ; Sleep Disorders 327, Neuroleptic-Induced Disorders 332, 333; Male sexual Disorders 607/608, Female sexual Disorders 625; Age-Related Cognitive Decline 780.93, d) clinical symptoms of androg
• the instant invention also relates to a method of increasing the pain threshold of a human subject comprising diagnosing a human subject to have any one of the indications defined by (1) in paragraph [0029] above; determining if the subject has androgen levels in the lower half of the appropriate reference range; and, if the subject has at least one of the indications defined by (1) in paragraph [0029] above, along with androgen levels in the lower half of the appropriate reference range; administering a composition comprising a pain threshold-increasing amount of an androgen to a human subject, wherein the subject's pain-threshold is increased safely and effectively.
• the instant invention further relates to a method for determining if a human subject would benefit from androgen administration comprising any combination of the following tests and evaluations, as needed: A) testing for any one of the indications defined by (1 ) in paragraph [0029] above, B) testing the subject's serum to determine if their androgen levels are in the lower half of the appropriate reference range; C) assessing the subject for clinical symptoms of androgen deficiency which may include, but is not limited to, loss of libido, sexual dysfunction, chronic fatigue, anemia, low muscle:fat ratio, and alopecia, D) assessing levels of pain, E) assessing the subject's pain threshold, and/or F) testing using metrics that may include, but are not limited to, those for evaluating pain, physical function, psychological function, global health and sleep. If the subject meets the criteria for androgen treatment, a composition comprising an androgen can be administered to the subject, wherein the subject's androgen serum
• the invention also relates to a kit for determining if a human subject would benefit from androgen administration comprising instructions for diagnosing a subject as having an androgen-deficiency treatable by administration of an androgen.
• the instructions can comprise instructing a health care provider how to test the subject's androgen serum levels and how to determine if the subject meets any of the criteria in paragraph [0029].
• the instructions can further comprise instructing the health care provider how to test the subject's pain threshold; and instructing the health care provider to administer a composition comprising an androgen to the subject if the subject has androgen levels in the lower half of the of the appropriate reference range, a low threshold of pain, and at least one of the indications in (1 ) in paragraph [0029] above; so that the subject's androgen serum levels are restored to the middle-upper portion of an appropriate reference range, and clinical symptoms or the low pain threshold are improved safely and effectively.
• the invention also relates to a method of increasing endogenous opioid peptide production in an androgen-deficient, endogenous opioid peptide-deficient human subject.
• the method comprises diagnosing a human subject to have at least one of a) elevated C- reactive protein, b) elevated erythrocyte sedimentation rate, c) DSM-IV disorder 307.80, d) DSM-IV disorder 307.89, or e) an unresolved stressor state; determining if the subject has androgen levels in the lower half of the appropriate reference range; determining if the subject low endogenous opioid peptide levels; and, if the subject has at least one of a) elevated C- reactive protein, b) elevated erythrocyte sedimentation rate, c) DSM-IV disorder 307.80, d) DSM-IV disorder 307.89, or e) an unresolved stressor state, along with androgen levels in the lower half of the appropriate reference range and low endogenous opioid peptide levels;
• compositions comprising an androgen to a human subject with androgen and opioid peptide deficiencies, wherein the subject's production of endogenous opioid peptides is increased.
• androgen therapy is the primary therapy to be administered for all of the above embodiments of the invention.
• subjects receiving primary androgen therapy may also receive adjunctive opioid therapy if they have exogenous opioid-induced hypogonadism or other conditions that might require such adjunctive opioid therapy in addition to the primary androgen therapy.
• adjunctive opioid therapy may also be received.
• other compounds such as, but not limited to, antidepressants may also be used.
• Figs 1 A-1C show that the serum total testosterone concentrations in a population of female patients are increased in response to testosterone gel therapy.
• Figs. 2A-2C show that the free testosterone concentrations in a population of female patients are increased in response to testosterone gel therapy.
• Figs. 3A-3B depict the hypothesized metabolic pathway for testosterone in relation to nociception in the central nervous system in normal (A) and deficient (B) subjects. Detailed Description of the Invention
• the invention relates to how and why androgens are a critical part of pain pathophysiology, such that when androgens are given therapeutically to individuals with chronic inflammatory pain, the androgen treatment should significantly resolve that pain.
• androgen therapy it is meant to include administration of a single androgen or a combination of androgens. Administration of the androgen can be a single administration or administration over a period of time.
• alleviate it is meant to make less hard to bear, reduce or decrease, or lighten or relieve patients of the symptoms of an illness or a condition.
• androgen-deficient or “androgen deficiency” it is meant that 1) a patient's testosterone serum levels are in the lower half of the reference range, and concomitant with at least one of the following: 2a) the presence of chronic or acute unresolved inflammatory pain (pain assessment as defined elsewhere herein) or state of distress or symptom of androgen deficiency, as described in paragraph [0028], 2b) the lack of a feeling of well-being combined with a low threshold of pain (threshold testing as defined elsewhere herein), or 2c) a failure to adapt to or resolve stress (stressors as defined elsewhere as a maladaptive and unresolved state of "distress").
• primary therapy it is meant to be the main or first-line therapy given to a subject for the treatment of chronic inflammatory pain, for increasing the pain-threshold of a subject, or for increasing a subject's production and/or levels of endogenous opioid peptides.
• adjuvant therapy it is meant to be a secondary therapy, given to a subject to augment or complement the subject's primary therapy.
• Pain and stressor states are related and defined. Further, the focus of the present invention is on pain associated with stressors of various kinds, including, but not limited to: 1) PTSD, which includes combat or shell shock or Gulf War Syndrome, 2) accident, 3) trauma, 4) surgery, 5) autoimmune disease such as rheumatologic disorders, including arthritis, 6) chronic unresolved or acute viral infection, 7) infectious disease, 8) cancer, 9) chronic exhaustion or physical distress, 10) neuropathy, 1 1) hyperalgesia, 12) allodynia, 13) grief, emotional distress, or depression, 14) surgical or pharmacologic-induced gonadectomy, or 15) dysthymia.
• DSM-IV disorder coding for these conditions include code 307.80, "Pain Disorder Associated with Psychological Factors” (psychological factor plays a major role in pain); and code 307.89 "Pain Disorder Associated with Both Psychological Factors and a General Medical Condition” (psychological factors may or may not play a role in pain);
• a subject may have a chronic medical state accompanied by an additional stressor state, that causes or exacerbates chronic pain.
• FIGS. 3A-3B show the hypothesized metabolic pathway for testosterone in relation to nociception in the central nervous system.
• FIG. 3A depicts the pathway in normal individuals.
• Overview of Circle Hypothesis in the healthy state A painful stimulus, state of stress, or trauma is signaled by an increase in Substance P. Pain, stress or trauma also causes serotonin levels (and other stress-mediating neurochemicals that help regulate the descending control of pain (M.J.
• Substance P has been found to stimulate the enzyme aromatase within the central nervous system nociceptive relay neurons in a highly regulated process that is mediated by protein kinases and phosphoprotein phosphatases, which phosphorylate and de- phosphorylate aromatase (respectively), consistent with their status as classic "gate-keeper" regulators of cell function.
• Aromatase is thereby stimulated to act upon its substrate testosterone, which can be provided from the periphery and can cross the blood-brain barrier (BBB) for this purpose (also a highly regulated process, see elsewhere herein), to convert it to 17-beta estradiol within the dorsal horn of the spinal cord in the CNS.
• BBB blood-brain barrier
• Increases in 17-beta estradiol cause the subsequent upregulation of mRNA encoding enkephalins (opioid peptides) in the spinal cord dorsal horn nociceptive relay neurons.
• opioid peptides can both down-regulate Substance P (Zachariou et al , Euro. J.
• Aromatase is not only found in the nociceptive relay neurons in the spinal cord, but also in the brain and the periphery, where it can be a critically important player with respect to pain pathways at any of these sites.
• testosterone over estrogen
• SHBG sex hormone binding globulin
• FIG. 3B shows the same cycle in patients having chronic pain, which may be related to any of the stressors as defined in paragraphs [0011] and [0029] .
• Chronic inflammatory pain states or unresolvable stress or trauma can lead to a dys-equilibrium, or state of distress, which is not appropriately resolved in these patients.
• patients with inadequate or too-low are patients having inadequate or too-low.
• Substance P remains elevated, serotonin remains reduced, and a patient will remain in a hypersensitive pain state, or at high risk of pain with an abnormally low threshold for pain, with a lack of feeling of well-being, until the pain processing cycle is restored, for example, via androgen or testosterone replacement therapy.
• chronic pain can exhaust testosterone, the cycle is frustrated, and pain is not appropriately processed.
• the insufficient testosterone levels fail to mediate recovery from a painful stimulus, inflammatory pain, a stressor, or a state of trauma, resulting in a new dys-equilibrium or state of distress, that, in time, sets up altered neuronal circuitry or patterns through a process called neuronal plasticity, thereby allowing the distressed state to become entrenched.
• Substance P is also a marker of inflammation.
• Substance P allows communication between the immune and neuroendocrine systems, and within the nervous system between the periphery and CNS, to mediate nociceptive signaling.
