METHODS AND COMPOSITIONS FOR TREATING DISTRESS DYSFUNCTION AND ENHANCING SAFETY AND EFFICACY

OF SPECIFIC MEDICATIONS

 

Field of Invention

The present invention relates to methods and compositions for reducing Distress Dysfunction by restoring and maintaining homeostatic balance in the neurotransmitter systems underlying the Stress Response and the experience of pain and hedonic tone.  Distress Dysfunction refers to the experience of dysfunctional emotional and physical distress that interferes with the individual’s quality of life and functioning.  While there are a wide variety of emotional and physical manifestations of this negative hedonic tone, it is often experienced as unwarranted and/or exaggerated fear, anger, anxiety, depression, cravings, addiction, hyperalgesia, and distressing physical discomfort and pain. This invention reduces dysfunctional emotional and physical distress by the co-administration of agents from four classes of agents that, together, improve, restore, and maintain homeostatic balance in the Stress Response, particularly the endogenous opioid, serotonin, dopamine, glutamate, norepinephrine, glutamate, and epinephrine neurotransmitter systems.  This invention teaches the surprising and dramatic synergistic reduction of emotional and physical distress that results from the combination of at least one agent from Class I with at least one agent from Classes II and/or III and/or IV, such that the combination is more effective for the reduction of emotional and/or physical symptoms of distress than the agents administered alone.  This invention also teaches that these novel formulations can be used to synergistically potentiate the therapeutic benefit of various medications, in surprising and dramatic ways, including analgesics, stimulants, and anti-depressant drugs and medications for respiratory and sexual disorders as well as for the reduction of distress symptoms (“side effects”) produced by these medications.  In this way, novel pharmaceutical formulations have been discovered for the treatment of a wide variety of Distress Dysfunctions as well as respiratory disorders, such as COPD and asthma.

 

Class I agents, including ultra-low-dose opioid antagonists and GM1 ganglioside blockers, such as neuramindase inhibitors, switch and rebalance the mode of endogenous opioid receptors, and potentially other stress-related neurotransmitter receptors, from protracted excitatory signaling to homeostatic basal inhibitory signaling (Receptor Switchers). Class II agents, such as cyclic AMP phosphodiesterase (PDE) inhibitors, particularly specific cAMP PDE-4 inhibitors, excitatory aminio acids, and endogenous opioid reuptake inhibitors (EORI), enhance and prolong the release of endogenous opioids, i.e., endorphins (Endorphin Enhancers).  Class III agents are exogenous opioid agonists (full, partial, mixed), such as tramadol, morphine and oxycodone, which function like endogenous opioids and bind to opioid receptors, triggering inhibitory and excitatory signaling (Exogenous Opioids). Class IV agents, including non-opioid analgesics, such as non-steroidal anti-inflammatory drugs (NSAID) and acetaminophen, selective serotonin reuptake inhibitors (SSRI), inhibitory serotongeric and adrenergic agents, selective norepineprhine reuptake inhibitors (SNRI), amphetamines, specific amino acids, vitamins and minerals, enhance the production, release, and functioning of neurotransmitters in the opioid, serotonin, dopamine, glutamate, norepinephrine, and epinephrine systems  and have synergistic interactions with the endogenous opioid system (Synergistic Enhancers).  Certain agents, such as ultra-low-dose naltrexone (Class I and IV) and tramadol (Class III and IV), have multiple class functions, making them particularly effective in these cotreatment formulations.

 

This invention teaches that dysfunctional emotional and physical distress and pain is more effectively reduced, calm and well being is enhanced, and healthy homeostatic neurotransmitter balance is better maintained when at least one agent from Class I agents is combined with at least one agent from Classes II and/or III and/or IV, as compared to the administration of the agents from each class alone. Furthermore, this invention teaches that the tendency of Class II and III agents to produce Distress Dysfunction symptoms, such as hyperalgesia, tolerance and dependence, are reversed when combined with one or more Class I agents. Therefore, this invention teaches the surprising discovery of an entire new set of pharmaceutical formulations for the remarkably safe and effective treatment of a wide variety of Distress Dysfunctions, including anxiety, depression, anger, pain, addiction, eating disorders, gastrointestinal disorders, and sexual disorders.  In addition, this invention teaches the surprising discovery that the administration of one of these novel formulations can be used to synergistically potentiate the therapeutic benefit and reduce the dysfunctional distress (“side effects”) caused by a variety of drugs and medications, such as analgesics, anti-anxiety, anti-depressants, and stimulants.  Finally, this invention teaches the surprising discovery of a new set of pharmaceutical formulations for the treatment of respiratory disorders that combine certain Class I agents, such as ultra-low-dose naltrexone (ULDN) and n-acetyl-cysteine (NAC), with certain Class II agents, such as roflumilast and theophylline, such that the therapeutic benefits and/or side effect profile of the cotreatment formulation are improved as compared to the use of these drugs alone.

 

Definitions.

1. HOMEOSTASIS means the tendency of an organism to actively regulate its internal conditions, usually by a system of feedback controls, so as to stabilize health and functioning, regardless of the changing conditions, as well as the ability of the body to actively seek and maintain a condition of equilibrium or stability within its internal environment when dealing with external changes.
2. POSITIVE HEDONIC TONE means a positive sense of well-being, happiness, pleasure and contentment.
3. NEGATIVE HEDONIC TONE means the diminution of happiness, pleasure, and contentment, and is typically associated with the experience of emotional and/or physical distress and alert.
4. HEDONIC TONE HOMEOSTASIS means the tendency of the opioidergic, serotonergic, dopaminergic and related neurotransmitter systems to maintain positive hedonic tone, when adaptive, and to restore positive hedonic tone following stressful conditions and stimuli, which may acutely produce negative hedonic tone.
5. DISTRESS means emotional and/or physical pain or suffering affecting the body, behavior, and/or the mind.
6. DISTRESSING PAIN means an exaggerated emotional and physical reaction to perceived or anticipated danger or harm, which typically includes hyperalgesia and dysfunctional hypersensitivity to perceived or real injury.
7. DISTRESS DYSFUNCTION means a constellation of conditions, symptoms, and disorders, whether (a) the result of an endogenous condition or (b) the result or side effect of an exogenous medication, drug, or other agent, wherein a component thereof is the presence of one or more of the following:   (a) signs or symptoms of distress (and/or a diminution of happiness, pleasure, contentment and a positive sense of well being), which interferes with an individual’s quality of life and functioning, or (b) unpleasant or deleterious side effects of a medication, drug, or other agent, which may, or may not, interfere with its potential therapeutic benefits. Distress Dysfunction includes, but is not limited to, the following conditions, symptoms and/or disorders:  (1) Anxiety Disorders, including, but not limited to, Panic Disorders, Agoraphobia, Specific Phobias, Social Phobias, Obsessive-Compulsive Disorder, Post-Traumatic Stress Disorder, Acute Stress Disorder, Generalized Anxiety Disorder, Substance-Induced Anxiety, Anxiety Related to Medical Disorders, Anxiety Disorder Not Otherwise Specified (NOS), as well as signs and symptoms of anxiety, stress, agitation, and worry that are not classified as an Anxiety Disorder; (2) Mood Disorders, including, but not limited to, Depressive Disorders, Dysthymic Disorder, Bipolar I Disorder, Bipolar II Disorder, Bipolar Disorder NOS, Cyclothymic Disorder, Mood Disorders Related to Medical Conditions, Seasonal Affective Disorder, Mood Disorders NOS, as well as signs and symptoms of depressed mood, anhedonia, despair, anhedonia, hypomania, mania, and negative hedonic tone that are not classified as a Mood Disorder; (3) Somatoform Disorders, including, but not limited to, Somatization Disorder, Somatoform Disorder, Conversion Disorder, Pain Disorder Associated with Psychological Factors, Pain Disorder Associated with Medical Conditions, Hypochondriasis, Body Dysmorphic Disorder, and Somatoform Disorder NOS; (4)  Factitious Disorders, including but not limited to, Factitious Disorders with Psychological Signs and Symptoms, Factitious Disorders with Physical Signs and Symptoms Factitious Disorders with Combined Psychological and Physical Signs and Symptoms, and Factitious Disorder NOS; (5) Dissociative Disorders; (6) Sexual Dysfunction, including, but not limited to, Sexual Desire Disorders, Sexual Arousal Disorders, Orgasmic Disorders, Premature Ejaculation, Erectile Dysfunction, Sexual Pain Disorder, Sexual Dysfunction to a General Medical Condition, Substance-Induced Sexual Dysfunction, Sexual Dysfunction NOS, as well as signs and symptoms of sexual dissatisfaction and dysfunction that are not classified as a Sexual Dysfunction disorder; (7) Eating Disorders, including, but not limited to, Bulimia Nervosa, Anorexia Nervosa, Binge Eating, Eating Disorder NOS, as well as signs and symptoms of eating and appetite problems that are not classified as an Eating Disorder; (8) Gastrointestinal Disorders, including, but not limited to, Irritable Bowel Syndrome (IBS) with Predominately Diarrhea, IBS with Predominately Constipation, and IBS Mixed Type, Crohn’s Disease, as well as GI distress including, but not limited to, nausea, vomiting, diarrhea, constipation, and bloating; (9) Pre-Menstrual Syndrome (PMS) and other hormonally-related distress signs and symptoms; (9) Movement Disorders, including, but not limited to, Restless Leg Syndrome; (10) Fibromyalgia; (11) Sleep Disorders, including, but not limited to, Insomnia, Dyssomnias  Parasomnias as well as signs and symptoms of sleep problems that are not classified as a Sleep Disorder; (12) Impulse-Control Disorders, including, but not limited to, Intermittent Explosive Disorder, Kleptomania, Pyromania, Pathological Gambling, Trichotillomania, Impulse Control Disorder NOS as well as signs and symptoms of impulsivity that are not classified as an Impulse-Control Disorder; (13) Psychological Factors Affecting Medical Conditions; (14) Medication-Induced Movement Disorders; (15) Alcohol-Related Disorders, including, but not limited to, Alcohol Dependence, Alcohol Abuse, Alcohol Addiction, Alcohol-Induced Disorders, Alcohol-Related Disorder NOS as well as alcohol-related problems that are not classified as an Alcohol-Related Disorder; (16) Opioid-Related Disorders, including, but not limited to, Opioid Dependence, Opioid Addiction, Opioid Abuse, Opioid-Induced Disorders, Opioid-Related Disorder NOS, as well as opioid-related problems that are not classified as an Opioid-Related Disorder;  (17) Caffeine-Related Disorders, including, but not limited to, Caffeine Dependence, Caffeine Addiction, Caffeine Abuse, Caffeine-Induced Disorders, Caffeine-Related Disorders NOS as well as caffeine-related problems that are not classified as a Caffeine-Related Disorder; (18) Cannabis-Related Disorders, including, but not limited to, Cannabis Dependence, Cannabis Addiction, Cannabis Abuse, Cannabis-Induced Disorders, and Cannabis-Related Disorder NOS; (19) Amphetamine (or Amphetamine-Like)-Related Disorders, including but not limited to, Amphetamine Dependence, Amphetamine Addiction, Amphetamine Abuse, Amphetamine-Induced Disorders, and Amphetamine-Related Disorder NOS; (20) Cocaine-Related Disorders, including, but not limited to, Cocaine Dependence, Cocaine Addiction, Cocaine Abuse, Cocaine-Induced Disorders, and Cocaine-Related Disorder NOS; (21) Nicotine-Related Disorders, including, but not limited to, Nicotine Dependence, Nicotine Addiction, Nicotine Abuse, Nicotine-Induced Disorders, and Nicotine-Related Disorder NOS; (22) Inhalant-Related Disorders, including, but not limited to, Inhalant Dependence, Inhalant Addiction, Inhalant Abuse, Inhalant-Induced Disorders, and Inhalant-Related Disorder NOS; (23) Phencyclidine-Related Disorders, including, but not limited to, Phencyclidine Dependence, Phencyclidine Addiction, Phencyclidine Abuse, Phencyclidine-Induced Disorders, and Phencyclidine- Related Disorder NOS; (24) Sedative-, Hypnotic-, or Anxiolytic-Related Disorders, including, but not limited to, Sedative-, Hypnotic-, or Anxiolytic Dependence, Addiction, and/or Abuse, Sedative-, Hypnotic-, or Anxiolytic-Induced Disorders, and Sedative-,Hypnotic-, or Anxiolytic-Related Disorder NOS; (25) Polysubstance-Related Disorders;(26)  Pervasive Developmental Disorders, including, but not limited to, Autism Disorder, Rhett’s Disorder, Aspberger’s Disorder, or Pervasive Developmental Disorder NOS; (27) Attention-Deficit and Disruptive Behavior Disorders, including, but not limited to Attention-Deficit/Hyperactivity Disorder, Conduct Disorder, Oppositional Disorder, Disruptive Behavior Disorder NOS as well as attentional and concentration problems that are not classified as an Attention-Deficit Disorder; (28) Chronic Fatigue Disorder, (29) Psychotic Disorders, (30) Behavioral addictions, compulsions, and dysfunctions, including, but not limited to, sex, pornography, gambling, shopping, eating, drinking, smoking, computer use, and cleaning, (31) Pain disorders, including, nociceptive, neuropathic, migraine and psychogenic pain, (32)  Psychotic disorders, including, but not limited to, schizophrenia; (33) Unpleasant or deleterious side effects of CLASS II,III, or IV agents when such agents are administered alone (i.e., without co-administration with an CLASS I agent) which may, or may not, interfere with the potential therapeutic benefits of CLASS II, III, or IV agents, including, but not limited to PDE inhibitors, opioid and non-opioid analgesics, stimulants, SSRIs, SNRIs, and amino acids; (34) Respiratory, inflammatory, and pain disorders including, but not limited to, asthma and COPD; (35) Allergic and non-allergic glutamate and mono-sodium glutamate related disorders, including “Chinese Food Syndrome”, and (36) Emotional and physical malaise, distress, discomfort, pain, restlessness, irritability, worries, cravings, compulsions, obsessions, agitation, addictions, and other related complaints and signs of protracted negative hedonic tone that may, or may not, be part of a traditional medical or psychiatric disorder. Distress Dysfunction is not limited to these conditions and diagnoses and is best defined by a variety of symptoms, conditions, syndromes, and disorders, characterized by dysfunctional emotional and physical distress and pain.
8. CLASS I AGENTS:  RECEPTOR SWITCHERS means an exogenous agent that blocks opioid excitatory receptor signaling, thereby switching protracted excitatory mode to homeostatic basal inhibitory mode.  CLASS I agents are functionally defined such that, when co-administered with CLASS II, III, and/or IV agents, reduce and/or resolve Distress Dysfunction symptoms.  CLASS I agents include, but are not limited to:  ultra-low-dose and very-low-dose opioid antagonists, ultra-low-dose and very-low-dose naltrexone, naloxone, diprenorphine, nalmefene, and norbinaltorphimine, agents that inhibit synthesis or activity of GM1 ganglioside, neuraminidase inhibitors, magnesium sulfate, chondroitin sulfate, sodium sulfate, n-acetyl-cysteine (NAC), oseltamivir, zanamivir, laninamivir, peramivir,, scutellaria, and 5,7,4′-trihydroxy-8-methoxyflavone.
9. CLASS II AGENTS:  ENDORPHIN ENHANCERS means an exogenous agent that directly or indirectly enhances the production, release and/or functioning of endogenous opioids, i.e., endorphins, and/or inhibits their reuptake. CLASS II agents are functionally defined such that, when co-administered with CLASS I agents, they reduce and/or resolve Distress Dysfunction symptoms.  CLASS I agents include, but are not limited to, cyclic adenosine monophosphate (cAMP) phosphodiesterase inhibitors (PDE-I) or agents that directly enhance cAMP, a cAMP phosphodiesterase (PDE) inhibitor, an agent that directly enhances cAMP, a specific or non-specific cAMP PDE inhibitor, a specific cAMP PDE-4 inhibitor, theophylline, roflumilast, ibudilast, cilomilast, ardenafil, tadalafil, sildenafil, zaprinast, rolipram, methylxanthine, milrinone, inamrinone, cilostazol, caffeine, forskolin, excitatory amino acids, a salt of an excitatory amino acid, all forms of excitatory amino acids, glutamic acid, aspartic acid, glutamine, mono-sodium glutamate (MSG), and N-methyl-D-asparate (NMDA), phenylalanine, and dl-phenylalanine (DLPA).
10. CLASS III AGENTS:  EXOGENOUS OPIOIDS means exogenous        agents that activate and/or bind with opioid receptors, triggering inhibitory and/or excitatory signaling. CLASS III agents include, but are not limited to, exogenous opioid agonists (full, partial, mixed), tramadol, morphine, oxycodone, hydrocodone, papaverine, codeine, dihydrocodeine, fentanyl, hydromorphone, buprenorphine, butorphanol, methadone, alfentanil, levorphanol, meperidine, nalbuphine, oxymorphone, pentazocine, pentazocine, propoxyphene, remifentanil, and sufenta.
11. CLASS IV AGENTS:  SYNERGISTIC ENHANCERS means exogenous agents that have a synergistic effect with the endogenous opioid system.  CLASS IV agents are functionally defined such that, when co-administered with CLASS I agents, they reduce and/or resolve Distress Dysfunction symptoms.  The addition of CLASS II and/or III agents may further enhance the therapeutic effects of a combination of CLASS I and IV agents.  CLASS IV agents include, but are not limited to, agents that support the functioning, production and release of endogenous opioid, serotonin, dopamine, epinephrine, norepinephrine, and glutamate neurotransmitters, non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, white willow bark, acetylsalicylic acid, salicin, ibuprofen, naproxen, ketoprofen, indomethacin, fenoprofen, tolmetin, sulindac, meclofenamate, piroxicam, flurbiprofen, diclofenac, stimulants, selective serotonin reuptake inhibitors (SSRI), serotonin agonists, antagonists and modulators, selective norepinephrine reuptake inhibitors (SNRIs), citalopram, dapoxetine, escitalopram, fluoxetine fluvoxamine, paroxetine, sertraline, fluvoxamine, zimelidine, dapoxetine, alosetron, ondansetron, granisetron, bemesetron, eplivanserine, deramciclane, agomelatine, elazasonan, pruvanserin, asenapine, zomari, valazodone, bifeprunox, buspirone, ritanseron, geperone, paliperidone, clomipram, doxepin, haloperidol, risperidone, amino acids, a salt of an inhibitory amino acid, all forms of  amino acids, gamma-aminobutrynic acid (GABA), glycine, taurine, tryptophan, 5HTP,phenylalanine, dl-phenylalanine (DLPA), valine, threonine, methionine, lysine, leucine, isoleucine, tyrosine, alanine, arginine, histidine, serine, selenocfysteine, proline, glycine, cysteine, aspargine, alanine, L-DOPA, vitamins and minerals, luteolin, quercetin, qercetin-3-O-methylether (3-MQ, 2), quercetin-3,7,4′-O-trimethylether, ayanin, quercetin-3,7,3′,4′-O- tetramethylether, quercetin-3,5,7,3′,4′-O-petamethylether, quercetin-3,5,7,3′,4′-O-pentaacetate, quercetin-3-O-methyl-5,7,3′,4′-O-tetraacetate, methylcobalamin, vitamin C, vitamin D, vitamin D-3,, vitamins B1, B2, B3, B6, and B12, folic acid, niacin, or niacinamide, folinic acid, calcium folinate, methylcobalamin, pyridoxal-5′-phosphate (P5P), alkaloids, flavonoids, and saponins, hesperetin, hesperidin, naringin, naringenin, epigallocatechin-3-gallate (EGCG), dioclein, genistein, daidzein, eriodictyol, prunetin, biochanin A, apigenin, myricetin, liquiritigenin, liquiritin, kaempferol, isoliquiritigenin, chrysin, rutin, cyanidin, delphinidin, pelargonidin, isorhamnetin, vitamin C, St. John’s Wort, passion flower, hyperforin, hypericin, biotin, vitamin B5 (pantothenic acid), magnesium, alpha-ketoglutarate, copper, zinc, L-theanine, iron, california poppy, ginseng (Panax spp.), licorice, night-blooming cereus (Selenicereus grandiflorus; Cactus grandiflorus), hordenine, nutmeg, myristicin, tyramine, scotch broom, green tea, ephedra, and yohimbe.