• the sex steroid hormones can induce opioid peptides within the spinal cord dorsal horn, and further, that opioid peptides can inhibit Substance P (Zachariou et al., Eur. J. Pharmacol., 1997, 323 : 159- 165).
• This invention relates to underlying causes of chronic pain states, and likely relates to individuals who experience a stressful event either 1) at a time when their sex steroid hormone concentrations are too low to properly attenuate pain signals, or 2) the stressor itself has exhausted the testosterone, either of which results in a failure to appropriately down-modulate nociceptive relay signals and dampen wind-up pain phenomena.
• a stressful event either 1) at a time when their sex steroid hormone concentrations are too low to properly attenuate pain signals, or 2) the stressor itself has exhausted the testosterone, either of which results in a failure to appropriately down-modulate nociceptive relay signals and dampen wind-up pain phenomena.
• Substance P (P stands for "powder,” as it was discovered in a dried acetone powder of a neural tissue extract) is one of several neurokinin peptides, which are also known as tachykinin neuropeptides. These peptides are generally from about ten to about 12 amino acids in length, and function to excite neurons, evoke behavioral responses, and to contract smooth muscles. In addition, these peptides are potent vasodilators. In humans, neurokinins are encoded by two tachykinin genes TAC1 and TAC3. TAC1 encodes neurokinin A (previously known as Substance K), neuropeptide K (also known as neurokinin K), neuropeptide gamma and
• Substance P The different splice forms of the TAC1 gene result in the production of the different neurokinins.
• the TAC3 gene encodes neurokinin B.
• Substance P is involved in nociception, transmitting painful inflammatory insults and information about tissue damage from peripheral receptors to the CNS, and as such, it is a well-known marker for inflammation. It functions as both a neurotransmitter and a neuromodulator.
• the thymus may also play a role in chronic inflammatory pain.
• the thymus is known as a "primary lymphatic organ” responsible for maturing and developing or “educating" thymic cells so they can emigrate to peripheral tissues and respond to "danger,” distress, pathogens, etc., that assail the host.
• Thymic T cells are a major component and driving force in inflammatory responses, responding to the dangers that are perceived by the immune system. These lymphocytes are tightly regulated in a bi-phasic way such that they initially proliferate (expansion phase) in response to disease such as infection.
• Chronic inflammatory pain states involve an out-of-balance and undampened expansion of immune cells, an environment of inflammation that can be autoimmune-like, and a failure to return to a quiescent non-inflammatory state, resulting in pain, soreness and inflammation that is not appropriately resolved (“distress").
• Common markers associated with chronic inflammatory pain states include, but are not limited to, Substance P, elevated erythrocyte sedimentation rate, and elevated C-reactive protein or CRP ⁇ see paragraph [0029]).
• Gonadal steroid hormones can act to dampen inflammatory cells ⁇ see paragraph [0014]), and concomitant with this, the conversion of testosterone to estrogen by aromatase within the CNS dampens nociception in the dorsal horn nociceptive relay neuron.
• This pain signaling down- modulation likely occurs within the CNS descending pathways of nociceptive relay neurons to resolve pain.
• the instant invention involves raising serum levels of testosterone to higher levels, levels that are safe within the reference range and clinically effective, and that can down-modulate inflammatory pain signaling and alleviate fatigue such that a healthy quiescent state (eustress) is promoted with feelings of well-being.
• Substance P can induce mast cell degranulation and release of histamine which can directly excite nociceptive neurons (along with inflammatory immune cells) and amplify wind-up phenomena in chronic pain states.
• a role for the sex steroid hormones in nociceptive vain processing Data support a role for androgens and estrogens in opiate production in the nociceptive relay cells that transmit pain signals in the dorsal horn of the spinal cord, providing a mechanistic basis for testosterone involvement in pain perception.
• This basis is likely related to "gate control theory,” in which negative modulatory neurologic signals down-modulate nociceptive pain signals and restore the resting healthy state or homeostasis (the state of "eustress”).
• the loss of homeostasis due to stressors (the state of "distress”) in chronic pain patients is likely exacerbated and driven by stress-induced exhaustion or catabolism of testosterone to the point of a testosterone deficient state.
• Neuronal plasticity the ability of neuroendocrine pathways to enter into an altered set of equilibria that can be associated with pathology, called “allostasis” or “allostatic load,” according to Melzack (Pain Mechanism: A New Theory, Science, 1965, 150(3699):971 -979) and others (or a state of "distress,” according to Selye), then allows for hypersensitivity to pain,
• Patients entering a stressor state are at high risk for chronic pain from two sources.
• the subject is at higher risk and has greater susceptibility to pain states and clinical "distress" states.
• Metab., 1992, 74(5): 1 176-1 183) discloses that personnel taking part in 5-day military endurance training courses that require physical activities on a round-the-clock basis show a decrease in the plasma levels of several androgenic compounds, including testosterone, dehydroepiandrosterone, androstenedione, as well as 17a-hydroxyprogesterone. Plasma levels of these compounds can decrease under stress conditions by as much as 60% to 80%.
• Testosterone is known to be important within the central nervous system in preclinical studies, although this has not translated into the clinic. Androgen receptors can be widely found in specific patterns of expression throughout the CNS in various animal models. And testosterone concentrations have been shown to be dramatically decreased in the brain and spinal cord of rats in response to pain-inducing subcutaneous injections of formalin into the paw. In these animals, the loss of testosterone in the central nervous system was demonstrated to be due to its metabolism by 5 -reductase to dihydrotestosterone (Amini, H. et al, Pharmacol. Biochem.
• GABA A receptor modulators in the limbic system are associated with feelings of fear.
• the GABA A receptor ion channel complex is an inhibitory ion channel in the brain.
• testosterone may be relevant not only for modulation of pain but also for feelings of emotional well-being via binding of its metabolites to the neurosteroid site of the GABA A receptor, although this remains to be verified.
• a cause-and-effect relationship between testosterone and pain sensation has been suggested in animal models.
• evidence supports the concept that sex hormones can elevate the pain threshold in rodents, for example, during pregnancy (Gintzler, A. R., Science, 1980, 210: 193-195), when testosterone concentrations, as well as estrogen and progesterone concentrations, are elevated both in animal models and humans (Bammann, B. L. et al , Am. J. Obstet. Gynecol., 1980 137:293-298).
• the usage of androgens in humans to either dampen chronic inflammatory pain or elevate an individual's pain threshold has not been considered or tested.
• aromatase which converts testosterone to 17 ⁇ - estradiol
• estrogen can induce the transcription of opiates in estrogen receptor-positive cells derived from the superficial layers of the spinal dorsal horn (Amandusson, A. et al, Neurosci. Lett., 1996 196:25-28; Amandusson, A. et al, Eur. J.
• estrogen While there is good reason to think it is testosterone, rather than estrogen, that is more important for dampening pain, due in part to differential regulation by SHBG (sex hormone binding globulin) of the ability of estrogen vs. androgens to cross the blood-brain barrier, an animal dosed with sufficient estrogen may still have a reduction in pain.
• SHBG serol binding globulin
• estrogen or estrogen-progestin hormone replacement therapy (HRT) in women is not known to be particularly effective with respect to being anti-nociceptive.
• androgens, rather than estrogens appear to be the relevant hormone for effective migration from the periphery into the CNS to dampen pain.
• HPG Hydrophilid Pituitary Gonadal
• Daniell cited the same studies as those cited by Tennant and concluded similarly that anti-nociception would be mediated by exogenous opioids, not testosterone, and that testosterone replacement therapy was acting to alleviate non-pain symptoms in patients on maintenance opioid therapy.
• Daniell et al. carried out an open-label study (without placebo) in males on maintenance or primary opioid therapy to determine if adjunctive testosterone therapy could reverse the non-pain symptoms of testosterone deficiency, including sexual function, mood and depression (Daniell et al, "Open-label pilot study of testosterone patch therapy in men with opioid-induced androgen deficiency," J. Pain, 2006, 7(3):200-210). Pain was assessed to determine if the action of the opioids as primary therapy could be improved, but no significant change was found in the pain severity score. Daniell concluded that "It is difficult to interpret these findings in the absence of a placebo group.”
• glucocorticoid (glucocorticoid) replacement) modulates the permeability of brain tissue to isotopically labeled BSA.
• Sex steroid hormones quite different functionally from glucocorticoids (although both are produced in the adrenal cortex), are not mentioned or contemplated in the Long and Holaday study.
• SHBG sex hormone binding globulin
• the invention relates to a method of reducing inflammatory pain or ameliorating a clinical state of "distress " in a patient with symptoms of androgen deficiency and/or with an abnormally low pain threshold (and consequently a high susceptibility or risk of having a chronic inflammatory pain state): Overview.
• the invention relates to a method of reducing inflammatory pain or a clinical state of distress, as described in paragraph [0029] for example, in an andro gen-deficient human subject comprising diagnosing a human subject to have at least one of the indications defined above in paragraphs [0029] or [0041]; determining if the subject has serum androgen levels in the lower half of the appropriate reference range; and if the subject has at least one of one of the indications defined above in paragraphs [0029] and
• the term "elevated” means at the high end or above the normal or reference range of values for the measured statistic, the measured statistic including, but not limited to, C-reactive protein, erythrocyte sedimentation rate, or Substance P levels.
• the term “decreased” means below or at the low end of the normal or reference range of values for the measured statistic, the measured statistic including, but not limited to, the levels of endogenous opioid peptides.
• the invention relates to methods of reducing: chronic inflammatory pain in a human subject. Specifically, the invention relates to a method of reducing chronic inflammatory pain in a human subject with androgen deficiency symptoms comprising diagnosing a human subject to have at least one of a) elevated C-reactive protein, b) elevated erythrocyte
• the method includes administering a composition comprising a pain-reducing amount of an androgen to the human subject with androgen deficiency symptoms, wherein pain is reduced safely and effectively.
• This embodiment of the invention also contemplates the administration of a composition consisting essentially of a pain-reducing amount of an androgen to a human subject having symptoms of androgen deficiency, wherein the subject's pain is reduced safely and effectively.
• the invention relates to a method of reducing chronic inflammatory pain in a human subject with androgen deficiency symptoms consisting essentially of diagnosing a human subject to have at least one of a) elevated C-reactive protein, b) elevated erythrocyte sedimentation rate, c) DSM-IV disorder 307.80, d) DSM-IV disorder 307.89, or e) an unresolved stressor state; determining if the subject has androgen levels in the lower half of the appropriate reference range.
• the method includes administering a composition comprising a pain- reducing amount of an androgen to the human subject with androgen deficiency symptoms, wherein pain is reduced safely and effectively.
• a composition consisting essentially of a pain-reducing amount of an androgen to a human subject having symptoms of androgen deficiency, wherein the subject's pain is reduced safely and effectively.
• the invention relates to methods of increasing the pain threshold in a human subject.
• the invention also relates to a method of increasing the pain threshold of an androgen- deficient human subject comprising diagnosing a human subject to have at least one of the indications defined above in paragraphs [0029] and [0041] ; determining if the subject has androgen levels in the lower half of the appropriate reference range; and, if the subject has at least one of the indications defined above in paragraphs [0029] and [0041] such as having an unresolvable state of distress, along with androgen levels in the lower half of the appropriate reference range; administering a composition comprising an androgen as primary therapy to human subject having symptoms of androgen deficiency, wherein the subject's pain-threshold is increased safely and effectively.
• This embodiment of the invention also contemplates the administration of a composition consisting essentially of a pain threshold increasing amount of an androgen to a human subject having symptoms of androgen deficiency, wherein the subject's
• the invention relates to a method of increasing the pain threshold of an androgen-deficient human subject consisting essentially of diagnosing a human subject to have at least one of a) elevated C-reactive protein, b) elevated erythrocyte
• the method includes administering a composition comprising a pain-threshold increasing amount of an androgen to a human subject with androgen deficiency, wherein the subject's pain threshold is increased safely and effectively.
• This embodiment of the invention also contemplates the administration of a composition consisting essentially of a pain threshold increasing amount of an androgen to a human subject having symptoms of androgen deficiency, wherein the subject's pain threshold is increased safely and effectively [0071]
• the invention relates to method of testing if a human subject would benefit from androgen administration.
• the invention further relates to a method for determining if a human subject would benefit from androgen administration comprising, testing for at least one of the indications defined above in paragraphs [0029] and [0041]; determining if the subject has androgen levels in the lower half of the appropriate reference range; testing the subject's pain threshold; and if the subject has at least one of the indications defined above in paragraphs
• compositions comprising an androgen to the subject as the primary therapy for pain treatment, wherein the subject's androgen serum levels are restored safely and effectively to the middle-upper range of an appropriate reference range.
• This embodiment of the invention also contemplates the administration of a composition consisting essentially of an androgen to the subject, wherein the subject's androgen serum levels are restored safely and effectively to the middle-upper range of the appropriate reference range.
• the invention relates to a method for determining if a human subject would benefit from androgen administration consisting essentially of testing for at least one of a) elevated C-reactive protein, b) elevated erythrocyte sedimentation rate, c) DSM-IV disorder 307.80, d) DSM-IV disorder 307.89, or e) an unresolved stressor state; determining if the subject has androgen levels in the lower half of the appropriate reference range; testing the subject's pain threshold.
• the subject has at least one of a) elevated C-reactive protein, b) elevated erythrocyte sedimentation rate, c) DSM-IV disorder 307.80, d) DSM-IV disorder 307.89, or e) an unresolved stressor state, along with androgen in the lower half of the appropriate reference range, and if the subject has androgen levels in the lower half of the appropriate reference range and a low threshold of pain, the subject would be a candidate for androgen therapy.
• This embodiment of the invention contemplates the administration of a composition either comprising or consisting essentially of a pain threshold increasing amount of an androgen to a human subject having symptoms of androgen deficiency, wherein the subject's androgen serum levels are restored safely and effectively to the middle-upper range of the appropriate reference range.
• doctor 's diagnostic kit for patient selection The invention also relates to a kit for determining if a human subject would benefit from androgen administration as a primary therapy comprising instructions for diagnosing a subject as having an androgen-deficiency related disorder that is treatable by administration of a composition comprising an androgen or by administration of a composition consisting essentially of an androgen.
• the instructions can comprise instructing a health care provider how to test the subject's androgen serum levels and how to determine if the subject has at least one of the indications defined above in paragraphs [0029] and [0041] .
• the instructions can further comprise instructing the health care provider how to testing the subject's pain threshold; and instructing the health care provider to administer an androgen to the subject if the subject has androgen levels in the lower half of the appropriate reference range, a low threshold of pain, and at least one of the indications defined above in paragraphs [0029] and [0041]; so that the subject's androgen serum levels are restored safely and effectively to the middle-upper portion of the appropriate reference range.
• the instructions can further direct the health care provider to exclude patients receiving exogenous opioid therapy or include such opioid therapy as an adjunctive, rather than primary, therapy.
• a medical doctor can either 1 ) use a diagnostic kit for patient selection, or 2) continue the treatment of someone already diagnosed as having testosterone serum levels in the lower half of the reference range, and with unresolved pain or distress or abnormally low pain threshold, such that continuation treatment is independent of the diagnostic kit for patient selection.
• An androgen-deficient subject generally will exhibit a variety of symptoms, including, but not limited to, unresolvable pain, a loss of a feeling of well-being, hot flashes, sweating, insomnia, nervousness, irritability, tiredness, loss of motivation, short-term memory problems, declining self-esteem, depression, decreased energy levels, decline or loss of libido, diminished muscle mass, hair loss, abdominal obesity, ⁇ see paragraphs [0008] and
• a reduced volume of semen and poor erectile function can be symptoms of androgen deficiency.
• the subjects that receive primary androgen treatment may or may not also be receiving concurrent adjunctive administration of an exogenous opioid.
• concurrently means sufficiently close in time to produce a combined effect (that is, concurrently may be simultaneously, or it may be two or more events occurring within a short time period before or after each other).
• the invention relates to a k for determining if a human subject would benefit from androgen administration comprising instructions for diagnosing a subject as having symptoms of an androgen-deficiency treatable by administration of an androgen.
• the instructions consist essentially of instructing a health care provider how to test the subject's androgen serum levels; instructing the health care provider to determine if the subject has at least one of a) elevated C-reactive protein, b) elevated erythrocyte sedimentation rate, c) DSM-IV disorder 307.80, d) DSM-IV disorder 307.89, or e) an unresolved stressor state; instructing the health care provider how to test the subject's pain threshold; and instructing the health care provider to administer a composition either comprising or consisting essentially of an androgen to the subject if the subject has androgen levels in the lower portion of the of the appropriate reference range, has a low threshold of pain, and at least one of a) elevated C-reactive protein, b) elevated erythrocyte sedimentation rate, c) DSM-IV disorder 307.80, d) DSM-IV disorder 307.89, or e) an unresolved stressor state; so that the subject's androgen serum levels
• the invention also relates to a method of increasing endogenous opioid peptide production an androgen-deficient, opioid peptide-deficient human subject comprising:
• the level of a subject's endogenous opioid peptides can be measured in cerebrospinal fluid, however, one of ordinary skill in the art would know how to test for endogenous opioid peptides at other sites including, but not limited to, the periphery. Further, one of skill in the art might also test for other indicators of pain or efficacy in the cerebrospinal fluid.
• This embodiment of the invention also contemplates the administration of a composition consisting essentially of an endogenous opioid peptide- increasing amount of an androgen to a human subject having symptoms of androgen deficiency, wherein the subject's levels of endogenous opioid peptides are increased safely and effectively
• the invention relates to a method of increasing endogenous opioid peptide production an androgen-deficient, endogenous opioid peptide deficient human subject consisting essentially of diagnosing a human subject to have at least one of a) elevated C- reactive protein, b) elevated erythrocyte sedimentation rate, c) DSM-IV disorder 307.80, d) DSM-IV disorder 307.89, or e) an unresolved stressor state; determining if the subject has androgen levels in the lower half of the appropriate reference range; determining if the subject has low endogenous opioid peptide levels.
• the method includes administering a composition comprising an androgen to a human subject with androgen and opioid peptide deficiencies, wherein the subject's production of endogenous opioid peptides is increased.