12. The terms defined above are used herein in the singular and plural as context indicates.

 

 

Summary of Invention

A basic understanding of the bimodal nature of endogenous opioid modulation of pain, distress, and hedonic tone can elucidate the potential neurophysiological mechanisms underlying the surprising and synergistic methods and compositions taught by this invention.  The following description, along with the accompanying diagrams contained in the Appendix, depict what we believe are the complex, subtle, and interrelated biochemical and physiological mechanisms underlying our novel pharmaceutical formulations.  While further research may either clarify or modify these explanations and diagrams, the remarkable efficacy and safety of the novel methods and composition taught by this invention to restore healthy functioning and treat the conditions and disorders, as described in this patent, are the essential teaching of this invention, regardless of the precise mechanisms underlying their therapeutic benefits.

 

Living organisms have a fundamental survival-based coping response to stressors.  There is evidence to suggest that receptors in the stress response neurotransmitter systems, especially the endogenous opioid system, are generally maintained in a basal inhibitory mode.  As a result, as long as there is no perceived danger or threat, the release of neurotransmitters, such as endogenous opioids, i.e., endorphins, trigger inhibitory signaling, minimizing pain and distress signaling.  Through synergistic processes, complex endorphinergic, serotonergic, dopaminergic, epinephrinergic, glutaminergic, and norepinephringeric interactions produce a positive hedonic tone, including a sense of calm and well being.

 

Acute injury or stress triggers acute reflexive pain signals mediated by non-opioid systems, leading to the adaptive reflexive experience of immediate pain and distress.  Simultaneously, acute injury or stress set opioid receptors in the excitatory mode and endogenous opioids (i.e., endorphins) are released.  The endogenous opioids bind with the opioid receptors, triggering excitatory signaling. Through G_s, excitatory signals enhance the release of cAMP, which by increasing Protein Kinase A (which increases Ca² conductance and decreases K⁺ conductance), excites pain-sensory neurons that trigger the sensation of pain as well as increased sensitivity toward pain (hyperalgesia).  The increased cAMP also enhances the release of endogenous opioids, maintaining the pain and distress cycle.  Through complex endorphinergic, serotonergic, dopaminergic, epinephrinergic, glutaminergic, and norepinephringeric interactions, a negative hedonic tone, characterized by a systemic state of alert including physical and emotional distress, leads the organism to an extended adaptive response to the noxious stimuli. However, as soon as the acute danger is reduced, in part as a result of an adaptive response to pain and distress, the opioid receptors are switched to inhibitory mode.  The endogenous opioids then trigger inhibitory signaling and, through G_o, (which decreases Ca²⁺ conductance and increases K⁺ conductance), inhibit pain-sensory neurons, which triggers reduced sensation of pain and produces analgesia.  At the same time, the opioid receptor inhibitory signaling, through G_i, inhibits cAMP, which, in turn, reduces endogenous opioids, which tunes down the entire endogenous opioid pain response system.  Again, through complex endorphinergic, serotonergic, dopaminergic, epinephrinergic, and norepinephringeric interactions, positive hedonic tone is restored, leading to a sense of calm and well being. In this way, normal healthy homeostatic balance is maintained within the bimodal opioid receptors and neurotransmitters as well as among the endorphinergic, serotonergic, dopaminergic, epinephrinergic, and norepinephringeric systems.

 

For a variety of reasons, this homeostatic stress response system can become imbalanced and dysfunctional.  Chronic or particularly intense physical and emotional stress and injury, drug and alcohol use, a variety of medications and chemicals, particularly exogenous opioids and cAMP enhancers, such as PDE inhibitors and excitatory amino acids, GM1 ganglioside, congenital vulnerabilities, and certain medical conditions can impair healthy homeostatic functioning of this system.  These factors can overwhelm the stress response system, leading neurotransmitter receptors to remain in a protracted excitatory mode, and neurotransmitter levels, such as endorphins, to be chronically diminished.  In this condition, endogenous opioids trigger mostly excitatory signaling, which results in chronic pain and hyperalgesia.  Any factor that triggers the release of endogenous opioids, including injury or stress and even reward states and various drugs, can potentiate pain.

 

While under some conditions, this constant state of alert and distress may be adaptive such as when physical and/or emotional survival is chronically at risk.  However, in most situations this protracted excitatory signaling of distress is maladaptive.   This protracted condition effectively “resets” the organism’s homeostatic basal condition from positive hedonic tone to varying degrees of negative hedonic tone by triggering homeostatic processes in related serotonin, dopamine, and other neurotransmitter systems, which produce a variety of signs and symptoms of emotional and physical distress.  This negative hedonic tone state may be reflected by the experience of anxiety, irritability, depression, cravings, addictive tendencies, and physical distress, including pain, hyperalgesia, and gastrointestinal symptoms.  Protracted opioid receptor excitatory mode conditions are a major component of a wide variety of Distress Dysfunction disorders, syndromes, and symptoms.  Unfortunately, typical coping patterns, including the use of drugs and alcohol, including exogenous opioids, perpetuate and exacerbate protracted excitatory signaling and its negative impact on negative hedonic tone,

 

This protracted state of alert is reflected in the experience of protracted distress manifested by hypervigilance, physical and emotional hypersensitivity, exaggerated perception and feeling of threat, hyperalgesia, distressing pain, impulsivity, irritability and anger, unwarranted fears, anxiety and panic, obsessions and compulsions, agitation, distractibility, concentration and attention impairments, despair and depression, anhedonia, sleeping difficulties, sexual problems, interpersonal conflicts, a sense of danger and that “something is wrong”, as well as desperate cravings for anything that can reduce this protracted distress.  These cravings are often for substances, such as drugs, alcohol, and food, as well as stress-reducing behaviors and situations, such as sexual activity, gambling, and other compulsions, even if inappropriate or ultimately maladaptive, leading to a vicious cycle.  In effect, these cravings, stemming from protracted receptor excitatory signaling, compel the individual toward substances and situations in an attempt to trigger receptor inhibitory signaling.  Unfortunately, increasing release of endorphins, when the receptors are fixed in the excitatory mode, triggers distress signals.  This increase in distress may occur paradoxically in any emotional situation, even when the context is positive, or when drugs and alcohol are consumed to increase neurotransmitter levels.

 

In contrast to nociceptive pain, which is a direct adaptive reaction to real injury, distressing pain is an exaggerated emotional and physical reaction to perceived and anticipated danger, which typically includes hyperalgesia and dysfunctional hypersensitivity to perceived or real injury.  The key is that all of these symptoms are signs of an underlying protracted state of dysfunctional distress, produced by protracted receptor excitatory signaling combined with diminished neurotransmitter levels.  When dysfunctional emotional and physical distress is alleviated, a basal positive hedonic tone and a general sense of emotional and physical well being is restored and the individual is able to realistically experience and respond adaptively to actual stress and injury, including normal nociceptive pain, through normal reflexive pain transmission processes.

 

This protracted state of distress underlies the symptoms suffered by individuals diagnosed with a wide variety of medical, psychiatric and psychological disorders.  Therefore, rather than treat each of these difficulties as different disorders, this invention’s novel approach is the discovery of a method that naturally restores homeostatic balance in the stress response, resolving the common neurophysiological condition that causes the dysfunctional distress.  By switching receptors from a protracted excitatory mode to a basal state of inhibitory signaling, and enhancing sufficient release of neurotransmitters to normal levels, healthy homeostatic balance can be restored.  In this state, a basal sense of calm and well-being is experienced, adaptively reflecting the relatively safe and benign state of the environment.  When stressors occur during healthy homeostasis, an immediate distress signal is triggered, but quickly inhibited as the individual adaptively responds to the situation.  By focusing upon and treating the underlying protracted distress condition, this invention provides a treatment that can safely and effectively reduce and/or eliminate a wide variety of dysfunctional symptoms, conditions, and disorders.

 

This invention describes the discovery of methods and compositions that reduce protracted emotional and physical distress by restoring and maintaining homeostatic balance in the endogenous opioid system as well as homeostatically related neurotransmitter systems.  The fundamental key to this invention is the surprising and remarkably effective synergistic effect that has been discovered when one or more agents that switch opioid receptors from a protracted excitatory mode to a basal inhibitory mode (Receptor Switchers), are combined with one or more agents from three other classes that impact on opioidergic, serotoninergic, dopaminergic, glutamergic, epinephrinergic, and norepinephrinergic neurotransmitter systems.  Receptor Switchers, including ultra-low-dose opioid antagonists, such as ultra-low-dose naltrexone (ULDN) and naloxone, and GM1 ganglioside attenuators, such as neuraminidase inhibitors (e.g., magnesium sulfate and n-acetyl-cysteine), selectively block the opioid receptor excitatory mode. Therefore, protracted excitatory signaling is eliminated, and inhibitory receptor signaling is enhanced. As a result, when endogenous opioids (i.e., endorphins) bind with the opioid receptor, the result is increased inhibitory signaling, producing analgesia and a sense of well being.  These agents have the potential to reverse both acute and protracted excitatory mode imbalances, helping to restore normal homeostatic functioning.  However, since protracted excitatory conditions lead to chronically diminished endogenous opioids, Receptor Switchers alone are typically insufficient to reduce Distress Dysfunction symptoms and to produce analgesia or to restore a sense of well being.