• This embodiment of the invention also contemplates the administration of a composition consisting essentially of an endogenous opioid peptide-increasing amount of an androgen to a human subject having symptoms of androgen deficiency, wherein the subject's levels of endogenous opioid peptides are increased safely and effectively
• Opioid peptides are a class of peptide molecules that function as
• Endogenous opioid peptides can be produced at sites within the central nervous system, including but not limited to, the pituitary gland, the hypothalamus, and the spinal cord. Endogenous opioid peptides can also be produced within the periphery. These endogenous opioid peptides resemble exogenous opioid compounds in their actions.
• the opioid peptides that can be used in the instant invention include, but are not limited to enkephalins, endorphins, dynorphins, adrenorphhin, amidorphin, and opiorphin. Each of these subgroups of opioid peptides also has several members.
• the endorphins include, but are not limited to, alpha-endorphin, beta-endorphin and gamma-endo hin.
• Enkephalins include but are not limited to, the active forms of enkephalin ala(2)-MePhe(4)-Gly(5), enkephalin D- Penicillamine(2,5), enkephalin leucine, and enkephalin methionine.
• Other opioid peptides include prooiomelanocortin (POMC), the gene for which codes for beta-endorphin and gamma- endorphin. As with exogenous opioid compounds, the endogenous opioid peptides bind to opioid receptors to exert their action.
• POMC prooiomelanocortin
• opioid receptors there are several subtypes of opioid receptors to which the opioid peptides can bind. For example, mul, mu2, kappal , kappa2, deltal, delta2 opioid receptors are among those that have been studied.
• Opioid peptides as defined herein, include those opioid peptides that bind to these opioid receptors and thereby mediate pharmacologic activity.
• one measurement of an indication that can be treated using an androgen composition includes measuring the level of a subject's endogenous opioid peptides, and if they are decreased below the normal level or reference range, the subject may be a candidate for treatment, if the other conditions of androgen deficiency or symptoms thereof are met.
• Another indication that can be measured is Substance P, and if the subject's Substance P level is increased above the normal level, the subject may be a candidate for treatment, if the other conditions of androgen deficiency or symptoms thereof are met.
• androgen therapy is the primary therapy to be administered for all of the above embodiments of the invention.
• subjects receiving primary androgen therapy may also receive adjunctive opioid therapy if they have exogenous opioid-induced hypogonadism or other conditions that might require such adjunctive opioid therapy in addition to the primary androgen therapy.
• adjunctive opioid therapy may also be administered as adjunctive therapies.
• kits can be designed to measure and/or test for the levels of a variety of metabolic functions and/or compounds that are important for such functions. For example, not only can the serum levels of androgens, such as, but not limited to, testosterone, be determined, but the level and activity of enzymes that catabolize androgens can be determined. Endogenous opioid peptides, such as enkephalins, can be measured, as can Substance P, an important marker for inflammatory pain.
• androgen therapy can be modulated and adjusted, depending upon the needs of the specific patients. The adjustment can depend upon the catabolic breakdown and saturation of androgens and their receptors. Further, by adjusting the level of androgen administered as a primary therapy, adjunctive therapies, such as opioids or antidepressants can be adjusted downwards, thus avoiding some of the detrimental side effects of these treatments.
• adjunctive therapies such as opioids or antidepressants can be adjusted downwards, thus avoiding some of the detrimental side effects of these treatments.
• a personalized medicine kit could consist of assessing the activity of enzymes that catabolize testosterone and other endogenous androgens, which could be assessed by targeted gene expression array profiling of these enzymes to determine if an individual has high catabolic activity, necessitating higher dosing of testosterone therapy for efficacy, or low catabolic activity, necessitating lower dosing of testosterone therapy for safety.
• an individual can be tested for endogenous
• testosterone dosing over time to determine whether the testosterone dosing is sufficient (enkephalins are raised into the normal range) or dosing needs to be increased (enkephalins have not yet been raised into the normal range).
• Substance P can be tested, and if its level is decreased to a normal resting state, the testosterone dose can be held constant, or even decreased if there are signs of androgen excess; and if Substance P levels are not decreased, the testosterone dose can be increased to a safe level that is still within the testosterone reference range.
• One of skill would know whether to test for levels of these molecules in the spinal cord or the periphery, and whether to test cerebrospinal fluid or serum.
• patients For purposes of selecting patients with chronic inflammatory pain for treatment, patients can be selected who have an abnormal erythrocyte sedimentation rate test result of > 22 mm hr for men or > 29 mm/hr for women, and/or an abnormal C-reactive protein test result of > 3mg/dL, indicating the patient has inflammatory pain.
• Substance P a neurokinin peptide, is also a marker for inflammatory pain.
• Substance P is another method that can be used to diagnose a chronic inflammatory pain state.
• total testosterone For accruing female patients who are in the lower half of the reference range, either total testosterone, free testosterone and/or bioavailable testosterone can be considered.
• the "lower half of the reference range for total testosterone” is defined as less than or equal to about 0.5 ng/mL when using the DSL total testosterone serum level assay; or less than or equal to about 0.4 ng/mL when using the Mayo Medical Labs total testosterone serum level assay (Table 1).
• a person of skill in the art would understand that he would be able to use other equivalent assay tests to define and test for the lower half of the reference range.
• lower half of the reference range for total testosterone is defined as less than or equal to about 6 ng ⁇ mL when using the Mayo Medical Labs total testosterone serum level assay. If using another test with its own reference range, a person of skill would assess patient accrual serum level limits in an equivalent way for males vs. females using the appropriate reference range.
• the methods of administerin androgen therapy relate to a method of treating a human subject with clinical symptoms of androgen deficiency, chronic inflammatory pain, or unresolvable states of distress (see paragraphs [0029] and [0041] above), whose serum levels of androgen are in the lower half of the appropriate reference range.
• the method is comprised of administering a composition comprising a pain-reducing amount of an androgen to a human subject as the primary therapy, such that the resultant serum levels are raised sufficiently for efficacy, but are not raised significantly above the upper end of the reference range.
• the invention further relates to a method of increasing the pain threshold of an androgen-deficient human subject with clinical symptoms of androgen deficiency, or unresolvable states of distress (see paragraphs [0029] and [0041] above), whose serum levels of androgen are in the lower half of the appropriate reference range, comprising administering a composition comprising a pain threshold-increasing amount of an androgen as the primary therapy, such that the resultant serum levels are raised sufficiently for efficacy, but are not raised significantly above the upper end of the reference range.
• the administration can be on a daily basis, or any basis including, but not limited to, weekly or monthly, depending upon the individual patient.
• the subject of the instant invention may be a female subject or a male subject.
• the pain to be treated can be caused by a number of circumstances, and further exacerbated by additional stressor(s) introduced into a subject's life. Further, a subject may have a chronic medical state accompanied by an additional stressor state, that causes or exacerbates chronic pain. A stressor state, defined elsewhere herein, may sometimes be the cause of chronic pain in a subject, and/or the subject may be susceptible to stress/distress due to too-low androgen levels.
• the composition can also consist essentially of an androgen.
• the androgen can be a biologically active androgen, and can be administered by a variety of means, including, but not limited to, transdermal administration, oral administration, buccal administration, injection, implanted pellets, or suppository.
• the maintenance dose can be determined by measuring the serum androgen levels at predetermined time points to ensure that steady state serum levels are reached and that these levels are maintained within the appropriate reference range. Should the serum androgen levels change over time, the maintenance dose can be altered accordingly.
• the androgen composition can be administered as a once daily dose, or a divided dose.
• the composition can be administered twice a day (e.g., morning and evening), three times a day (e.g., with meals), or using any other regimen.
• the subject's serum androgen levels should reach steady state, be maintained within the appropriate reference range, and can be adjusted over time.
• the dose and/or dosing regimen can be altered in the case of a change in a subject's health status (either positive or negative), so as to re-attain the steady state and androgen serum levels within the appropriate reference range.
• the levels of endogenous opioid peptides or Substance P can also be monitored, and the dose and/or dosing regimen altered as necessary, to ensure that the appropriate levels of endogenous opioid peptides or Substance P are maintained.
• the biologically active androgen may be a testosterone ester such as, but not limited to, testosterone enanthate or testosterone cypionate.
• the bioactive androgen is testosterone. As described above, this is applicable to treating chronic pain in a subject and/or for increasing the pain threshold in a subject.
• the invention relates to a method of reducing chronic pain in a human subject with symptoms of androgen deficiency, androgen-deficiency as defined in paragraphs [0008],
• [0029]-[0033], and [0041], comprising administering a pain-reducing amount of an androgen as primary therapy to a human subject with symptoms of androgen deficiency, wherein pain is reduced safely and effectively.
• the subject can be suffering from a condition selected from the group consisting of chronic pain, and pain caused by a chronic stressor state, stressor state as defined in paragraphs [0011], [0029], and [0041].
• the method also relates to a method of increasing the pain threshold in an androgen-deficient human subject comprising administering a pain-threshold-increasing amount of an androgen as primary therapy to the subject, so that the subject's pain threshold is increased safely and effectively, as defined elsewhere herein.
• the subject's androgen serum levels are restored to serum levels at or below the upper end of the appropriate reference range as defined by the mean of the upper end, plus or minus the standard error of the mean, SEM.
• an androgen serum level slightly above the reference range is both safe and efficacious, with "safety” defined as being within the standard error of the mean of the upper limit of the appropriate reference range and not causing clinical symptoms of androgen excess.
• the androgen used in the invention is a bioactive androgen. Bioactive androgens may be active in their native state, and/or may be a precursor or pro-drug that is metabolized to a bioactive state upon delivery to the subject.
• the method encompasses the administration of a biologically active androgen, which may be, but is not limited to, testosterone, androstenedione, androstendiol,
• dehydroepiandrosterone danazol, fluoxymesterone, oxandrolone, nandrolone decanoate, nandrolone phenpropionate, oxymethalone, stanozolol, methandrostenolone, testolactone, pregnenolone, dihydrotestosterone, methyltestosterone, bioactive androgen precursors, and testosterone esters. If a testosterone ester is administered it may be, but is not limited to, testosterone enanthate or testosterone cypionate. Testosterone can be the androgen employed by the invention.
• the methods of the invention can be practiced on both female and male subjects.
• the bioactive androgen can be transdermally administered in a daily unit dose of about 0. 1 mg to about 12.8 mg of the androgen in a pharmaceutically acceptable carrier formulated for daily topical administration as a gel and wherein the gel is formulated to deliver steady state total androgen serum levels without raising free androgen serum levels or twenty-four hour free androgen AUC above the levels required for therapeutic efficacy and safety.
• the bioactive androgen can be transdermally administered in a daily unit dose of about 35 mg to about 100 mg of the bioactive androgen in a
• pharmaceutically acceptable carrier formulated for daily topical administration as a gel and wherein the gel is formulated to deliver steady state total androgen serum levels without raising free androgen serum levels or twenty-four hour free androgen AUC above the levels required for therapeutic efficacy and safety.
• the serum levels of free testosterone can be raised to a level that is below or at the upper part of the reference range (+/- SEM).
• Androgens used in human studies - form and delivery Most trials involving hormone replacement therapy have used derivatives of hormones naturally found in women. These derivatized hormones have been promoted because of their patentability and their extended half-life. Androgens are no exception since the androgen hormone most prescribed for women has been methyltestosterone, where methylation at the C-17 position increases its oral bioavailability. A subset of patients do not tolerate derivatized hormones very well, however. Derivatized compounds are not metabolized normally, and therefore may not be the best candidates for commercialization.
• Non-derivatized exogenous hormones that are structurally identical to endogenous hormones can have short plasma/serum half-lives that range from 10- 100 minutes, however, making oral administration of native hormones problematic.
• transdermal delivery systems have been developed for testosterone, which provide sustained delivery while minimizing first pass hep ato toxicity, which can be problematic with oral formulations of pharmacotherapeutics.
• transdermal gel delivery also avoids the skin irritation many patients experience with repeated use of a transdermal patch delivery system.
• other forms of androgen delivery are available, each having both benefits and drawbacks.
• testosterone serum blood levels within the reference range and avoiding clinical symptoms of androgen excess must be coupled with efficacy as demonstrated by significantly raising testosterone blood levels from baseline levels in the lower half of the reference range to the upper half of the reference range, while significantly decreasing clinical symptoms of androgen deficiency. Examples of these changes and side effects are discussed below.
• upper limit of the reference range for free testosterone is defined as less than or equal to about 3.3 pg/mL when using the DSL free testosterone serum level assay (Table 1); and less than or equal to about 19 pg/mL when using the Mayo Medical Labs free testosterone serum level assay. If using another test with its own reference range, a person of skill would assess safety serum level limits in an equivalent way.
• the "upper limit of the reference range for free testosterone" is defined as less than or equal to about 300 pg/mL when using the Mayo Medical Labs free testosterone serum level assay. If using another test with its own reference range, a person of skill would assess safety serum level limits in an equivalent way.
• Chem., 1997, 43(7): 1262) disclose that over-administration of anabolic steroids can cause many health problems, including weight gain, acne, hirsutism, alteration of libido, edema, function and structural liver damage. Gooren further teaches that the risk of testosterone-induced side-effects, including cardiovascular disease and hirsutism, are reversed in female-to-male transsexuals who stop receiving testosterone.
• testosterone and other bioactive androgens are Schedule C-III controlled substances under the Anabolic Steroid Control Act and, as such, can be dangerous to over-administer in view of the dangerous side-effects of cancer, liver disease, and cardiac disease.
• safety it is meant that serum levels are within the standard error of the mean SEM of the upper end of the reference range, and there are no unhealthy clinical symptoms of androgen excess.
• effective it is meant that 1) androgen therapy raises baseline serum levels from the lower half of the reference range to significantly higher serum levels that are still safe within the reference range, and 2) androgen therapy results in significant clinical improvement.
• the androgen therapy can raise the serum androgen levels from the baseline to the middle or upper portion of the appropriate reference range, and even slightly higher, so long as the safety profile is maintained. While total testosterone is a factor when considering the serum levels of testosterone, it is the free testosterone that is an indicator of the testosterone that is available for biologic action in vivo.
• free and bioavailable testosterone generally remain in a constant ratio and are reliable indicators of biologic availability, while SHBG-bound testosterone, which is not bioavailable, varies in response to changes in the total pool (Felig, P. and L.A. Frohman, "Endocrinology and Metabolism” McGraw Hill, 4th edition, 2001, 647).
• the reference ranges for women and men differ by a factor of about ten times.
• Table 1 shows the reference ranges for both women and men, and presents data from two different reference range detection methods (male reference ranges only shown using one testing method).
• DSL Diagnostic Systems Laboratories
• the reference range determined using the Mayo Medical Laboratories diagnostic test is from about 0.08 ng/mL to about 0.6 mg/mL. Reference ranges are known to differ slightly depending on the detection kit and method used to measure serum levels.
• the reference range for men is about 2.4 ng/mL to about 9.5 ng/mL. It is important to remember that, when comparing serum testosterone reference ranges, one must translate the reference range from one test to another.
• diagnostic tests vary in their reference ranges, according to which, and whether, monoclonal antibody (mAb) was used for detection (earlier detection systems such as DSL use a detection mAb), or whether no mAb was used for detection (more recently developed detection systems such as Mayo Medical Labs, which use tandem mass spectrometry for detection instead).
• the upper end of a safe total testosterone serum level range would be at about 1.0 ng/dL when using the DSL test, versus about 0.6 ng/dL when using the Mayo Medical Labs test.
• the upper end of a safe free testosterone range would be at about 3.3 pg/mL when using the DSL test, versus about 19 pg/mL when using the Mayo Medical Labs test.
• the reference range is only an approximation of what would be the "normal” range in individuals, since the reference range would be skewed downward if the "control" population included significant data from subjects with a deficiency.
• TT total testosterone (free testosterone + testosterone weakly bound to albumin + testosterone tightly bound to sex hormone binding globulin SHBG);
• BioT bioavailable (or bioactive) testosterone (free testosterone + testosterone weakly bound to albumin)
• Mayo Mayo Medical Laboratories
• FT and BioT analysis by tandem mass spec after AmS0 4 precipitation
• Claims based on the reference range from an antibody detection test such as DSL must be converted to the Mayo Medical Labs reference range, which does not rely on antibody detection of testosterone, in order to make comparisons.
• the above table can be used for this purpose.
• Male testosterone levels are generally on the order of lOx female testosterone levels; Free testosterone is on the order of 1-5% of total testosterone.
• chronic pain is inflammatory pain and is distinct from the noninflammatory tender point muscle pain of fibromyalgia.
• the chronic inflammatory pain group of patients (having pain for at least three months, or with unresolvable pain) can be screened for androgen serum levels. Patients to be treated will present an androgen serum level in the lower half of the appropriate reference range.
• the low pain threshold group of patients includes those patients with substantial stress that cannot be resolved through coping or adaptation (i.e., stress becomes distress). These patients would be likely to have clinical signs or conditions of stress, as discussed in paragraphs [0011], [0029] and [0041] above. Or they could have clinical signs, for example a lack of feeling of well-being or a low libido (lacking the ability to enjoy life), that suggest a high risk of more overt symptoms of clinical distress.
• the serum androgen levels can be checked and if found to be in the lower half of the appropriate reference range, these patients can also be checked for a low pain threshold using a dolorimeter (or other appropriate measurement system or metric). A low pain threshold correlated with serum androgen levels in the lower half of the appropriate reference range would constitute the group of patients to be treated.
• patients as described above can be stratified by lower half of androgen (or testosterone) reference range and low threshold of pain versus those patients having serum levels in the upper half of the reference range and a normal threshold of pain.
• the first group are candidates for treatment according to the methods of the invention. Those in the second group should not be treated by these methods, or they can be used in a placebo arm.
• Numerous clinical states relate to decreased androgen levels and thus to a high risk for chronic pain and chronic stressor states.
• the treatment disclosed herein can alleviate any of these conditions and further alleviate problems caused by other therapeutics, wherein the conditions and therapeutically-induced problems relate to or cause decreased or low testosterone.
• hypopituitarisms of any cause including, but not limited to, Sheehan's syndrome, and adrenal disease, including Addison's disease, can cause low testosterone levels.
• chronic illnesses including, but not limited to, anorexia nervosa, clinical depression, advanced cancer, and burn trauma are also causative of low testosterone concentrations.
• advancing age is also associated with reduced levels of testosterone and its precursors, DHEA and androstenedione. This likely is caused by natural aging of the ovaries/testes and adrenal glands.