 

Therefore, one class of agents that have remarkable synergy with Receptor Switchers are those that enhance the production, release, or functioning of endogenous opioids (Endorphin Enhancers). Cyclic AMP enhancers, particularly specific cAMP PDE-4 inhibitors, such as roflumilast and ginkgo biloba, as well as, non-specific cAMP PDE inhibitors, such as theophylline and caffeine, enhance the release of cAMP, which, in turn, enhances the release of endogenous opioids (i.e., endorphins). In addition to cAMP PDE inhibitors, less potent cAMP enhancers include excitatory amino acids, such as glutamic acid, as well as forskolin. In addition, endogenous opioid reuptake inhibitors, such as DLPA, both enhance the release of endogenous opioids as well as block the enzymes that reuptake them, provide an enhanced level of endorphins for longer periods of time.  When administered alone, Endorphin Enhancers have the potential for increased inhibitory signaling, but more likely produce excitatory signaling when injuries or stress are present, or when the receptors are set in an excitatory mode, thereby iatrogenically triggering symptoms of Distress Dysfunction, such as pain, hyperalgesia, anxiety, and gastrointestinal symptoms, rather than reducing them.  Unfortunately, most clinical use of these agents is conducted in the treatment of conditions and diagnoses that are, in fact, forms of Distress Dysfunction but heretofore have not been so identified. This mechanism explains the typical side effects seen with these agents.  However, when co-administered with Receptor Switchers, Endorphin Enhancers trigger inhibitory signaling, leading to enhanced and prolonged analgesia and well being. Therefore, combining one or more Receptor Switchers, such as ULDN or NAC, with one or more Endorphin Enhancers, such as roflumilast or ginkgo biloba, creates a remarkable new generation of non-opioid pharmaceutical formulations for the treatment of a wide variety of Distress Dysfunctions, by rebalancing the endogenous opioid system, restoring a basal homeostatic inhibitory mode together with normal levels of endorphins.

 

A second class of agents that has remarkable synergy with Receptor Switchers is exogenous opioid agonists (Exogenous Opioids). Exogenous Opioid agonist drugs (full, partial, mixed), such as tramadol, oxycodone, and morphine, clearly have a dramatic impact on the endogenous opioid system.  Exogenous Opioids act like endogenous opioids, binding with opioid receptors, and their impact depends on the mode of the bimodally-acting opioid receptors.  In a balanced system, their impact initially leads to inhibitory signaling, resulting in analgesia and even a sense of well being.  However, fairly quickly, this increased inhibitory signaling results in a homeostatic balancing response that includes, through cAMP, a reduction in endogenous opioid levels as well as a receptor shift to the excitatory mode.  Over time, this leads to a protracted excitatory receptor mode and diminished endogenous opioid levels, producing chronic pain, hyperalgesia, tolerance, dependence, and addiction as well as emotional and physical distress. These iatrogenic problems are greatly exacerbated when the endogenous opioid system is already in a protracted excitatory mode, resulting more immediately in excitatory signaling, leading to an exacerbation of pain and hyperalgesia, tolerance, as well as negative hedonic mode.  Thus, while often initially therapeutic, Exogenous Opioids can rapidly lead to the development of serious and significant Distress Dysfunction, even long after the Exogenous Opioids are discontinued.

 

However, by administering one or more Receptor Switchers with one or more Exogenous Opioids, excitatory signaling is minimized, resulting in enhanced analgesia as well as a dramatic reduction in protracted excitatory mode conditions, reducing and/or eliminating many of the noxious effects of Exogenous Opioids, including hyperalgesia, tolerance, dependence, addiction, and other side effects.  Therefore, Exogenous Opioids should generally be co-administered with Receptor Balancers in the treatment of Distress Dysfunction conditions, including pain, addiction, anxiety, and depression.  Given the inherent problems with Exogenous Opioids, however, formulations that primarily include Receptor Balancers with Endorphin Enhancers are preferable, thereby utilizing endogenous opioids rather than exogenous opioids that can both interfere with the body’s natural opioid system and, as a result, cause signficiant, undesirable side effects.  However, low-dose Exogenous Opioids can be added to these formulations, with remarkable synergistic effects, for particularly severe and resistant symptoms.  Therefore, this discovery leads to the development of a new generation of remarkably safe and effective pharmaceutical formulations for the treatment of Distress Dysfunctions, including severe chronic pain and addiction, that include the combination of Receptor Switchers, such as ULDN, Endorphin Enhancers, such as roflumilast, and Exogenous Opioids, such as tramadol.

 

A third agent class that has remarkable synergy with Receptor Switchers include a variety of agents have a synergistic effect with the endogenous opioid system through the G_i –mediated metabolic processes that trigger the inhibition of pain-sensory neurons (Synergistic Enhancers). There is evidence to suggest that higher levels of Gi that are produced by enhanced inhibitory signaling potentiate the pain-relieving effects of non-opioid analgesics, such as NSAIDs and acetaminophen.  Therefore, there is a synergistic potentiation produced by the combination of non-opioid analgesics, such as acetaminophen or white willow bark, withReceptor Switchers, such as ultra-low-dose naltrexone or NAC, creating a new generation of enhanced non-opioid analgesics.  These novel formulations can be further potentiated by combining one or more Receptor Receptors, such as ULDN or NAC, together with an Endorphin Enhancer, such as roflumilast or ginkgo biloba, and a Synergistic Enhancer, such as acetaminophen or white willow bark.

 

Similarly, synergistic potentiation occurs with selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), such that increased relief from depression, anxiety, pain, addiction, and other Distress Dysfunctions is produced by the combination of SSRIs and SNRIs, such as escitalopram oxalate and venlafaxine, with Receptor Switchers, such as ULDN or NAC. Therefore, a new generation of enhanced SSRI formulations for depression, anxiety, pain, and addiction are created by this invention. In addition to SSRIs and SNRIs, inhibitory serontonergic and adrenergic agents can function as Synergistic Enhancers.  Specific amino acids that enhance release of serotonin and dopamine, such as tryptophan and 5HTP, can also act as Synergistic Enhancers in these novel cotreatment formulations.

 

Finally, there is evidence to suggest that ULDN has a synergistic effect through this G_i metabolic process in addition to its function as a Receptor Switcher, making ULDN a particularly powerful agent in all cotreatment formulations.  Similarly, certain multi-function agents, such as tramadol, have particularly potent therapeutic effects in these novel pharmaceutical formulations since they function as both Exogenous Opioids and Synergistic Enhancers. [Tramadol has the added advantage of not being listed by the FDA as a controlled substance.] Therefore, given their relative potency in cotreatment formulations, ULDN, tramadol, and roflumilast, are preferred agents in formulations for certain indications.  At the same time, over-the-counter agents, such as NAC, gingko biloba, and white willow bark, would be useful as non-prescription formulations.

 

Therefore, an entirely new generation of pharmaceutical formulations for the treatment of a wide variety of Distress Dysfunctions, has been discovered by the combination of at least one Receptor Balancer together with at least one Endorphin Enhancer, Synergistic Enhancers and/or Exogenous Opioids.  These novel formulations restore homoeostatic balance in the endogenous opioid and related neurotransmitter systems, thereby producing a completely unexpected and dramatic reduction in a wide range of distress-related symptoms including hypervigilance, physical and emotional hypersensitivity, exaggerated perception and fears of threat, distressing pain, impulsivity, irritability and anger, unwarranted fears, anxiety and panic, obsessions and compulsions, agitation, distractibility, concentration and attention impairments, despair and depression, anhedonia, sleeping difficulties, sexual problems, interpersonal conflicts, a sense of danger and that “something is wrong”, as well as desperate cravings for anything that can reduce this protracted distress, including substances, such as drugs, alcohol, and food, and stress-reducing behaviors and situations, such as addictions and compulsions.  By reducing protracted emotional and physical distress, these cotreatment formulations produce a positive basal hedonic tone, providing a general sense of well-being and satisfaction, thereby reducing and/or eliminating dysfunctional compulsive and addictive behaviors as well. An adaptive response to stressors, including painful stimuli, is maintained, but the maladaptive distress reactions are reduced and/or eliminated.

 

This invention also teaches that formulations that contain Receptor Balancers (e.g., ultra-low-dose opioid antagonists and/or neuraminidase inhibitors) alone, or in combination with Endorphin Enhancers (e.g., PDE inhibitors or excitatory amino acids) and/or Synergistic Enhancers (e.g., amino acids)  can be administered therapeutically when an individual is already taking certain Synergistic Enhancers (e.g, SSRI or SNRI) or Exogenous Opioids  (e.g., tramadol, oxycodone or morphine) in order to enhance their therapeutic benefit, reduce side effects, and minimize the dose of the medications.

 

Finally, this invention teaches the development of a new generation of pharmaceutical formulations for the treatment of certain medical conditions that are traditionally treated by any drugs or medications that are known to  impair the healthy functioning of the endogenous opioid or related neurotransmitter systems when administered alone (e.g., PDE inhibitors, analgesics, stimulants).  In particular, the treatment of respiratory conditions, such as COPD and asthma, often includes cAMP PDE inhibitors, such as theophylline and roflumilast.  Unfortunately, these cAMP PDE inhibitors are known to produce Distress Dysfunction, triggering side effects such as hyperalgesia, anxiety, and gastrointestinal symptoms, which are counter-productive in their treatment of these medical conditions.  Therefore, a new generation of pharmaceutical formulations for the treatment of respiratory disorders is taught by this invention.  These novel enhanced formulations contain one or more Receptor Balancers (e.g., ULDN or NAC) and a cAMP PDE inhibitor (e.g., roflumilast or theophylline) .  Given NAC’s anti-inflammatory and anti-viral effects, which are known to improve respiratory conditions, and roflumilast’s potent specific PDE-4 inhibitory effects, which are particularly potent with regard to respiratory conditions, the combination NAC and roflumilast is a preferred embodiment of a novel formulation for respiratory conditions, such as COPD and asthma, simultaneously improving respiration and pain relief, with minimal side effects.

 

A detailed description of the bimodal opioid modulation of pain and hedonic tone is included in the Appendix.  In addition, diagrams are included that detail:  (1) Bimodal Endorphinergic Modulation of Pain and Hedonic Tone (basic biochemical processes); (2) Bimodal Endorphinergic Impact on Pain and Hedonic Tone (transmission of normal pain and distress signals); (3) Acute Unbalanced Endorphinergic Impact on Pain and Hedonic Tone (acute impact of conventional drugs); (4) Chronic Unbalanced Endorphinergic Impact on Pain and Hedonic Tone (long-term impact of conventional drugs); and (5) Balanced Endorphinergic Impact on Pain Hedonic Tone (acute and long-term impact of novel balanced cotreatment formulations).

 

 

 

Prior Art and Teaching

 

Without the understanding taught by this invention, prior teachings and practice have focused on limited and, at times, iatrogenic treatments for Distress Dysfunctions.  Treatment for emotional and physical distress, such as anxiety, depression, addiction, anger, eating disorders and distressing pain, has generally involved the administration of exogenous opioid agonist and non-opioid analgesics, anti-anxiety and anti-depressant medications, and stimulants.  These treatments have been limited and are often less effective as well as the cause of serious, but avoidable, side effects.  Conventional treatment lacks the knowledge and teaching described and developed through this invention, especially regarding the critical role of the protracted excitatory receptor mode and diminished neurotransmitter levels, in endogenous opioid and related systems, characteristic of most Distress Dysfunction disorders, conditions, and symptoms.

 

Prior teachings and practices frequently resorted to replacing neurotransmitters with exogenous substitutes, such as the extensive use of narcotic opioid drugs.  Unfortunately, this approach has revealed very serious and dangerous consequences including the development of hyperalgesia, tolerance, dependence, and addiction, which result directly from the homeostatic compensatory response of the endogenous opioid system that includes protracted suppression of endogenous neurotransmitters, such as endorphins, as well protracted fixation of the receptors in the excitatory mode.  In other words, use of exogenous opioids literally produces a protracted imbalance in the endogenous opioid system, exacerbating protracted distress symptoms, increasing the reliance on these drugs, and setting the stage for drug dependence and addiction. A similar problem exists in current opioid addiction treatment, in which “treatment” is simply administering more exogenous opioid drugs, such as buprenorphine, which literally continues the drug dependency and impairment of the homeostatic functioning of the stress-related neurotransmitter systems.

 

There is also growing evidence that many other pain and distress relieving agents, such as NSAIDs and acetaminophen, negatively impact the stress-related neurotransmitter systems, including the endogenous opioid system, as shown in cross-tolerance studies.  As a result, noxious side effects, including tolerance and gastrointestinal symptoms, often occur.  Furthermore, the pain relieving effects, as shown in induced pain and clinical trials are rather weak with non-opioid analgesics, and not sufficient for moderate-to-severe pain.  Therefore, conventional treatment for emotional and physical distress is limited, with the more potent pharmaceuticals causing very dangerous and, at times, fatal consequences.

 

Clearly, neurotransmitter replacements, such as exogenous opioid and non-opioid analgesics, have had an important role in the management of physical distress, especially for pain, despite their serious problems. However, using the discoveries underlying this invention, fortunately they can now be used as a last resort, in very small doses, in formulations that have been developed to minimize the need for, and the iatrogenic impact of, agents that compete with, and interfere with, healthy functioning of the stress response neurotransmitter systems.

 

An alternative approach to the treatment of emotional and physical distress has been the administration of agents that may increase the production, release, and functioning of neurotransmitters in the stress response system, rather than attempt to replace them with exogenous substitutes. This approach has some merit and worth considering.  For instance, the popular use of SSRI medications, which increase the level of serotonin, has shown partial effectiveness, with estimates that they generally may reduce distress symptoms of depression by about 10%.  The variability of effectiveness is also striking, with many individuals having no benefit, or even an exacerbation of symptoms, using SSRI medications.  The problem, discovered by this invention, is that this popular treatment does not consider the important homeostatic interrelationship among the serontonergic and opioidergic and related neurotransmitter systems and the critical role of protracted excitatory opioid receptor signaling in reducing the therapeutic benefits from SSRIs, SNRIs, and other neurotransmitter enhancing agents. Cross-tolerance studies of exogenous serotonin and opioid agents demonstrate this underlying problem. There is evidence to suggest that tolerance and withdrawal effects often develop with the use of various anti-anxiety and anti-depressant medications, producing imbalances in these systems, ironically leading to increased protracted distress over time.

 

A similar problem exists in the growing field of supplements used to reduce emotional and physical distress. This approach attempts to stimulate the production and release of stress-related neurotransmitters in order to enhance healthy neurotransmitter functioning.  Most of this field focuses on administering forms of amino acids, vitamins and minerals, which target the production and release of specific neurotransmitters.  For instance, tryptophan and 5HTP are often used to trigger the release of serotonin in an attempt to reduce distress and increase a sense of well-being.  Similarly, DLPA has been used to increase the release and maintenance of endorphins. This may have modest effectiveness when the receptors are in healthy homeostatic balance.  Unfortunately, these agents provide either minimal effectiveness, or paradoxically, an increase in distress when they are used by individuals who use them because they are suffering from Distress Dysfunction symptoms, caused by protracted opioid receptor excitatory signaling. This understanding explains the limited and highly variable effectiveness of simply administering these supplements without the use of a Receptor Switcher. In fact, ironically, clinical experience has revealed that the more distress an individual experienced chronically, the more the administration of amino acid supplements, such as DLPA, produced increased, rather than reduced, distress.  Until this invention, however, there was no explanation or solution to this variable and, at times, iatrogenic effects of neurotransmitter enhancing agents.