• Drugs given to subjects systemically can also cause decreased testosterone levels.
• examples of pharmaceutical agents that can cause decreased testosterone levels include, but are not limited to, systemic glucocorticoids or oral estrogens.
• the decreased levels of testosterone are associated with the suppression of adrenocorticotropic hormone levels with glucocorticoid use and luteinizing hormone levels with oral estrogen therapy.
• Oral estrogen users have significantly lower levels of free testosterone, due to increased levels of sex hormone- binding globulin (SHBG). Both hyperthyroidism and excessive thyroid medication also increase SHBG levels, which lead to lower levels of free testosterone. In these cases, both the conditions and the treatments can cause lower levels of testosterone.
• SHBG sex hormone- binding globulin
• pharmacological agents that can lower testosterone directly include, but are not limited to, trazodone, imipramine, muscle relaxants, analgesics (e.g., non-steroidal antiinflammatory drugs (NSAIDS), COX-2 inhibitors (e.g., celecoxib, tramadol), sleep medications (e.g. , Zolpidem, alprazonam), barbiturates, sedatives, clonidine, methyldopa, spironolactone (which has anti androgenic properties), and selective androgen receptor modulators (SARMs).
• NSAIDS non-steroidal antiinflammatory drugs
• COX-2 inhibitors e.g., celecoxib, tramadol
• sleep medications e.g. , Zolpidem, alprazonam
• barbiturates e.g. , Zolpidem, alprazonam
• barbiturates e.g. , Zolpidem, alprazonam
• These drugs include, but are not limited to, competitive inhibitors of 5-alpha reductase (the enzyme that converts testosterone to dihydrotestosterone) (e.g., finasteride, dutasteride), gonadotropin-releasing hormone (GnRH) agonists (e.g., goserelin, which deprives tumors of testosterone, leuprolide, buserelin, naferelin, deslorelin), GnRH antagonists (e.g., cetrorelix, abarelix, ganirelix, degarelix), anti-androgens that bind to androgen receptors as an antagonist (e.g., bicalutamide, flutamide, both used to treat prostate cancer), corticosteroids (e.g., Cortisol, aldosterone, cortisone, prednisone,
• GnRH gonadotropin-releasing hormone
• GnRH antagonists e.g., c
• dexamethasone triamcinolone, budesonide
• ketoconazole
• Chronic medical conditions that are treated, for example with antidepressants can also be associated with decreased testosterone levels.
• One set of medical conditions can include, but is not limited to, medical conditions being treated with certain medications, especially antidepressants.
• Specific indications might be decreased sexual function in both men and women. Such indications include psychosocial issues and psychological disorders (including, but not limited to, depression and anxiety), physiological/medical conditions (including, but not limited to menopause, age-related sexual drive decline, and fatigue).
• Another set of medical conditions that might be treated with antidepressants includes all forms of chronic illnesses (including, but not limited to cardiovascular disease, diabetes mellitus, arthritis, renal failure and cancer. Gynecological and/or breast cancer can be particularly causative of such problems).
• Patients exhibiting the aforementioned conditions, which also have a component relating to a low sex drive and/or low testosterone levels can be treated by a variety of pharmacological agents.
• depression and anxiety can be treated with any one of a number of agents, including but not limited to, tricyclic antidepressants (e.g., amitriptyline, clomipramine, butriptyline, doxepin), selective serotonin reuptake inhibitors (SSRIs) (e.g., fluoxetine, sertraline, citalopram, paroxetine), serotonin-norepinephrine reuptake inhibitors (SNRls) (e.g., duloxetine, venlafaxine, desvenlafaxine), anxiolytics and antipsychotics (e.g., antidepressants, antihistamines, benzodiazepines, azaspirones), and beta blockers (e.g., carvedio
• the instant invention can be used as a primary therapy and concurrently with the aforementioned pharmacological agents, and can counteract the decreased sexual function and low levels of testosterone resulting from the conditions being treated, as well as the pharmacological agents being used to treat those conditions.
• antidepressants can also be taken as an adjunctive therapy in conjunction with primary androgen therapy.
• the invention further relates to 1 ) the treatment of pain comprising administering an androgen alone or in combination with an antidepressant, or 2) the treatment of depression as an unresolvable state of distress or combined with a lack of feeling of well-being, comprising administering an androgen alone or in combination with an antidepressant, and 3) when these patients have serum levels of androgen in the lower half of the reference range.
• the androgen can be those previously described.
• the antidepressant can be selected from SSRIs or SNRIs including duloxetine, fluoxetine, sertraline, and a tricyclic antidepressant.
• the dosage of the antidepressant compounds can be the usual range of administration for these compounds.
• Treatment can be the androgen either alone or in combination with antidepressant compounds.
• the Circle Hypothesis provides a mechanistic basis and the overall bioloeic context or paradigm for a rational treatment of clinical symptoms of androgen deficiency.
• the underlying circle hypothesis applies to both the chronic pain, and/or the abnormally low pain threshold patient populations comprised of patients in a state of distress or lacking a feeling of well-being. Using the information gleaned from the testing protocols, one can appropriately select the patients for androgen therapy.
• Methods for evaluating and treating, subjects also relates to a method of determining if a subject should be treated with androgen therapy.
• a method can comprise testing a subject for androgen serum levels; testing the subject for the subject's pain threshold, wherein if the subject has low androgen serum levels and a low threshold of pain or clinical evidence or symptoms of androgen deficiency as defined elsewhere, an androgen is administered to the subject.
• the bioactive androgen may be a testosterone ester such as, but not limited to, testosterone enanthate or testosterone cypionate.
• the bioactive androgen is testosterone. As described above, this is applicable to both the method of treating chronic pain in a subject and the method of increasing the pain threshold in a subject.
• the androgen can be administered in a unit dose of about 0.1 mg to about 12.8 mg of the androgen.
• the androgen can be formulated as a transdermal preparation in a pharmaceutically acceptable carrier formulated for daily topical
• the daily unit dose of the androgen is from about 1.0 mg to about 12.8 mg. More preferably, the daily unit dose of the androgen is from about 2.5 mg to about 10.0 mg. Even more preferably, the daily unit dose of the androgen is from about 3.2 mg to about 9.6 mg. Most preferably, the daily unit dose of the androgen is from about 6.0 mg to about 8.0 mg. The daily unit dose of the androgen can be about 6.5 mg or about 7.5 mg.
• the dosing range can be incremental.
• the dose to be administered to a female subject can be about 2.5 mg; 5.0 mg; 7.5 mg; or 10.0 mg.
• a physician may start the patient on a low dose, and titrate the dose upwards until a dose that is both effective and safe is reached.
• the incremental dosage rate can start at 3.2 mg, and rise progressively to 6.4 mg, 9.6 mg, and 12.8 mg, using a 0.8% gel formulation.
• patients can be started with 2 packets of 0.8%
• each packet can contain 400 mg of 0.8% testosterone gel (3.2 mg testosterone, to deliver 10% or 320 ⁇ g bioavailable testosterone) or 400 mg placebo gel in it.
• any patient who tests > 3.3 pg/mL for serum free testosterone can decrease the dose by one gel packet/day.
• Any patient who tests ⁇ .9 pg/mL for serum free testosterone (within or below the lower half of the DSL testosterone reference range) can increase the dose by one gel packet/day until the serum level is raised to between about the mid-range and the upper end of the reference range +/- SEM. It is the level of free testosterone and/or bioavailable testosterone, rather than total testosterone, that is important to maintain within the reference range +/-SEM, since it is free testosterone or bioavailable testosterone that correlates tightly with safety.
• the daily unit dose can be delivered via a transdermal gel having about 0.1 % to about 10.0% of the androgen.
• the transdermal gel can have about 0.5% to about 5.0% of the androgen. More preferably, the transdermal gel can have about 0.5% to about 2.5% of the androgen. Most preferably, the transdermal gel can have about 0.8-1.0%) of the androgen.
• the daily unit dose of the androgen can be from about 4.0 mg to about 10.0 mg, or from about 6.0 mg to about 8.0 mg.
• the daily unit dose-to-be-delivered of the androgen can be from about 0.4 mg to about 1.0 mg, or from about 0.6 mg to about 0.8 mg androgen.
• the formulation of the invention will preferably be used at a unit dose of 800 mg gel of 0.8% testosterone (6.4 mg testosterone), and then, depending on serum levels at 4 weeks, adjusting down to 400 mg gel of 0.8% testosterone (3.2 mg testosterone), or adjusting up to 1200 mg gel of 0.8% testosterone (9.6 mg testosterone), to maintain the unit dose to achieve safe and effective serum levels.
• testosterone can be administered to females in a variety of different ways, including, but not limited to injection, oral administration, buccal administration, implanted pellets, or suppositories. If an alternate method of administration is chosen for females, the regimen of administration may also be varied, as described above in paragraph
• the daily unit dose of the androgen may be selected to maintain steady state total androgen serum levels within a range of between about 0.7 ng/mL and about 1.6 ng/mL, and preferably between about 0.9 ng/mL and about 1.4 ng/mL for at least 24 hours after administration without raising free androgen serum levels or twenty- four hour free androgen AUC above the levels required for therapeutic efficacy and safety, as defined elsewhere herein. Further, the free androgen serum levels and twenty-four hour free androgen AUC should not be raised above levels required for therapeutic efficacy and safety.