 

Another approach to the reduction of distress, especially used in the field of drug and alcohol dependence, has been to administer a large dose of neurotransmitter antagonists, such as naltrexone, in an attempt to reduce cravings and prevent the effects of these abused substances on the neurotransmitter system.  This treatment has very poor compliance because individuals typically become anhedonic, leading to limited motivation to continue taking the antagonist.  Recently approved medications remove the daily choice from this method of treatment by administering long-term dosing of these drugs.  Unfortunately, this approach to treating distress dysfunction is counterproductive because it blocks the release of endogenous opioids and related neurotransmitters, thereby dramatically impairing homeostatic balance in these systems and causing a continuous state of anhedonia, which, in turn, mitigates against long-term success and compliance.  In certain ways, it could be considered a more finely tuned chemical lobotomy.  Fortunately, the discoveries underlying this invention eliminate the need for this approach; yet, ironically, the use of neurotransmitter antagonists led to the important discovery of Receptor Switchers.

 

Dr. Stanley Crain discovered the existence and function of agents that block excitatory opioid receptor signaling during his pioneering electrophysiological nervous tissue culture studies.  His research led to the discovery that endogenous opioid receptors are bimodal and have two signaling modes – inhibitory and excitatory.  When the receptor is in the inhibitory mode, endogenous opioids, such as endorphins, trigger inhibitory signaling, leading to immediate reduction of distressful pain signals.  However, when the receptor is in the excitatory mode, endorphins trigger excitatory signaling, sending out distressing alert signals, often experienced as pain.  If the neurotransmitter system is in homeostatic balance, the system is very efficient and effective, switching back and forth between excitatory (distress) and inhibitory (relief) signaling.  However, Dr. Crain discovered that when exogenous opioid agents are administered, the system adapts rather quickly, leading to protracted excitatory signaling.  In subsequent studies, Dr. Crain discovered that certain agents, such as ultra-low-dose opioid antagonists, reduced and/or eliminated protracted excitatory signaling.  Dr. Crain later discovered that GM1 ganglioside attenuators, such as neuraminidase inhibitors, also block excitatory opioid receptor signaling.

 

Dr. Crain used these discoveries to develop improved approaches for the treatment of nociceptive pain and opioid drug addiction.  He developed a method to reduce many of the noxious side effects of exogenous opioid drugs, such as tolerance and dependence, using co-treatment formulations that added agents, such as ultra-low-dose opioid antagonists and neuraminidase inhibitors, when administering opioid drugs.  This cotreatment approach has been shown to be effective in nociceptive pain and opioid dependence clinical trials.  Dr. Crain has recently developed methods for treating nociceptive pain that suggest the potential effectiveness of combining an agent that switches the opioid receptor mode with an agent that enhances the release of endogenous opioids.  He has been able to demonstrate increased pain tolerance using this cotreatment method in hot-water tail-flick mouse studies, combining agents such as ultra-low-dose naltrexone combined with rolipram.  Therefore, Dr. Crain’s research has revealed the importance of combining Receptor Switchers (e.g., ultra-low-dose naltrexone) with either Endorphin Enhancers (e.g., rolipram) or Exogenous Opioids (e.g., morphine).  However, his teaching and research was focused on nociceptive pain and the endogenous opioid system and not on emotional and physical distress syndromes and the critical interconnected role of other stress-related neurotransmitter systems, such as the serotonin, dopamine, glutamate, epinephrine, and norepinephrine systems.

 

One group of investigators has found evidence that a ibudilast, a non-specific cAMP PDE inhibitor, can be used for the treatment of pain and various addictions, though they attribute the benefits to glial cell mechanism and not to its cAMP PDE inhibition functions. However, these investigators assert that the effectiveness of ibudilast for these disorders is based on its administration as a stand-alone medication. As a result, they suggest no teachings regarding the critical need for the co-administration of any agent, such as a Receptor Switcher, with ibudilast, or other PDE inhibitors, for the most effective treatment of pain and addiction.  Moreover, the administration of ibudilast, and other PDE-inhibitors, without a Receptor Switcher is likely to leave the receptors in the endogenous opioid system in a protracted excitatory state, making it much less effective for treating Distress Dysfunction and might even exacerbate emotional and physical distress.

 

There has been no prior teaching that has developed a comprehensive understanding of Distress Dysfunction, as defined in this invention, nor of the neurophysiological process that underlie the wide variety of disorders, conditions, and symptoms that are manifested by Distress Dysfunction, as defined in this invention. Therefore, there has been no prior teaching or art regarding the improved safety, side effect profile, or therapeutic efficacy of combining Receptor Switchers, as defined in this patent, with Endorphin Enhancers, as defined in this patent, for the purpose of reducing emotional and physical distress, as defined in this patent, such as dysfunctional fears and anxieties, anger and irritability, despair and depression, gastrointestinal disorders, sexual disorders, eating disorders, distressing pain, as well as alcohol, drug, and behavioral addictions. Furthermore, there has been no prior teaching regarding the increased safety, side effect profile, or therapeutic efficacy of combining Receptor Switchers and Endorphin Enhancers, with low-dose Exogenous Opioids, as defined in this patent, for the purpose of reducing emotional and physical distress, as defined in this patent.  Furthermore, there has been no prior teaching or art regarding the increased safety, side effect profile, or therapeutic efficacy of combining Receptor Switchers, as defined by this patent, with Synergistic Enhancers, as defined in this patent, for the purpose of reducing emotional and physical distress, as defined in this patent.

 

Dr. Stanley Crain’s combination of Receptor Balancers, such as ultra-low-dose-naltrexone, with either Exogenous Opioids or Endorphin Enhancers, such as rolipram, was limited to nociceptive pain and opioid withdrawal.  Dr. Crain neither addressed nor articulated any principles that predicted or contemplated the role of these formulations in the treatment of the comprehensive set of disorders, conditions, and symptoms that are manifested by Distress Dysfunction, as defined in this patent, such as dysfunctional worries and anxieties, anger and irritability, despair and depression, sexual and sleep impairments, cravings for alcohol and food, or hypersensitivity or exaggerated responsitivity to perceived pain and stress.  Moreover, regarding the treatment of pain, Dr. Crain’s teachings are silent regarding the critical importance of using Exogenous Opioids only in combination with both Receptor Switchers and Endorphin Enhancers. Therefore, this invention involves unexpected and remarkable discoveries, never taught before, that have enormous clinical importance for millions of sufferers of emotional and physical distress.

 

This invention provides innovative methods that have a profound impact on reducing a wide variety of emotional and physical distress syndromes.  By using principles that combine agents in a novel way that restores homeostatic balance to the underlying stress-related neurotransmitter systems, for the first time, this paradigm teaches a method of developing formulations that simultaneously reduces and resolves a wide variety of emotional and physical distress syndromes, rather than prior art which teaches symptom-based medical treatments that often iatrogenically exacerbate dysfunctional distress (side effects).  No prior art has taught a method to reduce and/or resolve the fundamental experience of emotional and physical distress, restoring a sense of basal positive hedonic tone and well-being.  And no prior art has taught the therapeutic benefits for Distress Dysfunction of combining agents such as NAC, an amino acid compound known for boosting the immune system, with agents such as ginkgo biloba, an herb known for enhancing memory functions, or roflumilast, a drug for treating COPD, or MSG, a flavor enhancer.  And while certain agents have been used for treating certain forms of Distress Dysfunctions, such as SSRIs, SNRIs, DLPA, 5HTP, and L-Tryptophan, there has been no teaching that would suggest that adding ultra-low-dose naltrexone or NAC could dramatically potentiate the therapeutic benefit of these agents.  Furthermore, no prior teaching has suggested that adding innocuous agents such as a small amount of Epsom salts or an amino acid, such as NAC, could reduce the distressing side effects, and may even improve the efficacy, of many commonly used drugs, such as asthma, COPD, analgesic, and stimulant drugs.

 

 

 

Detailed Description of Invention

Distress Dysfunction

 

This invention details the discovery of a discrete condition that had previously been diagnosed and treated as a wide variety of unrelated disorders and syndromes.  Distress Dysfunction underlies many of the symptoms and functional impairments that are now identified as components of emotional and physical distress.  Not only does this invention provide an explanation of the neurophysiological imbalances that underlie many symptoms of emotional and physical distress, but it offers a clear set of principles that identify specific classes of agents that, when combined together in formulations guided by these principles, provide a remarkably safe and effective treatment for individuals suffering from Distress Dysfunction as well as a method for maintaining healthy neurotransmitter functioning to prevent the development of dysfunctional distress.

Distress Dysfunction can be identified by the experience of one or more of a wide variety of forms of emotional and physical distress, including, but not limited to hyperalgesia, distressing pain, anxiety and panic, exaggerated worries and fears, hypervigilance, physical and emotional hypersensitivity,  impulsivity, irritability and anger, obsessions and compulsions, agitation, distractibility, concentration and attention impairments, despair and depression, anhedonia, sleeping difficulties, sexual problems, interpersonal conflicts, a sense of danger and that “something is wrong”, as well as desperate cravings for anything that can reduce this protracted distress.  These cravings are often for substances, such as drugs, alcohol, and food, as well as stress-reducing behaviors and situations, such as sexual activity, gambling, and other compulsions. In contrast to nociceptive pain, which is a direct adaptive reaction to real injury, distressing pain is an exaggerated dysfunctional reaction to perceived and anticipated danger, which typically includes hyperalgesia and hypersensitivity to perceived or real injury as well as neuropathic and psychogenic pain.

 

This invention teaches that these symptoms of emotional and physical distress, at least in part, are signs of an underlying dysfunctional imbalance in stress-related neurotransmitter systems that reflect a protracted state of alert.   Traditional medical, psychiatric, and psychological diagnoses are often made based on symptoms that reflect this underlying neurophysiological imbalance.  For the first time, this invention teaches methods that can be used to restore healthy balances in the underlying neurotransmitter systems that are responsible for the symptoms of emotional and physical distress.  Therefore, these novel formulations can be used to safely and effectively treat symptoms and conditions presented by individuals diagnosed with a variety of disorders that, we postulate, are, in fact, manifestations of Distress Dysfunction.

 

In order to functionally assess Distress Dysfunction, we suggest that the following constellation of conditions, symptoms, and disorders be considered:, whether (a) the result of an endogenous condition or (b) the result or side effect of an exogenous medication, drug, or other agent, wherein a component thereof is the presence of one or more of the following:   (a) signs or symptoms of distress (and/or a diminution of happiness, pleasure, contentment and a positive sense of well being), which interferes with an individual’s quality of life and functioning, or (b) unpleasant or deleterious side effects of a medication, drug, or other agent, which may, or may not, interfere with its potential therapeutic benefits.

 

Distress Dysfunction includes, but is not limited to, the following conditions, symptoms and/or disorders:  (1) Anxiety Disorders, including, but not limited to, Panic Disorders, Agoraphobia, Specific Phobias, Social Phobias, Obsessive-Compulsive Disorder, Post-Traumatic Stress Disorder, Acute Stress Disorder, Generalized Anxiety Disorder, Substance-Induced Anxiety, Anxiety Related to Medical Disorders, Anxiety Disorder Not Otherwise Specified (NOS), as well as signs and symptoms of anxiety, stress, agitation, and worry that are not classified as an Anxiety Disorder; (2) Mood Disorders, including, but not limited to, Depressive Disorders, Dysthymic Disorder, Bipolar I Disorder, Bipolar II Disorder, Bipolar Disorder NOS, Cyclothymic Disorder, Mood Disorders Related to Medical Conditions, Seasonal Affective Disorder, Mood Disorders NOS, as well as signs and symptoms of depressed mood, anhedonia, despair, anhedonia, hypomania, mania, and negative hedonic tone that are not classified as a Mood Disorder; (3) Somatoform Disorders, including, but not limited to, Somatization Disorder, Somatoform Disorder, Conversion Disorder, Pain Disorder Associated with Psychological Factors, Pain Disorder Associated with Medical Conditions, Hypochondriasis, Body Dysmorphic Disorder, and Somatoform Disorder NOS; (4)  Factitious Disorders, including but not limited to, Factitious Disorders with Psychological Signs and Symptoms, Factitious Disorders with Physical Signs and Symptoms Factitious Disorders with Combined Psychological and Physical Signs and Symptoms, and Factitious Disorder NOS; (5) Dissociative Disorders; (6) Sexual Dysfunction, including, but not limited to, Sexual Desire Disorders, Sexual Arousal Disorders, Orgasmic Disorders, Premature Ejaculation, Erectile Dysfunction, Sexual Pain Disorder, Sexual Dysfunction to a General Medical Condition, Substance-Induced Sexual Dysfunction, Sexual Dysfunction NOS, as well as signs and symptoms of sexual dissatisfaction and dysfunction that are not classified as a Sexual Dysfunction disorder; (7) Eating Disorders, including, but not limited to, Bulimia Nervosa, Anorexia Nervosa, Binge Eating, Eating Disorder NOS, as well as signs and symptoms of eating and appetite problems that are not classified as an Eating Disorder; (8) Gastrointestinal Disorders, including, but not limited to, Irritable Bowel Syndrome (IBS) with Predominately Diarrhea, IBS with Predominately Constipation, and IBS Mixed Type, Crohn’s Disease, as well as GI distress including, but not limited to, nausea, vomiting, diarrhea, constipation, and bloating; (9) Pre-Menstrual Syndrome (PMS) and other hormonally-related distress signs and symptoms; (9) Movement Disorders, including, but not limited to, Restless Leg Syndrome; (10) Fibromyalgia; (11) Sleep Disorders, including, but not limited to, Insomnia, Dyssomnias  Parasomnias as well as signs and symptoms of sleep problems that are not classified as a Sleep Disorder; (12) Impulse-Control Disorders, including, but not limited to, Intermittent Explosive Disorder, Kleptomania, Pyromania, Pathological Gambling, Trichotillomania, Impulse Control Disorder NOS as well as signs and symptoms of impulsivity that are not classified as an Impulse-Control Disorder; (13) Psychological Factors Affecting Medical Conditions; (14) Medication-Induced Movement Disorders; (15) Alcohol-Related Disorders, including, but not limited to, Alcohol Dependence, Alcohol Abuse, Alcohol Addiction, Alcohol-Induced Disorders, Alcohol-Related Disorder NOS as well as alcohol-related problems that are not classified as an Alcohol-Related Disorder; (16) Opioid-Related Disorders, including, but not limited to, Opioid Dependence, Opioid Addiction, Opioid Abuse, Opioid-Induced Disorders, Opioid-Related Disorder NOS, as well as opioid-related problems that are not classified as an Opioid-Related Disorder;  (17) Caffeine-Related Disorders, including, but not limited to, Caffeine Dependence, Caffeine Addiction, Caffeine Abuse, Caffeine-Induced Disorders, Caffeine-Related Disorders NOS as well as caffeine-related problems that are not classified as a Caffeine-Related Disorder; (18) Cannabis-Related Disorders, including, but not limited to, Cannabis Dependence, Cannabis Addiction, Cannabis Abuse, Cannabis-Induced Disorders, and Cannabis-Related Disorder NOS; (19) Amphetamine (or Amphetamine-Like)-Related Disorders, including but not limited to, Amphetamine Dependence, Amphetamine Addiction, Amphetamine Abuse, Amphetamine-Induced Disorders, and Amphetamine-Related Disorder NOS; (20) Cocaine-Related Disorders, including, but not limited to, Cocaine Dependence, Cocaine Addiction, Cocaine Abuse, Cocaine-Induced Disorders, and Cocaine-Related Disorder NOS; (21) Nicotine-Related Disorders, including, but not limited to, Nicotine Dependence, Nicotine Addiction, Nicotine Abuse, Nicotine-Induced Disorders, and Nicotine-Related Disorder NOS; (22) Inhalant-Related Disorders, including, but not limited to, Inhalant Dependence, Inhalant Addiction, Inhalant Abuse, Inhalant-Induced Disorders, and Inhalant-Related Disorder NOS; (23) Phencyclidine-Related Disorders, including, but not limited to, Phencyclidine Dependence, Phencyclidine Addiction, Phencyclidine Abuse, Phencyclidine-Induced Disorders, and Phencyclidine- Related Disorder NOS; (24) Sedative-, Hypnotic-, or Anxiolytic-Related Disorders, including, but not limited to, Sedative-, Hypnotic-, or Anxiolytic Dependence, Addiction, and/or Abuse, Sedative-, Hypnotic-, or Anxiolytic-Induced Disorders, and Sedative-,Hypnotic-, or Anxiolytic-Related Disorder NOS; (25) Polysubstance-Related Disorders;(26)  Pervasive Developmental Disorders, including, but not limited to, Autism Disorder, Rhett’s Disorder, Aspberger’s Disorder, or Pervasive Developmental Disorder NOS; (27) Attention-Deficit and Disruptive Behavior Disorders, including, but not limited to Attention-Deficit/Hyperactivity Disorder, Conduct Disorder, Oppositional Disorder, Disruptive Behavior Disorder NOS as well as attentional and concentration problems that are not classified as an Attention-Deficit Disorder; (28) Chronic Fatigue Disorder, (29) Psychotic Disorders, (30) Behavioral addictions, compulsions, and dysfunctions, including, but not limited to, sex, pornography, gambling, shopping, eating, drinking, smoking, computer use, and cleaning, (31) Pain disorders, including, nociceptive, neuropathic, migraine and psychogenic pain, (32)  Psychotic disorders, including, but not limited to, schizophrenia; (33) Unpleasant or deleterious side effects of CLASS II,III, or IV agents when such agents are administered alone (i.e., without co-administration with an CLASS I agent) which may, or may not, interfere with the potential therapeutic benefits of CLASS II, III, or IV agents, including, but not limited to PDE inhibitors, opioid and non-opioid analgesics, stimulants, SSRIs, SNRIs, and amino acids; (34) Respiratory, inflammatory, and pain disorders including, but not limited to, asthma and COPD; (35) Allergic and non-allergic glutamate and mono-sodium glutamate related disorders, including “Chinese Food Syndrome”, and (36) Emotional and physical malaise, distress, discomfort, pain, restlessness, irritability, worries, cravings, compulsions, obsessions, agitation, addictions, and other related complaints and signs of protracted negative hedonic tone that may, or may not, be part of a traditional medical or psychiatric disorder. Distress Dysfunction is not limited to these conditions and diagnoses and is best defined by a variety of symptoms, conditions, syndromes, and disorders, characterized by dysfunctional emotional and physical distress and pain.