• the free androgen serum levels can be raised to between about 1.00 pg mL and about 3.3 pg/mL +/- 2 SEM. (About 3.3 pg/mL using the DSL test is equivalent to about 19 pg/mL using the Mayo Medical Labs mass spectrophotometry method of measuring free testosterone, Table 1. The upper end of the reference range is determined by which method of measuring free testosterone is used).
• the twenty-four hour free androgen AUC levels can be raised to between about 35.18 pg-h mL and about 72.60 pg-h/mL; more preferably the free androgen serum levels can be raised to between about 2.00 pg/mL and about 3.3 pg/mL and the twenty- four hour free androgen AUC levels can be raised to between about 40 pg-h/mL and about 65 pg-h/mL.
• the full reference range of the premenopausal woman can be used to determine the optimal desired serum testosterone level.
• the androgen is administered in a unit dose of about 35 mg to about 100 mg of the androgen.
• the androgen can be formulated as a transdermal preparation in a pharmaceutically acceptable carrier formulated for daily topical administration as a gel. Further, the gel is formulated to deliver steady state total androgen serum levels without raising free androgen serum levels or twenty-four hour free androgen AUC above the levels required for both therapeutic efficacy and safety.
• the daily unit dose of the androgen for a male can be from about 50 mg to about 90 mg/day or from about 65 mg to about 85 mg.
• the daily unit dose of the androgen can be about 75 mg or about 80 mg.
• the unit dose above can be administered as a once-a-day daily unit dose of a transdermal gel, whereby steady state serum androgen levels are reached within 24 hours.
• Alternative formulations and dosing can be used (as discussed above in paragraph [0087], although the preferred embodiment is a formulation that holds to the safe delivery of "not-too- much-too-fast" testosterone, i.e., without unsafe spiking while raising blood levels above baseline to achieve clinical efficacy, and a delivery rate that achieves steady state within days of initiating therapy.
• the dosage can be easily varied by one of ordinary skill in the art.
• the safe and effective reduction of pain and the concomitant desired serum levels of the androgen can be obtained using varied routes of administration and varied dosage levels, which can be determined on a case-by-case basis.
• the dosing range can be incremental.
• the dose to be administered to a male subject can be about 50 mg; 75 mg; 80 mg; or 90.0 mg.
• a physician may start the patient on a low dose, and titrate the dose upwards until a dose that is both effective and safe is reached.
• the incremental dosage rate can start at 50 mg, and rise progressively to 70 mg, 80mg, and 90 mg.
• patients can be started with an appropriate number packets of a testosterone gel formulated for males by one of ordinary skill in the art or placebo gel per day for the first four weeks.
• Each packet can contain the appropriate amount of a testosterone gel or the corresponding placebo gel.
• any patient who tests above the appropriate male reference range for serum free testosterone can decrease the dose over time until the appropriate reference range is reached and maintained.
• Any patient who tests at or below the lower half of the male reference range for serum free can increase the dose over time until the serum level is raised to between about the mid-range and the upper end of the reference range +/- SEM.
• the daily unit dose can be delivered via a transdermal gel having about 0.1% to about 10.0% of the androgen.
• the transdermal gel can have about 0.5% to about 5.0% of the androgen. More preferably, the transdermal gel can have about 0.5% to about 2.5% of the androgen. Most preferably, the transdermal gel can have about 0.8-1.0% of the androgen.
• testosterone can be administered to males in a variety of different ways, including, but not limited to injection, oral administration, buccal administration, implanted pellets, or suppositories. If an alternate method of administration is chosen for males, the regimen of administration may also be varied as described above in paragraph [0087].
• Androgen serum level targets for males.
• the daily unit dose of the androgen for a male can be selected to maintain steady state total androgen serum levels within a range of between about 2.4 ng/mL to about 9.5 ng/mL for at least 24 hours after administration.
• the free androgen serum levels and twenty-four hour free androgen AUC should not be raised above the levels required for therapeutic efficacy and safety, as defined elsewhere herein.
• the free androgen serum levels can be raised to between about 90 pg/mL and about 300 pg/mL and the twenty-four hour free androgen AUC levels can be raised to between about 350 pg-h/mL and about 800 pg-h/mL; more preferably the free androgen serum levels can be raised to between about 150 pg/mL and about 300 pg/mL and the twenty- four hour free androgen AUC levels can be raised to between about 400 pg-h/mL and about 700 pg-h/mL. As above, these preferred ranges can be adjusted for the Mayo Medical Labs reference ranges or any other reference laboratory.
• the unit dose for male subjects can be selected to maintain steady state total androgen serum levels within a range of between about 4.0 ng/mL and about 9.5 ng/mL, preferably between about 6.0 ng/mL and about 9.5 ng/mL, for at least 24 hours after administration without raising free androgen serum levels or twenty- four hour free androgen AUC above the levels required for therapeutic efficacy and safety, as defined elsewhere herein.
• Transdermal gel formulations for an androgen and at least one pharmaceutically acceptable carrier are standard and well known in the art, and can contain a wide variety of components, including penetration enhancers.
• Penetration enhancers have different strengths and can be optimized to obtain the desired transdermal delivery effect.
• penetration enhancers such as oleic acid and sodium hydroxide are stronger and allow for more and faster delivery of a transdermally-delivered drug and are frequently used in androgen compositions approved for male use.
• These formulations are based on the idea that inclusion of such male-specific penetration enhancers may help achieve absorption of the relatively high amounts of testosterone that males require. If too potent a penetration enhancer is used, the blood stream can be flooded with drug too fast, resulting in "too-much-too-fast" delivery profiles.
• transdermal formulations using less potent or no penetration enhancers can be absorbed into the skin at a more even rate without unsafe spiking.
• penetration enhancers are employed for the instant invention and can be used such that unsafe spiking is avoided while robust and safe delivery is achieved, even in males.
• a portion of the androgen goes directly into the blood stream and a portion of the androgen is absorbed by fatty tissues.
• the invention relates to the safe and effective administration of a transdermal composition
• a transdermal composition comprising an androgen to treat chronic pain, to increase the pain threshold of a subject, and to increase production of endogenous opioid peptides in a subject.
• the composition can also consist essentially of an androgen.
• the invention further relates to administration of a transdermal composition that significantly and uniquely raises serum levels of the androgen (e.g., testosterone) to a level approximating the upper portion of the appropriate reference range.
• the invention also relates to administration of an androgen composition as the primary therapy to patients that are either undergoing exogenous opioid treatment as an adjunctive therapy, as well as administration of the androgen composition to patients who are not undergoing concurrent exogenous opioid therapy.
• other compounds such as, but not limited to, antidepressants can also be administered as an adjunctive therapy to the primary androgen therapy.
• the formulation chosen would improve clinical symptoms of androgen deficiency, pain, and/or distress without causing either unsafe clinical symptoms of androgen excess or an ineffective androgen administration.
• the transdermal gel formulation has advantages over current methods, as well as transdermal patch methods, that include 1) steady state within about 24 hours, 2) even delivery over each daily 24 hour period with once-a-day dosing and without over-shooting the upper limit of the reference range, 3) avoidance of delivering too-much-drug-too-fast and the resultant unsafe serum spiking profile over each 24 hour period of time, 4) avoidance of first pass metabolism effect, 5) avoidance of skin irritation seen with some other gels and with the patch, 6) all of which optimize safety and efficacy with respect to raising serum testosterone levels significantly above baseline levels, and with respect to achieving significant clinical efficacy in reducing inflammatory pain or increasing the pain threshold or increasing endogenous opioid peptides without evidence of androgen excess or harmful clinical side effects.
• the androgen can be administered transdermally, orally (as an immediate release tablet or capsule, an orally disintegrating tablet or capsule, and enterically coated tablet or capsule, and a delayed release tablet or capsule, or a form of an androgen as a prodrug), by injection (intramuscular, intraperitoneal, intravenous, or subcutaneous); by buccal
• the bioactive androgen can be formulated with a pharmaceutically acceptable carrier.
• a pharmaceutically acceptable carrier include, but are not limited to, saline, buffered saline, dextrose, water, glycerol, ethanol, and combinations thereof.
• the term specifically excludes cell culture medium.
• pharmaceutically acceptable carriers include, but are not limited to pharmaceutically acceptable excipients such as inert diluents, disintegrating agents, binding agents, lubricating agents, sweetening agents, flavoring agents, coloring agents and
• Suitable inert diluents include sodium and calcium carbonate, sodium and calcium phosphate, and lactose, while corn starch and alginic acid are suitable disintegrating agents.
• Binding agents may include starch and gelatin, while the lubricating agent, if present, will generally be magnesium stearate, stearic acid or talc. If desired, the tablets may be coated with a material such as glyceryl monostearate or glyceryl distearate, to delay absorption in the gastrointestinal tract.
• the formulation can include, but is not limited to, the androgen, a penetration enhancer or excipient, an emulsifier, a gelling agent; a lubricant, a thickening agent, a solvent or co-solvent, emollient, humectant, protein stabilizer, moisturizer, crystallization inhibitor, neutralizing agent, a buffer, an alcohol, and water.
• the formulation and routes of administration will be evident to one of skill in the art such that, upon administration of the bioactive androgen, both safe and effective serum levels of androgen are obtained.