 

This invention teaches that a fundamental neurophysiological impairment underlies the development of many of the signs and symptoms of Distress Dysfunction. There is evidence that imbalances in the endogenous opioid system as well in serotonin, dopamine, norepinephrine, epinephrine, and glutamate neurotransmitter systems play a significant role in producing a wide variety of symptoms of emotional and physical distress.  Specifically, it is hypothesized that various conditions, including chronic stress, injury, drugs and alcohol, congenital factors, and maladaptive life styles, can lead to a chronic state of alert in these stress-related neurotransmitter systems, manifested by protracted opioid receptor excitatory signaling and diminished availability and functioning of endogenous opioids.  Given the homeostatic processes throughout the stress-related neurotransmitter systems, the result is a negative hedonic tone characterized by signs and symptoms of emotional and physical distress, described as Distress Dysfunction.

 

Therefore, until the teachings of this invention, all prior art and practice have resulted in limited treatment for protracted distress and many strategies that clearly exacerbate imbalances in the stress response system, resulting in even more serious protracted distress.  No prior teaching or art has developed an approach that is specifically focused on resolving both receptor and neurotransmitter imbalances in the stress-related systems that underlie protracted distress syndromes, thereby restoring healthy homeostatic functioning of the body’s stress response system.

 

 

 

Novel Treatment for Distress Dysfunction

 

A fundamental principle of this novel invention teaches that an appropriate method for reducing dysfunctional emotional and physical distress involves restoring and maintaining a healthy stress response system.  In order to restore balance in the stress-related neurotransmitter systems, treatment needs to simultaneously restore balance in the stress-related receptors and neurotransmitters.  Specifically, protracted excitatory signaling in opioid receptors needs to be switched to basal homeostatic inhibitory signaling, and healthy levels of endogenous opioids needs to be restored.  If endogenous opioids remain insufficient, exogenous opioids may be used to supplement this insufficiency.  This invention also teaches that, in addition to rebalancing opioid receptors and endogenous/exogenous opioids, agents can be added to the formulation to treat certain symptoms of Distress Dysfunction (e.g., pain, depression) that have synergistic impact on the endogenous opioid system as well as on the homeostatically related serotonin, dopamine, norepinephrine, epinephrine, and glutamate neurotransmitter systems.

 

Effective endorphinergic treatment of Distress Dysfunction includes both:  (1) at least one Class I agent that restores and maintains stress-related neurotransmitter receptors in a basal inhibitory mode (Receptor Switcher), and (2) at least one of the following (a) one or more Class II agents that restore, maintain, and release sufficient levels of endogenous opioids (i.e., endorphins) for healthy functioning (Endorphin Enhancers), and/or (b) one or more Class III agents that bind with opioid receptors (i.e., exogenous opioid agonists) (Exogenous Opioids), and/or (c) one or more Class IV agents that have a synergistic effect with the endogenous opioid system as well as related neurotransmitter systems (Synergistic Enhancers).  Treatment methods that do not restore and maintain balance in both receptor mode and neurotransmitter levels are not only insufficient, but can literally exacerbate imbalances and, therefore, distress symptoms in many individuals.  A visual comparison of the dramatically different effects of the balanced cotreatment formulations taught by this invention and conventional unbalanced formulations is seen in the diagrams included in the Appendix.

 

The classes of agents used in this invention are all known to have an impact on one or more of the stress-related neurotransmitter systems including the endogenous opioid, serotonin, dopamine, glutamate, epinephrine, norepinephrine and other related systems.  Since there is growing evidence that all of these neurotransmitter systems function in homeostatic balance as the organism responds to stress, modifying important functions of one system has powerful effects across the stress response system.  Therefore, while the agents used in these novel formulations may be thought to have impact on one particular neurotransmitter system, it is clear that therapeutically impacting one system has important effects throughout the entire stress response system.  There is also growing evidence to suggest that the agents used in this method have an impact on more than one neurotransmitter system.

 

Class I Agents: Receptor Switchers

 

Regarding agents that switch stress-related neurotransmitter receptors from a protracted excitatory mode to a basal inhibitory mode, two categories of agents have been discovered that function for this purpose:  (1) ultra-low doses and very-low doses of opioid antagonists; and (2) agents that inhibit synthesis or activity of GM1-ganglioside.  Opioid antagonists include, but are not limited to, naltrexone, naloxone, norbinaltorphimine, diprenorphine, and similarly acting opioid peptides and alkaloids.  Agents that inhibit synthesis or activity of GM-1 ganglioside include, but are not limited to neuraminidase inhibitors, such as n-acetyl-cysteine (NAC), magnesium sulfate, chondroitin sulfate, sodium sulfate, oseltamivir, zanamivir, laninamivir, peramivir, scutellaria, 5,7,4′-trihydroxy-8-methoxyflavone, and similarly acting neuraminidase inhibitors.  Agents that inhibit activity of GM-1 ganglioside include, but are not limited to, CTX-B, anti-GM1-ganglioside antibody, and oligonucleotide antisense to GM1-ganglioside, and similarly acting GM-1 inhibitors. While prior teaching suggests that these classes of agents block or inhibit excitatory signaling in the endogenous opioid system, the discoveries underlying this invention suggest that these agents have synergistic serotoninergic, dopaminergic, epinephrinergic, norepinephrinergic, and glutamatergic effects, given the homeostatic interconnectedness of the stress-related neurotransmitter systems.

 

Therefore, these two categories of agents, ultra-low-dose and very-low-dose opioid antagonists and GM1 ganglioside inhibitors, are used in this invention for the functional Class I agents that selectively switch stress-related neurotransmitter receptors from a protracted excitatory mode to a basal inhibitory mode. This invention includes these and any other agents that function to inhibit or block excitatory receptor signaling and/or enhance inhibitory receptor signaling in the opioid, serotonin, dopamine, glutamate, epinephrine, and/or norepinephrine neurotransmitter systems.  Alone, these Class I agents have less impact on reducing dysfunctional distress than the synergistic benefits from combining Class I agents with Class II and/or III and/or IV agents.  In fact, in many cases, Receptor Switchers, when administered alone, have minimal or no therapeutic impact on reducing symptoms of Distress Dysfunction.

 

Preferred Receptor Switchers are ultra-low and very-low dose naltrexone and naloxone as well as neuraminidase inhibitors including n-acetyl-cysteine (NAC), magnesium sulfate, and oseltamivir.  All of these agents have been shown to have very surprising and dramatic synergistic effects in the cotreatment formulations studied using the principles taught by this invention.  They also are all known for being remarkably safe.  Since they all appear to be effective in combination with a variety of agents, which are known to enhance different neurotransmitter systems, and these combination have been shown to reduce a variety of symptoms, including both physical and emotional dysfunctional distress, these Receptor Switchers appear to function in a similar way.  This set of findings also suggests that they restore basal opioid receptor inhibitory signaling in such a way that the receptor switch impacts a variety of stress-related neurotransmitter systems.  The choice of Receptor Switcher can  be made dependent on a variety of factors including further studies to determine maximum benefit for different indications.

 

For certain embodiments of this invention, the preferred Receptor Switchers are naltrexone and nalexone.

 

For certain embodiments of this invention, the preferred Receptor Switcher is ultra-low-dose naltrexone (25 micrograms or less).

 

For certain embodiments of this invention, the preferred Receptor Switcher is very-low-dose naltrexone (25-250 micrograms).

 

For certain embodiments of this invention, the preferred Receptor Switcher is low-dose naltrexone (250-1000 micrograms).

 

For certain embodiments of this invention, the preferred Receptor Switcher is ultra-low-dose naloxone.

 

For certain embodiments of this invention, the preferred Receptor Switcher is very-low-dose naloxone.

 

For certain embodiments of this invention, the preferred Receptor Switcher is low-dose naloxone.

 

For certain embodiments of this invention, the preferred Receptor Switcher is n-acetyl-cysteine (NAC).

 

For certain embodiments of this invention, the preferred Receptor Switcher is magnesium sulfate.

 

Validation studies of this invention have suggested that ultra-low-dose naltrexone (ULDN) is particularly effective in most oral cotreatment formulations for a wide variety of Distress Dysfunction symptoms. Ultra-low-dose naloxone is the preferred Receptor Balancer for intravenous and sublingual administrations. Since the formulations used in this invention involve naltrexone doses that are about 1/10,000 times lower than those used for other indications, ULDN is a remarkably innocuous and safe agent for this application. While NAC and magnesium sulfate are non-prescription agents, they require higher dosing than the opioid antagonists.  NAC has the added benefit of anti-inflammatory, anti-oxidant, and anti-viral effects, which may be important in certain applications, as in the treatment of respiratory conditions.  Magnesium sulfate, or Epsom salts, can be useful in certain indications to prevent constipation, such as in the treatment of certain forms of IBS.

 

Class II Agents: Endorphin Enhancers

 

Regarding agents that enhance the production, release and/or functioning of endogenous opioids (i.e., endorphins), several categories of agents have been discovered that function for this purpose.  All of these agents have variable impact on Distress Dysfunction when taken without co-administration with an agent that reduces excitatory opioid receptor signaling (Receptor Balancers).  In fact, Endorphin Enhancers can have a negative impact if taken alone when the opioid receptors are in a protracted excitatory mode, which is typical when treating Distress Dysfunction.  In this condition, the increased release of endorphins triggered by these agents can result in excitatory signaling, producing increased pain and negative hedonic tone, creating and exacerbating Distress Dysfunction.  Without the understanding that is taught by this invention, there was no clear explanation for the highly variable findings of studies and treatments using Endorphin Enhancers alone.

 

However, when combined with an agent that reduces protracted excitatory signaling (Receptor Balancer), these Endorphin Enhancers have a surprising and dramatic effect on reducing acute and chronic emotional and physical distress.  These agents, by enhancing the release of endorphins, facilitate endogenous opioid receptor inhibitory signaling, as long as a Receptor Switcher is present to maintain opioid receptors in the inhibitory mode. This cotreatment formulation is remarkably effective in reducing and/or resolving a wide variety of Distress Dysfunction symptoms,  providing positive hedonic tone including calm and well being.

 

Endorphin Enhancers include agents that enhance the release of endogenous opioids (i.e., endorphins) directly, such as forskolin. However, preferred Endorphin Enhancers include agents that enhance endorphins indirectly.  Many of these agents trigger the release of cyclic-AMP (cAMP), which in turn enhances the release of endorphins.   Endorphin Enhancers that can be effective for this purpose include excitatory amino acids, such as glutamic acid and aspartic acid as well as salts of excitatory amino acids, such as monosodium glutamate (MSG).  Glutamic acid and MSG have been shown to be remarkably effective for a wide variety of Distress Dysfunction symptoms when combined with Receptor Switchers in all validation studies for this invention.  Certain amino acids, such as phenylalanine and dl-phenylalanine (DLPA), not only trigger the release of endorphins, but also block the enzymes that remove endorphins from the system.  DLPA is a particularly effective selective endorphin reuptake inhibitor (SERI) and has been shown to enhance and prolong the therapeutic benefits of a variety of balanced cotreatment formulations in the validation studies for this invention.  These amino acids have been widely used for other applications and have an excellent safety profile.

 

A particularly effective group of agents that trigger the release of cAMP, and therefore endorphins, are cAMP phosphodiesterase (PDE) inhibitors. The most potent of this group are specific cAMP PDE-4 inhibitors, known for their impact on the release of cAMP and, therefore, can be used at remarkably low doses.  Therefore, preferred Endorphin Enhancers include specific cAMP PDE-4 inhibitors, such as roflumilast and rolipram.  Roflumilast is a particularly compelling choice since it has been recommended for approval as safe and effective in Europe for the treatment of COPD, and is currently being reviewed in the U.S. for this purpose.  Remarkably low doses of roflumilast have been shown to be extremely effective for a wide variety of Distress Dysfunction symptoms, when combined with a Receptor Switcher, in validation studies for this invention.  Gingko biloba also functions as a cAMP PDE-4 inhibitor, and has certain benefits as a natural non-prescription agent.  While less potent, gingko biloba has been shown to be very effective, when combined with Receptor Balancers, such as NAC, for a variety of Distress Dysfunction symptoms, particularly emotional distress, which makes this a preferred non-prescription formulation.  Non-specific cAMP PDE inhibitors, such as theophylline, ibudulast, methyxanthines, caffeine, and isobutylmethylxanthine (IBMX), also function as Endorphin Enhancers, though require higher doses than specific PDE-4 inhibitors.  Theophylline and caffeine have been shown to be effective for a variety of Distress Dysfunction symptoms, when combined with Receptor Balancers, in validation studies for this invention.  Theophylline has the advantage of decades of clinical use as a prescription medication for asthma, whereas caffeine is an extremely useful agent for non-prescription formulations.

 

For certain embodiments of this invention, the preferred Endorphin Enhancer is roflumilast.

 

For certain embodiments of this invention, the preferred Endorphin Enhancer is theophylline.

 

For certain embodiments of this invention, the preferred Endorphin Enhancer is ginkgo biloba.

 

For certain embodiments of this invention, the preferred Endorphin Enhancer is caffeine.

 

For certain embodiments of this invention, the preferred Endorphin Enhancer is glutamic acid or MSG.

 

For certain embodiments of this invention, the preferred Endorphin Enhancer is DLPA.

 

For certain embodiments of this invention, the preferred Endorphin Enhancer is ibudilast.

 

For certain embodiments of this invention, the preferred Endorphin Enhancer is forskolin.

 

In certain circumstances, this invention teaches the method that at least one Receptor Switcher can be administered to a subject who is already taking an Endorphin Enhancer.  For instance, when cAMP PDE inhibitors, such as theophylline or roflumilast, are administered in the treatment of respiratory conditions, such as COPD or asthma, they can cause various side effects, including hyperalgesia, anxiety, and GI symptoms, essentially producing Distress Dysfunction.  The administration of at least one Receptor Switcher, such as ULDN or NAC, can not only reduce and/or eliminate these side effects, but can also reverse these effects, producing greater pain relief and calm.

 

This invention also teaches a novel treatment for respiratory conditions, such as COPD and asthma.  By combining an appropriate cAMP PDE inhibitor, such as roflumilast, theophylline, or ginkgo biloba, with a Receptor Switcher, such as ULDN or NAC, an enhanced formulation for the treatment of respiratory conditions is created, which reduces and/or eliminates side effects and produces greater relief and calm.  A preferred Receptor Switcher for these formulations is NAC, since it provides potent anti-inflammatory, anti-oxidant, and anti-viral effects, which can enhance the relief of respiratory symptoms in addition to reducing side effects and increasing pain relief and calm. Given its potency in respiratory therapy, a preferred prescription formulation is roflumilast with NAC.  While less potent, a potential non-prescription formulation for the treatment of respiratory conditions is NAC with ginkgo biloba.

 

Class III Agents: Exogenous Opioids

Exogenous opioid agonists bind with endogenous opioid receptors in ways similar to endogenous opioids, thereby triggering excitatory or inhibitory signaling, depending on the mode of the receptor.  However, the use of these Exogenous Opioids can create serious problems since they tend to inhibit the release of endogenous opioids and lock the opioid receptors in an excitatory mode over time.  Given the well-knownl side effects of exogenous opioid agonists such as oxycodone and morphine, preferred formulations for the treatment of Distress Dysfunction consist of at least one Receptor Balancer with at least one Endorphin Enhancer.  This method uses the natural healing power of balancing opioid receptors and neurotransmitters, maximizing use of endorphins in resolving Distress Dysfunction.  This endorphinergic treatment has been shown to be remarkably effective in reducing and/or resolving a wide variety of Distress Dysfunction symptoms, including moderate-to-severe distressing pain.

 

However, there may be circumstances in which the endogenous opioids may be insufficient to effectively resolve symptoms.  In this case, low-dose exogenous opioid agonists (Exogenous Opioids) can be added to the combination of Receptor Switcher and Endorphin Enhancer, in order to supplement the endogenous opioids (i.e., endorphins).  The evidence strongly suggests that, as long as at least one Receptor Switcher is included in the formulation, most noxious side effects of the Exogenous Opioid are reduced and/or eliminated including tolerance, dependence, hyperalgesia, and GI symptoms.  However, the preferred treatment includes at least one Receptor Switcher and Endorphin Enhancer with an Exogenous Opioid.  There is also evidence to suggest that this formulation dramatically enhances the analgesic potency of the Exogenous Opioid.

 

Exogenous Opioids include tramadol, morphine, oxycodone, hydrocodone, papaverine, codeine, dihydrocodeine, fentanyl, hydromorphone, buprenorphine, butorphanol, methadone, alfentanil, levorphanol, meperidine, nalbuphine, oxymorphone, pentazocine, pentazocine, propoxyphene, remifentanil, and sufenta.  While a weaker opioid, tramadol is a preferred Exogenous Opioid since it has therapeutic benefits through several neurotransmitter systems, all of which are enhanced by the addition of a Receptor Switcher, as seen in validation studies for this invention.  Low-dose oxycodone is also a preferred Exogenous Opioid since the balanced cotreatment formulation has been shown to dramatically enhance its pain relieving effects.  Low-dose morphine is also preferred in balanced cotreatment formulations, using ultra-low-dose naloxone, for intravenous and sublingual administration.

 

For certain embodiments of this invention, the preferred Exogenous Opioid is tramadol.

 

For certain embodiments of this invention, the preferred Exogenous Opioid is oxycodone.

 

For certain embodiments of this invention, the preferred Exogenous Opioid is morphine.

 

For certain embodiments of this invention, the preferred Exogenous Opioid is hydrocodone.

 

For certain embodiments of this invention, the preferred Exogenous Opioid is buprenorphren.

 

For certain embodiments of this invention, the preferred Exogenous Opioid is methadone.

 

This invention also teaches the method in which at least one Receptor Switcher alone, or in combination with an Endorphin Enhancer, can be administered to a subject already taking an Exogenous Opioid.  This strategy can be useful to reduce the potentially serious side effects produced by the exogenous opioid agonist as well as enhance its therapeutic benefits.

 

Class IV Agents: Synergistic Enhancers

 

Class IV agents have synergy with Receptor Switchers, including a variety of agents which have a synergistic effect with the endogenous opioid system through the G_i –mediated metabolic processes that trigger the inhibition of pain-sensory neurons (Synergistic Enhancers). There is evidence to suggest that higher levels of Gi that are produced by enhanced inhibitory signaling potentiate the pain-relieving effects of non-opioid analgesics, such as NSAIDs and acetaminophen.  Therefore, there is a synergistic potentiation produced by the combination of non-opioid analgesics, such as acetaminophen or white willow bark, with Receptor Switchers, such as ultra-low-dose naltrexone or NAC, creating a new generation of enhanced non-opioid analgesics.  These novel formulations can be further potentiated by combining one or more Receptor Receptors, such as ULDN or NAC, together with an Endorphin Enhancer, such as roflumilast or ginkgo biloba, and a Synergistic Enhancer, such as acetaminophen or white willow bark.

 

Similarly, synergistic potentiation occurs with selective serotonin reuptake inhibitors (SSRIs) and selective norepinephrine reuptake inhibitors (SNRIs), such that increased relief from depression, anxiety, pain, addiction, and other Distress Dysfunctions is produced by the combination of SSRIs and SNRIs, such as escitalopram oxalate and venlafaxine, with Receptor Switchers, such as ULDN or NAC. Therefore, a new generation of enhanced SSRI formulations for depression, anxiety, pain, and addiction are created by this invention. In addition to SSRIs and SNRIs, inhibitory serontonergic and adrenergic agents can function as Synergistic Enhancers.  Specific amino acids that enhance release of serotonin and dopamine, such as tryptophan and 5HTP, can also act as Synergistic Enhancers in these novel cotreatment formulations.

 

Finally, there is evidence to suggest that ULDN has a synergistic effect through this G_i metabolic process in addition to its function as a Receptor Switcher, making ULDN a particularly powerful agent in all cotreatment formulations.  Similarly, certain multi-function agents, such as tramadol, have particularly potent therapeutic effects in these novel pharmaceutical formulations since they function as both Exogenous Opioids and Synergistic Enhancers. Therefore, given their relative potency in cotreatment formulations, ULDN, tramadol, and roflumilast, are preferred agents in formulations for certain indications.  At the same time, over-the-counter agents, such as NAC, gingko biloba, and white willow bark, would be useful as non-prescription formulations.

 

For certain embodiments of this invention, the preferred Synergistic Enhancer is a selective serotonin reuptake inhibitor (SSRI) or a selective norepinephrine reuptake inhibitor (SNRI).

 

For certain embodiments of this invention, the preferred Synergistic Enhancer is a non-steroidal anti-inflammatory drug (NSAID).

 

For certain embodiments of this invention, the preferred Synergistic Enhancer is acetaminophen.

 

For certain embodiments of this invention, the preferred Synergistic Enhancer is white willow bark

 

For certain embodiments of this invention, the preferred Synergistic Enhancer is aspirin.

 

For certain embodiments of this invention, the preferred Synergistic Enhancer is ibuprofen.

 

For certain embodiments of this invention, the preferred Synergistic Enhancer is tramadol.

 

For certain embodiments of this invention, the preferred Synergistic Enhancer is an amino acid.

 

For certain embodiments of this invention, the preferred Synergistic Enhancer is tryptophan or 5HTP.

 

For certain embodiments of this invention, the preferred Synergistic Enhancer is tyrosine or taurine.

 

For certain embodiments of this invention, the preferred Synergistic Enhancer is SamE.

 

For certain embodiments of this invention, the preferred Synergistic Enhancer is MSM.

 

For certain embodiments of this invention, the preferred Synergistic Enhancer is a vitamin or mineral.

 

Balanced Pharmaceutical Formulations

 

An entirely new generation of pharmaceutical formulations for the treatment of a wide variety of Distress Dysfunction has been discovered by the combination of at least one Receptor Balancer together with at least one Endorphin Enhancer, Synergistic Enhancer and/or Exogenous Opioid.  These novel formulations restore homoeostatic balance in the endogenous opioid and related neurotransmitter systems, thereby producing a completely unexpected and dramatic reduction in a wide range of distress-related symptoms including hypervigilance, physical and emotional hypersensitivity, exaggerated perception and fears of threat, distressing pain, impulsivity, irritability and anger, unwarranted fears, anxiety and panic, obsessions and compulsions, agitation, distractibility, concentration and attention impairments, despair and depression, anhedonia, sleeping difficulties, sexual problems, interpersonal conflicts, a sense of danger and that “something is wrong”, as well as desperate cravings for anything that can reduce this protracted distress, including substances, such as drugs, alcohol, and food, and stress-reducing behaviors and situations, such as addictions and compulsions.  By reducing protracted emotional and physical distress, these cotreatment formulations produce a positive basal hedonic tone, providing a general sense of well-being and satisfaction, thereby reducing and/or eliminating dysfunctional compulsive and addictive behaviors as well. An adaptive response to stressors, including painful stimuli, is maintained, but the maladaptive distress reactions are reduced and/or eliminated.

 

This invention also teaches that formulations that contain Receptor Balancers (e.g., ultra-low-dose opioid antagonists or neuraminidase inhibitors) alone, or in combination with Endorphin Enhancers (e.g., PDE inhibitors or excitatory amino acids) and/or Synergistic Enhancers (e.g., amino acids) can be administered therapeutically when an individual is already taking certain Synergistic Enhancers (e.g, SSRI or SNRI) or Exogenous Opioids  (e.g., tramadol, oxycodone or morphine) in order to enhance their therapeutic benefit, reduce side effects, and minimize the dose of the medications.

 

Finally, this invention teaches the development of a new generation of pharmaceutical formulations for the treatment of certain medical conditions that are traditionally treated by medications that are known to impair the healthy functioning of the endogenous opioid or related neurotransmitter systems when administered alone (e.g., PDE inhibitors, analgesics, stimulants).  In particular, the treatment of respiratory conditions, such as COPD and asthma, often includes cAMP PDE inhibitors, such as theophylline and roflumilast.  Unfortunately, these cAMP PDE inhibitors are known to produce Distress Dysfunction, triggering side effects such as hyperalgesia, anxiety, and gastrointestinal symptoms, which are counter-productive in their treatment of these medical conditions.  Therefore, a new generation of pharmaceutical formulations for the treatment of respiratory disorders is taught by this invention.  These novel enhanced formulations contain one or more Receptor Balancers (e.g., ULDN or NAC) and a cAMP PDE inhibitor (e.g., roflumilast or theophylline).  Given NAC’s anti-inflammatory, anti-oxidant, and anti-viral effects, which are known to improve respiratory conditions, and roflumilast’s potent specific PDE-4 inhibitory effects, which are particularly potent with regard to respiratory conditions, the combination NAC and roflumilast is a preferred embodiment of a novel formulation for respiratory conditions, such as COPD and asthma, simultaneously improving respiration and pain relief, with minimal side effects.

 

A detailed description of the bimodal opioid modulation of pain and hedonic tone is included in the Appendix.  In addition, diagrams are included that detail:  (1) Bimodal Endorphinergic Modulation of Pain and Hedonic Tone (basic biochemical processes); (2) Bimodal Endorphinergic Impact on Pain and Hedonic Tone (transmission of normal pain and distress signals); (3) Acute Unbalanced Endorphinergic Impact on Pain and Hedonic Tone (acute impact of conventional drugs); (4) Chronic Unbalanced Endorphinergic Impact on Pain and Hedonic Tone (long-term impact of conventional drugs); and (5) Balanced Endorphinergic Impact on Pain Hedonic Tone (acute and long-term impact of novel balanced cotreatment formulations).

 

Validation studies, based on this invention, using a variety of the agents used in these balanced cotreatment formulations for Distress Dysfunction, indicate that, while certain agents are thought to impact on particular neurotransmitter systems, they appear to have more general effects on a variety of symptoms of emotional and physical distress, confirming the homeostatic interconnections among these stress-related neurotransmitter systems. These studies have determined that a wide variety of neurotransmitter enhancers, when combined with one or more Receptor Switchers, have surprising and remarkable therapeutic effects on the reduction and/or elimination of a wide variety of emotional and physical symptoms of distress, including unwarranted and/or exaggerated fears and worries, irritability and anger, anxiety, depression, distressing pain, cravings, obsessions and compulsions, sexual problems, and addictions.  Further studies will help determine, together with the skills of a person skilled in the art, the particular combination of Receptor Switchers, Endorphin Enhancers, Exogenous Opioids, and Synergistic Enhancers that have the most therapeutic impact on reducing Distress Dysfunction symptoms.

 

The principles taught by this invention result in a large number of formulations that can be effectively used to reduce and/or eliminate a wide variety of symptoms of emotional and physical dysfunctional distress.  Given the synergistic homeostatic balancing processes within the Stress Response system, evidence accumulated during the development of these principles suggest that, as long as the principles are appropriately applied, and therapeutic doses of appropriate agents are chosen by those skilled in the art, a variety of formulas can be therapeutically used to restore balance in the stress response system.  Therefore, while certain agents may be more effective than others for certain indications and individual cases, as long as these principles are used, any one of a number of reasonable formulations can be used to reduce a wide variety of symptoms of emotional and physical distress, reflecting an effective restoration of homeostatic balance in the stress response system.