• the androgen compositions of the invention will generally be provided in sterile aqueous solutions or suspensions, buffered to an appropriate pH and isotonicity.
• Suitable aqueous vehicles include Ringer's solution and isotonic sodium chloride.
• Aqueous suspensions according to the invention may include suspending agents such as cellulose derivatives, sodium alginate, polyvinylpyrrolidone and gum tragacanth, and a wetting agent such as lecithin.
• Suitable preservatives for aqueous suspensions include ethyl and n-propyl p-hydroxybenzoate.
• androgen therapy provides a useful means for alleviating unresolvable pain, both acute and chronic.
• Chronic pain is defined by neurologists as pain lasting three months or longer. Chronic pain is particularly debilitating, and can be diffuse or localized. Acute pain, or pain lasting less than three months, can likely also be treated with androgen therapy, as long as the acute pain is associated with a concurrent androgen deficiency or symptoms of androgen deficiency.
• An acute pain appropriate for treatment would likely be related to an unresolvable stress or state of distress and/or an abnormally low threshold of pain.
• the androgen administered as the primary pain therapy is testosterone, an active metabolite of testosterone such as dihydro testosterone or androstenedione or a testosterone derivative such as methyltestosterone, testosterone enanthate or testosterone cypionate.
• testosterone an active metabolite of testosterone
• a testosterone derivative such as methyltestosterone, testosterone enanthate or testosterone cypionate.
• available pharmacologic preparations of androgens believed to be useful in this invention include, but are not limited to danazol, fluoxymesterone, oxandrolone, methyltestosterone, nandrolone decanoate, nandrolone phenpropionate, oxymethalone, stanozolol, methandrostenolone, testolactone, pregnenolone and
• DHEA dehydroepiandrosterone
• FIGS. 3A-3B show the proposed metabolic pathway for testosterone in relation to nociception. Other bioactive androgens may also be employed in the treatment of chronic pain.
• Figs. 3A-3B show the hypothesized metabolic pathway in normal subjects and subjects with chronic pain.
• FIG. 3 A shows that, in normal individuals, a painful/stressful stimulus upregulates Substance P in nociceptive relay neurons and concurrently serotonin levels drop. This is consistent with a loss of feeling of well-being.
• Substance P in turn has been found to stimulate aromatase, which allows for the conversion of testosterone to estradiol within the central nervous system, with subsequent upregulation of opiates and/or enkephalinergics and other pain dampening mediators, with consequent dampening of pain and Substance P.
• aromatase which allows for the conversion of testosterone to estradiol within the central nervous system, with subsequent upregulation of opiates and/or enkephalinergics and other pain dampening mediators, with consequent dampening of pain and Substance P.
• FIG. 3B subjects with deficient levels of testosterone are predicted to have a frustrated cycle in which aromatase fails to convert testosterone to estradiol due to the deficiency of androgen, leading to insufficient induction of opiate peptides and/or other mediators to dampen Substance P and nociceptive signals, resulting in abnormal chronic, diffuse, widespread pain, as well as wind-up exacerbation of pain and clinical states of distress.
• testosterone metabolism is stepped up as a mechanism to cope with and overcome pain.
• androgens such as testosterone, are depleted, which they are under conditions of stress (Opstad, J., 2002, 74: 99-204), then the body's pain-fighting mechanisms break down.
• Androgen therapy can thus break this frustrated cycle, and alleviate both acute and chronic pain that is exacerbated with androgen deficiency, or symptoms of androgen deficiency.
• the distinct difference between fibromyalgia and the chronic inflammatory pain states in the present invention is evidenced by 1) the different and non-overlapping types of clinicians who normally treat the two types of pain, 2) distinct differences in DSM diagnostic criteria, 3) distinct differences in the genesis of chronic pain and their etiologies (fibromyalgia muscle tender point pain is known to be uniquely noninflammatory), and 4) distinct differences in symptoms and clinical treatments.
• an expert knowledgeable in the treatment of chronic inflammatory pain would not think to utilize androgen gel therapy for a chronic inflammatory pain state. This is underscored by the fact that androgen therapy is not currently used to treat any chronic inflammatory pain states in the clinic.
• the present invention offers a unique and distinct indication and treatment method.
• the afore-mentioned study shows that a transdermal androgen gel formulation can be used to significantly raise the serum levels of testosterone in women with fibromyalgia safely and in a clinically effective way.
• testosterone was formulated as a gel and used to treat women with low androgen levels.
• Pharmacokinetic analysis of the serum testosterone concentration data from these testosterone gel treated patients revealed that mean serum total and free testosterone concentrations were significantly increased from levels in the lower half of the reference range to levels in the upper portion of the reference range in response to therapy.
• Mean serum concentrations were increased quickly, within a few hours, with steady state being reached within 24 hours, with no unsafe spiking, and maintained to the end of the 28 day time course. Thus, in response to therapy, these increased serum levels equilibrated at steady state and remained at safe levels.
• Tender point examinations (a test designed specifically to measure fibromyalgia-related symptoms) were administered by a qualified rheumatologist experienced in and knowledgeable about the criteria specified by the American College of Rheumatology. It is noted that these patients saw a rheumatologist, rather than a neurologist. A chronic inflammatory pain patient would see a neurologist who has different training and skill sets to treat this condition.
• the strong clinical safety profile included the following components: 1 ) normal cardiac function, liver function and kidney function after blood panel assessment, 2) clinical assessment showing maintenance of good overall general health in the study patients, 3) no adverse events attributable to the treatment, and 4) no clinical evidence of androgen excess such as hirsutism or unhealthy change in cardiovascular parameters. Others have shown that androgen excess in women, for example female-to-male transgender patients, readily have these symptoms of androgen excess.
• male formulations by necessity, require excipients or skin permeation enhancers to quickly and effectively deliver the large bolus of androgen that men require for effective clinical treatment.
• male gel formulations can deliver a bolus of too much testosterone too fast, overwhelming biologic pathways that are uniquely different in female androgen physiology.
• Such gels can inherently have properties such that they may either be used at too low a volume of gel in order to maintain safety and avoid overshooting the female reference range, or they can be used at an unsafe and too high a volume in order to maintain clinically effective delivery of drug after the early peak of high serum levels, i.e., during the second half of the 24 hour delivery profile when levels are too low to maintain efficacy over the entire 24 hour period.
• Example 1 offers proof of concept that women with decreased androgen levels can receive a transdermal testosterone gel formulation, with a delivery profile designed uniquely appropriate for women that avoids the inherent pitfalls associated with the usage of a male testosterone gel formulation in women.
• Clinical studies in two different types of patients will be conducted in the future to confirm the effectiveness of androgen therapy to 1) alleviate pain and 2) increase the threshold of pain. Specifically, patients will be examined for reductions in chronic pain and modulation of pain threshold following an improvement in serum androgen levels.
• the initial drug delivery vehicle will be a gel formulation using a transdermal delivery system androgen that will result in safe and effective serum levels. After initial treatment, serum levels will be
• Pain patients will be categorized by gender and may include, but are not limited to, cancer patients, post-surgical patients, accident victims, combat veterans, patients with neuropathy, hyperalgesia, allodynia, depression, and rheumatologic/autoimmune disorders. These subsets of patients will also be stratified by assessment of their clinical symptoms of androgen deficiency. Blood will be taken by venipuncture at the start of treatment and again at each of several specific time points in the study for each of the patient groups. Androgen levels will be determined by a laboratory expert in handling clinical trial samples and testing hormone levels in humans.
• a Visual Analog Scale (VAS) pain perceived assessment test is an example of such a test. Blood will be drawn at a common time of day, preferably the peak time for androgens, at 8 AM, after fasting since midnight. Other testing might include total serum hormone levels, free serum hormone levels, serum binding globulins, serum estradiol levels, evaluations of cardiac health, kidney function and liver function, physical function, psychological function, and metrics for restorative sleep. The study physicians will also complete a Physician's Form. Results will be stratified by androgen serum levels and symptoms of androgen deficiency.
• Example 2 To assess their symptoms and level of pain in a quantitative manner, similar at least in part to Example 1 , to demonstrate efficacy of testosterone therapy in treating pain. Conventional statistical analysis will be applied.
• Patients will be pain threshold-tested or challenged using any of a number of methods, including but not limited to the following: validated motor functional limitations testing coupled with pain assessment (Mannerkorpi et al., 1999 Arthritis Care and Research, 12: 193), application of pressure to specific susceptible tender points of the skin by a dolorimeter coupled with VAS pain scoring (standard rheumatologic assessment technique), or the application of controlled increases in pressure stimuli by hydraulic piston to the left thumbnail coupled with VAS pain scoring (Gracely et al., 2002 Arthritis & Rheumatism 46: 1333).
• Additional methods of evaluating pain and discomfort may include, in addition to the previous pain threshold testing, the SF-36 Health Survey, metrics for physical function and psychological function, and/or other similar validated instruments and metrics.
• an open label population study will be conducted in patients with one of many longstanding stressors, whose testosterone levels are shown to be in the lower half of the appropriate reference range, and whose pain threshold is low. Androgen therapy will then be utilized to safely and effectively increase the patient's testosterone level to show significant improvement in the low pain threshold.

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