 

In general, this invention teaches that an initial assessment should indicate that the individual is experiencing any one or more symptoms of emotional and/or physical distress, as described by this patent.  One or more Receptor Switchers should be selected, by a person skilled in the art, and combined with one or more Endorphin Enhancers.  This combination can be used both for the acute and long-term reduction and/or elimination of these emotional and physical distress-related symptoms.  For most individuals, this formula will be sufficient to reduce and/or eliminate most symptoms of dysfunctional distress.

 

When the combination of Receptor Switchers and Endorphin Enhancers is insufficient to reduce symptoms of emotional and/or physical distress, an Exogneous Opioid  can be added to the formula, acutely or chronically.  This strategy is most likely encountered in reducing distressing pain, in which case a low-dose analgesic agent can be added to the basic formula.  Evidence accumulated in the development of this invention suggests that low-dose analgesics are dramatically potentiated when combined with Receptor Switchers and Endorphin Enhancers.  In fact, non-opioid analgesics, such as NSAIDs, have been shown to have powerful synergistic pain-relieving effects in these formulations.  While opioid analgesics are generally not required, and to be avoided given their noxious side effects, very-low doses have been found to have synergistic therapeutic effects in these formulations, with minimal side effects.

 

This invention also teaches that these novel formulations can be used to restore and maintain healthy homeostatic balance in the stress response system and, in this way, help to prevent the development of Distress Dysfunction.  As a formula to maintain healthy functioning, no presenting symptoms of distress dysfunction need to be present.  Given the stress and toxic elements of modern civilization, which create dysfunctional distress, the use of these formulations is recommended for most individuals in our society.  In particular, these formulations are strongly encouraged for anyone predisposed to, experiencing, or with a history of, Distress Dysfunction, as well as those who are using drugs or other agents that impact on the stress response system.

The clinical studies that led to the development of this invention have demonstrated the remarkable therapeutic effects of these safe and healthy formulations for a wide variety of emotional and physical dysfunctional distress syndromes.  What is particularly striking about these findings is that the formulas use agents that on their own provide little or no relief for distress dysfunction, yet have healthy benefits for other concerns, such as the anti-oxidant and anti-viral benefits of NAC or the circulation benefits and potential reduction of memory impairments of ginkgo biloba.  Therefore, rather than using drugs that often have noxious impact, such as high dose narcotic opioid drugs, stimulants, NSAIDs, and tranquillizers, these novel formulations combine agents that enhance healthy functioning of the neurotransmitter systems.

 

While these formulations have been shown to reduce a variety of symptoms of dysfunctional emotional and physical distress, further studies will be needed to clarify relative efficacy for specific indications and populations.   Future studies are also expected that will provide individualized assessments that include neurotransmitter levels and receptor mode analysis in addition to symptom evaluation in order to further refine the selection of specific agents, doses, and formulations.  Furthermore, those trained in the art are expected to use the novel principles taught by this invention to select appropriate agents, doses, formulations, and methods of administration that would be most appropriate for the individual application.

 

Discovery of Invention

The discovery of this invention came from the sudden and unexpected convergence of two independent lines of research, one from the world of the psychotherapy consultation room and the other from the nervous tissue culture laboratory, suddenly coming together.  The result was a surprising and remarkable set of discoveries.

 

In his clinical psychotherapy practice over thirty years, Dr. Steven Crain, present co-inventor, identified the existence of a clearly definable syndrome, which appeared to emerge in patients suffering from a wide variety of disorders and conditions.  Despite major progress in psychotherapy in which cognitive and psychodynamic dysfunctional patterns, family issues, irrational and maladaptive beliefs and values were resolved, many patients clearly continued to suffer from a syndrome characterized by chronic or recurrent emotional and physical distress – unwarranted fears and worries, ruminations and obsessions that they could not stop, a sense of catastrophic dread, hypervigilance, emotional hypersensitivity, irritability and anger, impulsive reactions, compulsive behaviors, as well as  cravings  and addictions for food, alcohol, drugs, opioids, and stimulants. Many of the same patients complained of chronic aches and pains, hyperalgesia, and distressing pain.  All of these symptoms seemed highly related – a sense of emotional and physical distress, a sense of alert producing a basal state of negative hedonic tone, despite the fact the life circumstances would normally be expected to produce a positive hedonic tone and a sense of calm and well being.  Conventional SSRIs, SNRIs, and tranquillizers could help, at times, but often were insufficient, and often these positive effects often deteriorated over time.

 

Dr. Crain continued to search for biochemical answers.  He began to identify what seemed like an imbalance in the stress-related neurotransmitter systems, which were locked into an alert distress mode!  While many patients had had trauma in their life, stressful situations, and conflicted family history, as well as alcohol and drug abuse, may individuals simply seemed to be “wired” with these dysfunctional patterns. Dr. Crain also observed that many people who never sought treatment seemed to be suffering from various forms of the same problem.  Dr. Crain further observed that long term drug and alcohol use, and even treatment with SSRIs, SNRIs, tranquillizers, analgesics, and stimulants often made their symptoms worse over time. Over the years, Dr. Crain systematically explored the importance of nutrition and exercise, and discovered the clinical utility of certain supplements and vitamins.  However, a critical part of the puzzle was missing, until the set of discoveries that led to this invention.

 

A completely independent line of research, Dr. Stanley Crain’s basic neurophysiological preclinical tissue culture and animal studies, over the same 30-year period, eventually focused on the mechanisms underlying the impact of exogenous opiods on the nervous system.  This line of research led to a series of discoveries in Dr. Crain’s search for a safe and non-addictive medication for nociceptive pain.

 

This invention resulted from a series of preliminary clinical studies initially conducted to test Dr. Crain’s formulations in first human trials.  In a series of unexpected and serendipitous discoveries, this invention was developed, which revealed an entirely novel understanding of the neurophysiological mechanisms underlying the emotional and physical distress syndrome that Dr. Steven Crain had been observing in his patients over the years.  Moreover, Dr. Stanley Crain’s basic opioid studies provided the stimulus for the discovery of the remarkably safe and effective novel methods to reduce and eliminate the protracted emotional and physical distress symptoms and restore healthy functioning to the body’s emotional and physical stress response system.

 

From this serendipitous convergence between the psychotherapy office and the nervous tissue culture laboratory emerged the discovery of Distress Dysfunction as a discrete and identifiable syndrome that is amenable to a safe and effective treatment.  Moreover, these converging lines of research have led to an hypothesized understanding of the neurophysiological mechanisms that may explain the dramatic success of this novel treatment.

 

The moment of discovery arose when, in providing certain agents, which were suggested from Dr. Crain’s preclinical nociceptive pain studies, to subjects in a simple induced pain paradigm, these initial formulations resulted in dramatic and completely unexpected transformations in emotional and physical symptoms that were not predicted from any prior research or clinical practice.  Subjects suddenly reported a dramatic reduction in unrealistic fears, initially focused on the pain paradigm itself.  However, these emotional changes clearly reflected a much more profound sense of calm and well being, and a reduction in the individual’s protracted emotional and physical distress.  Subjects felt more relaxed, yet with no drug effect.  They reported a dramatic reduction in worries and anxieties as well as irritability and anger. All felt much more “right with their lives”.  Aches and pains were reduced, and when nociceptive pain did occur, there was a greater sense of acceptance and adaptive coping response, without their typical maladaptive distressing pain reactions.  Subjects who had craving issues in their lives found that these cravings were significantly ameliorated, including food, alcohol, and opioid drugs.  Instead of their normal emotional and physical distress, they felt a greater sense of peace and comfort.  There were no reports of “highs”, euphoria, or even any “drug effects” at all.  Moreover, no side effects were reported.  The discovery of a treatment for protracted dysfunctional distress suddenly emerged, launching over a year of informal trials and clinical case studies.

 

Clinical Trials and Case Studies

Clinical examples are provided to assist in understanding the invention.  Particular materials, dosages, and conditions employed are merely illustrative and not intended to limit the scope of the invention in any way.

 

Example 1

The surprising discovery that led to the novel method and composition of the present invention came from a series of clinical trials using drug formulations that were developed by present co-inventor Dr. Stanley M. Crain for the specific purpose of the control of moderate-to-severe nociceptive pain.  Dr. Crain demonstrated that a combination of certain agents, such as rolipram, caffeine, and isobutylmethylxanthine (IBMX), combined with other agents, such as naltrexone and naloxone, resulted in a formulation that could increase mouse tail-flick latencies in a hot-water immersion analgesia study.  In this way, Dr. Crain proposed that certain combinations of these agents could eventually be used as an alternative to traditional nociceptive pain medications.

 

Our study of Dr. Crain’s preclinical formulations was designed and intended to ascertain whether the analgesia (pain relief) demonstrated in the preclinical tail-flick studies could be duplicated in humans. The co-treatment formulations for these studies included combinations of two agents.  One of the following was used in relatively low dose – caffeine (50-200 mg), theophylline (100-300 mg), rolipram (1-50 ug), and forskolin (200 mg) – in combination with an ultra-low-dose of naltrexone (1-100 ug) (ULDN) or a moderately low-dose of magnesium sulfate (0.7-5 g).  In addition, each of these drugs was administered alone, to determine the potential synergistic effects of co-treatment.

 

For these trials, a hot-water finger-immersion pain paradigm was used, measuring both pain threshold and tolerance.  During these studies, a total of 60 subjects were given one or more of these formulations.  Some of these subjects were given a single dose; others were given twice-daily dosing for several days. One subject was given a co-treatment formulation for eight months.  As predicted, the co-treatment formulations, but neither agent administered alone, generally increased pain thresholds and tolerance, supporting Dr. Crain’s concept that the combination of these drugs could produce analgesia.

 

However, spontaneous, unsolicited reports from the majority of subjects in these trials revealed an unexpected set of therapeutic benefits from these co-treatment formulations, separate and distinct from the issue of nocieceptive pain relief, which was, at the outset, the sole purpose of the study.  Completely unplanned and unexpected was the entirely new discovery that these agents, in all co-treatment formulations, dramatically reduced a surprising variety of symptoms in the subjects separate and distinct from nociceptive pain, including gastrointestinal disturbances, emotional and physical agitation, impulsive anger, premature ejaculation, drug cravings, and PMS symptoms. In further studying this phenomenon, another surprising pattern emerged.  The formulations were most effective in reducing these non-pain-related symptoms in subjects who initially had relatively low pain thresholds and tolerance prior to taking the drugs, suggesting underlying hyperalgesia.

 

Nearly half the subjects, after taking the co-treatment formulations, indicated that they experienced a sense of positive sense of well-being (positive hedonic tone), in contrast to their accustomed level of stress, anxiety, and irritability. When asked, the others reported that their baseline emotional state was one of a positive feeling of well-being. Thus, in addition to changing physical pain thresholds and tolerance, these formulations demonstrated a remarkable ability to reduce long-standing emotional distress.  In fact, two subjects reported an improved ability to control their tendency to respond to events with inappropriate anger and reactivity, giving them a sense of relative peace and self-control.

 

Another unexpected and surprising finding was seen in the reports of eight subjects who reported that they felt a calming sensation in their gut.  They reported that they typically experience discomfort and bloating in their gut, as well as frequent urges to defecate, typical of IBS patients.  However, during the days of the trials, they noticed that these gastrointestinal symptoms had remarkably decreased.

 

Yet another unexpected and surprising finding concerned a female subject who reported that she had been, as was typical for her, experiencing PMS symptoms at the start of the study.  Her symptoms included malaise, irritability, and upset stomach. After taking the study formulations, she reported a rapid and dramatic reduction of her PMS symptoms.

 

One of the more dramatic and surprising findings of the trial was the report by one subject that her long-standing cravings for opioid drugs and alcohol had essentially disappeared, and that she was finally able to completely stop abusing these substances.  Needless to say, she is being continued on a combination of theophylline and ultra-low-dose naltrexone for maintenance, which has been successful for the past eight months.

 

Yet another unexpected and surprising finding concerned a male who has asthma and has taken theophylline for the over 25 years.  Therefore, for the purpose of the study, the only addition to his normal drugs was ultra-low-dose naltrexone (1 µg) taken with each normal dose of theophylline (300 mg SR), twice daily, other than the first day when 100 µg of naltrexone was administered.  The subject felt a fairly rapid elimination of symptoms that he had experienced for years, including restlessness, muscular tension, irritability, anger, and anxiety. After a few days, the subject experienced a sense of well-being, contentment, relaxation and calm. These dramatic improvements, emotionally and physically, were sustained throughout an eight-month trial. The therapeutic benefits slowly lessened during periods when the naltrexone was withdrawn for a few days and the prior symptoms began to return.  However, symptom relief was rapidly restored within hours of adding naltrexone back to the formulation.

 

With a common thread of lowered pain thresholds and the benefits of these particular drug combinations, it became evident that these subjects had various forms of Distress Dysfunction, and that a safe and effective treatment for Distress Dysfunction had been discovered for the first time.

 

Once this discovery was made, a series of retrospective questions were posed to the subjects in order to assess whether any other benefits occurred.  Obviously, this type of inquiry may not be as valid as the independent and spontaneous reports of the subjects during the trial.  Nevertheless, this inquiry resulted in confirmation of these symptom relief patterns as well as several other unexpected findings.  For instance, these inquiries revealed that two males in the study had experienced significant reduction in premature ejaculation while in the study, a satisfying effect that continued for several days.  They both reported a decrease in penile hypersensitivity and increase in ejaculatory control.  This finding is consistent with an understanding that premature ejaculation is a manifestation of Distress Dysfunction hypersensitivity.

 

A consistent pattern among these findings was that symptom reduction remained steady or increased over the course of the twice daily dosing, multi-day trials, suggesting the potential for successful long-term treatment.

 

One feature of these trials was that the subjects were not aware of whether they were being administered a single agent or combined agents, in order to determine the potential synergy of cotreatment as well as to reduce placebo effects.

 

Moreover, another remarkable, unexpected, surprising, synergistic and paradoxical finding concerned the substances used in the study.  Theophylline, rolipram, and caffeine are well known for increasing anxiety, restlessness, headaches, and various gastrointestinal symptoms. A number of subjects in these trials complained of these symptoms when given these drugs alone.  However, the addition of ultra-low-dose naltrexone or low-dose magnesium sulfate paradoxically reversed the ordinary and expected effect of these drugs, and resulted in a positive, unexpected, dramatic and synergistic effect, reversing patterns of symptoms normally seen with these drugs alone.  Not only were complaints of side effects and hyperalgesia eliminated in the co-treatment condition, but, as reported above, subjects experienced a dramatic improvement in positive hedonic tone, which included a significant reduction in symptoms that they had been experiencing prior to the study.  At the same time the low-dose naltrexone and magnesium sulfate, alone, had neither benefit nor side effects. Not only did these findings confirm the unexpected synergistic therapeutic effects of these co-treatment formulations, but they also suggested a completely novel method for reducing the typical side effects of these medications.

 

Discussion of Example 1

The surprising set of findings in these preliminary trials led to a search for an explanation.   In reviewing the scientific and clinical literature, a very interesting pattern emerged.  Patients with certain clinical disorders, such as IBS, PMS, acting out anger, psychogenic pain, alcohol and drug abuse, premature ejaculation, restless leg syndrome, substance abuse, and many children with autism have been found to have unusually low pain thresholds in standard pain tolerance studies.  Inference from these patterns suggested that these disorders could be linked to a disturbance in the endogenous opioid system.  In reflecting on the importance of hyperalgesia and the concept of distressing pain, a sudden connection was made as to the critical role of emotional and physical distress as a common characteristic throughout many of these disorders. These findings and observations strongly suggested that a common condition, Distress Dysfunction, underlies these diverse clinical patterns that have heretofore been considered to be separate and diverse as to both etiology and treatment.  Furthermore, given the dramatic effectiveness of these formulations, which were known to impact the endogenous opioid system, it suddenly and unexpectedly became clear that the neuropsychological mechanism underlying Distress Dysfunction involved imbalances in the endogenous opioid system as well as with related neurotransmitter systems that mediate hedonic tone.

 

Moreover, in addition to validating the existence of Distress Dysfunction, the elusive treatment for emotional and physical distress that Dr. Steven Crain had been searching for had suddenly been discovered. This pivotal study, as well as subsequent informal research, suggested that a safe and effective treatment for a wide variety of clinical disorders and symptoms had unexpectedly been discovered.  This treatment could consist of surprisingly low doses of specific agents that, when combined using principles that are based on this novel understanding of the stress response neurotransmitter systems, have a dramatic and synergistic effect on reducing hyperalgesia as well as a variety of other noxious symptoms of Distress Dysfunction.

 

Example 2

A preliminary study of Distress Dysfunction that we conducted included four patients in psychotherapy, all of whom suffered from years of Distress Dysfunction, characterized by chronic emotional distress, anxiety, irritability, and anhedonia, which were not improved by traditional psychiatric medication or years of psychotherapy.  The patients took a daily formulation of caffeine pills and magnesium sulfate solution, which, over the course of a few days, produced meaningful relief from these chronic symptoms. This rapid relief of chronic intractable symptoms was remarkable.  However, when it became clear that one patient had dramatically greater improvement than the others, an assessment revealed that he regularly consumed acetylsalicylic acid and acetaminophen to help him sleep.  Theorizing that these agents were having a dramatic and synergistic interaction with our formulation, the other three patients agreed to add one of these analgesics as well. The results showed an increased improvement in all four patients.  As one of these patients described the effect of this enhanced formulation, “for the first time in my life I feel normal, like I have a thicker skin.” More recently, these patients were given a consistent twice-daily formulation of acetaminophen (500 mg), caffeine (65 mg), and naltrexone (1 µg).  This formulation has produced very reliable relief of chronic emotional distress for the past eight months with no side effects.

 

Given these unexpected, dramatic findings, a patient suffering from Distress Dysfunction characterized by chronic alcohol and opioid cravings and abuse over many years was recently given this formulation.  Much to her surprise, the simple combination of acetaminophen, (500 mg), caffeine, (65 mg), and very-low-dose naltrexone (50 µg), given three times daily, completely eliminated her alcohol and drug cravings as well as any substance use.  Years of psychotherapy and traditional medications had no impact on these serious symptoms.  This treatment has been completely successful for the past six months.  In order to test the efficacy of the formula, without the patient’s awareness, the naltrexone was replaced by a placebo for one week.  Within a few days, cravings returned and the patient was tempted to relapse on several occasions.  The full formula was continued after the week, and the patient’s cravings were, once again, completely eliminated.

 

Discussion of Example 2

Since there is evidence that the analgesic effect of acetaminophen and acetylsalicylic acid may be the result of increased opioid receptor inhibitory signaling, it is reasonable to conclude that acetaminophen, and other non-opioid analgesics, act synergistically to achieve balance in the endogenous opioid system.

 

Therefore, in another embodiment, the Distress Dysfunction treatment formulation includes a Receptor Balancer co-administered with either one or more low-dose non-opioid analgesics, such as acetylsalicylic acid, acetaminophen, or white willow bark, together with one or more Endorphin Enhancers, such as caffeine, theophylline, ibudilast or roflumilast. These case studies clearly suggest that this enhanced formulation can resolve a wide variety of Distress Dysfunction symptoms, including chronic emotional distress and agitation, drug and alcohol cravings and abuse, addictions, psychogenic and neuropathic pain, gastrointestinal distress, anxiety and depression, irritability and angry outbursts, hypersensitivity, anhedonia, leading to emotional stability and a sense of well-being. There appears to be a dramatic and unexpected synergistic effect wherein the addition of a modest dose of a non-opioid analgesic (Synergistic Enhancer) can both potentiate the therapeutic efficacy of cotreatment formulations in order to relieve more serious symptoms of Distress Dysfunction.  Similarly, low-dose opioid analgesics, such as morphine, oxycodone, hydrocodone, tramadol, buprenorphine, methadone, and codeine are effective for this purpose when symptoms are particularly intractable and resistant to treatment.

 

Example 3

In order to assess the efficacy of this innovative treatment for Distress Dysfunction with a very serious, chronic disorder that is typically considered to be “untreatable”, a young adult female, diagnosed with autism, was treated with ultra-low-dose naltrexone and caffeine.  Relevant symptoms included the following:  limited eye contact, avoidant of even minor stimulation or frustration, highly reactive emotionally and physically to minor frustrations, extremely irritable and quick to anger, fearful of any arousal (both positive and negative), isolation and anhedonia.  She historically avoided caffeine as well as physical exertion and excitement of any kind, since she believed that caffeine and these activities would make her intensely agitated.  Despite this chronic caffeine reaction, the treatment consisted of ULDN and caffeine.  Paradoxically, for the first time in her life, she experienced positive hedonic tone (a positive sense of well-being, happiness, pleasure and contentment): paradoxically, she felt a calming as well as an energizing response from the caffeine with none of the agitation she had always experienced in the past.  Moreover, she began to realize that her normal reactivity to even minor stresses disappeared.  She felt “normal” for the first time in her life, able to experience some simple pleasures, including a budding enjoyment of spending time with others, and even laughing with them.  As she put it, “I don’t have to keep myself in an emotional straightjacket for fear of getting all worked up and losing control.”

 

Discussion of Example 3

This novel treatment of a patient with autism is a striking example of the power of this co-treatment paradigm.  The patient had been in treatment of various types, including psychiatric medications, for most of her life, with no meaningful improvement.  Within a few days of taking this formulation, her life-long chronic condition began to improve for the first time in her life.  This finding supports our conclusion that this treatment can resolve chronic Distress Dysfunction symptoms and disorders with relatively innocuous agents.  This case also specifically reveals the relevance of this formulation for the treatment of autism.  The paradoxical caffeine reaction supports our conceptual understanding of the role of, and the ability to restore healthy functioning to the opioid and related neurotransmitter systems.

 

 

Example 4

In conducting these trials, it became clear that certain subjects had a markedly greater increase in pain thresholds and pain tolerance when given a co-treatment of a Receptor Switcher with Endorphin and Synergistic Enhancers, as compared to the more typical response of either given alone.  Upon questioning the subjects, a completely unexpected discovery was made.  Most of these “outliers” were, coincidentally, taking some form of exogenous non-opioid analgesic, such as acetaminophen, ibuprofen, or “baby aspirin.”  (The investigators had not screened for non-prescription drug usage prior to study participation.)  What was particularly surprising and unexpected was that the subjects who took an exogenous non-opioid analgesic during the study, did not, on average, have higher baseline pain threshold/tolerance scores than subjects who were not. Therefore, there was clear evidence of a marked synergistic combination of the exogenous non-opioid analgesic with the Receptor Switcher, since this produced the greatest analgesic response.

 

In order to confirm this finding, the same pain threshold/tolerance hot-water finger-immersion paradigm was used with five subjects who were given, during separate testing sessions: (1) acetaminophen (500 mg) alone; (2) theophylline (300 mg) combined with ultra low dose naltrexone (1 µg); and (3) (1) and (2) combined.  The increase in pain threshold/tolerance (over baseline), in order of greatest pain relief, was (3), then (2) then (1).  Moreover, a dramatic synergy was uncovered since the increase in pain tolerance scores for (3) was greater than the sum of (1) + (2).  In fact, the same results were found when using “baby aspirin” (81 mg) instead of acetaminophen.  Although the “baby aspirin” showed no change in pain threshold when administered alone, surprisingly and unexpectedly the combined formulation produced the most dramatic analgesia, again demonstrating the synergistic potentiation of the exogenous non-opioid analgesic using this formula.

 

These findings were dramatic and completely unexpected since there had been no prior teaching regarding the ability of a Receptor Switcher and an Endorphin Enhancer to potentiate analgesia produced by an exogenous non-opioid analgesic; nor had there been any teaching to suggest combining either a Receptor Switcher or an Endorphin Enhancer with an exogenous non-opioid analgesic to enhance its pain-relieving effects.  The implications are significant.  For the first time, there is evidence to suggest that an enhanced non-opioid formulation might be sufficiently potent for moderate-to-severe pain.  Although it is generally accepted that exogenous opioid drugs create analgesia through their impact on the endogenous opioid system, there is no well-accepted understanding of how exogenous non-opioid analgesics actually work.   There has been, however, some speculation that the analgesic effect of NSAIDs (A. Pernia-Andrade, V. Tortorici, H. Vanegas Pain, Volume 111, Issue 1, Pages 191-200 2004) and acetaminophen (Raffa & Walker, European Journal of Pharmacology Volume 503, Issues 1-2, 25 October 2004, Pages 209-210 2004) involve opioidergic mechanisms.

Example 5

In order to determine the relative benefits of administering agents alone as compared to their combined synergistic benefits, an ongoing trial with patients in psychotherapy suffering from various Distress Dysfunction conditions, including anxiety, obsessive-compulsive disorders, depression, drug and alcohol addictions, behavioral addictions, psychogenic and neuropathic pain, eating disorders, and sexual dysfunctions, is being conducted.  Without identifying the agents, patients are being given one, or a combination, of the following agents:  ultra-low-dose naltrexone, very-low-dose roflumilast, caffeine, and acetaminophen. An ongoing assessment is being completed, using a within-subject design. The results to-date are extremely encouraging and dramatically support the safety and efficacy of treating a wide variety of Distress Dysfunction conditions and symptoms using our co-treatment formulations. While the overall results will be analyzed and published when the trial is completed, a very surprising and unexpected portion of the findings is presented here.

 

In general, the administration of single agents has had very little or no impact on reducing Distress Dysfunction conditions or symptoms, supporting the critical importance of our co-treatment formulations.  While most patients experienced no effect from ULDN alone, surprising and completely unexpectedly, several patients had dramatic improvement in their symptoms when taking ultra-low-dose naltrexone alone. Long-standing symptoms that were significantly reduced and/or eliminated included depression, anxiety, drug and food cravings, anger and irritability, emotional hypersensitivity and reactivity, aches and pains, as well as general malaise and agitation.  Instead, for the first time in years, these patients felt a sense of normalcy and well-being, without their normal feelings of distress and unease.  Inquiry into the differences between this subset of patients and the others revealed a very clear pattern – therapeutic benefits occurred for patients that were on SSRI and SNRI medications, including Lexapro, Prozac, Paxil, and Effexor.  Suddenly, and unexpectedly, it became clear that the ULDN was able to combine in a synergistic way with an SSRI or SNRI to dramatically potentiate their therapeutic benefits in reducing chronic Distress Dysfunction symptoms, which had not improved despite several years of psychotherapy and medication.

 

Discussion of Example 5

This finding that ULDN and SSRI agents combine synergistically led to a search for an explanation.  There were no prior teachings directly on this subject, though certain lines of research and reasoning generated a potential explanation.  While it is well-known that SSRI agents have therapeutic serotonergic effects, a growing body of research has revealed opioidergic  effects as well.  These opioidergic mechanisms appear to be responsible for certain analgesic effects of SSRI agents.  In fact, high dose naltrexone has been shown to block these analgesic effects, suggesting the involvement of the endogenous opioid system, and perhaps serotonin and dopamamine systems as well.  (Duman, et al, J Pharmacol Sci. 2004 Feb;94(2):161-5).  Therefore, an explanation for our unexpected findings emerged, suggesting that SSRI and SNRI activity synergistically interacts with the endogenous opioid, serotonin, dopamine, norepinephrine and related neurotransmitter systems. Together, ULDN and SSRI/SNRI agents appear to attenuate an underlying dysfunction in the endogenous opioid system, and perhaps the serotonin and dopamine systems as well. Thus we have discovered, for the first time, the dramatic synergistic therapeutic impact of combining ULDN, and, perhaps other Receptor Balancers, with an SSRI, and perhaps other serotonin-related, agents.  Combined, these agents provide a new generation of pharmaceutical formulations for the safe and effective treatment of a wide variety of Distress Dysfunction conditions, including chronic anxiety, depression, drug and food cravings, pain, addictions, agitation, emotional and physical hypersensitivity, anger and irritability, agitation and distress, and other neuropsychological symptoms and disorders.

 

Example 6

In order to test the effects of a selective cAMP PDE4 inhibitor and an Receptor Switcher on Distress Dysfunction symptoms, four subjects were given ultra-low-dose roflumilast with ultra-low-dose naltrexone for a period of four weeks.  All four subjects reported similar benefits from the co-treatment formulation.  Each of them independently described that they felt an increased calm, a greater sense of general “well being” and a decrease in worries and stresses.  They all indicated that they were less emotional reactive to minor stresses, yet more able than usual to respond appropriately to situations with being distracted by their usual exaggerated “catastrophic” emotional and cognitive overreactions.  They also noted that they had less of their normal aches and pains, particularly on individual with mild arthritis who felt a much greater sense of mobility in addition to a reduction in pain.  However, all of them noted that they did not feel any type of drug state or “high” of any kind, just a sense of normalcy.  One subject noted that he had a very mild headache during the trial, but that it went away by the end of the fourth day. All therapeutic benefits consistently improved over the course of the trial.

 

Discussion of Example 6

What was remarkable about this small trial was the remarkably ultra-low-doses of both agents – literally one microgram of each agent, twice daily.  Roflumilast is conventionally used at 500 micrograms for COPD, and naltrexone is used at 50 milligrams for addiction.  Therefore, these doses are 1/500^th to 1/50,000^th of the normal doses of these agents. Yet, this novel cotreatment formulation had rather significant effects in reducing symptoms of Distress Dysfunction, both regarding emotional and cognitive anxieties and worries as well as aches and pains of conditions and mobility problems, such as arthritis.  What is also remarkable is that these low doses produced, with the exception of one mild headache, no side effects or signs of withdrawal, nor did they produce any altered cognitive or emotional states, other than a sense of normal well being.  Thus, it would appear that this simple formulation was able to produce positive emotional and physical hedonic homeostasis.

 

Example 7

Several subjects with asthma, already taking theophylline, were given ultra-low-dose naltrexone over periods ranging from days to a year.  Remarkably and unexpectedly, these subjects experienced a dramatic reduction in a variety of side effects from the medication, including hyperalgesia, agitation, anxiety, and various gastrointestinal symptoms.  Sensitivity to pain was greatly reduced, including chest pain associated with asthma. Subjects were also given roflumilast, instead of theophylline.  Roflumilast alone, like theophylline, often produced side effects, such as increased pain sensitivity, anxiety, and GI symptoms.  However, when cotreated with ultra-low-dose naltrexone, these side effects generally resolved.  Furthermore, given the increased calming influence and pain relief from the cotreatment formula, it clearly provided a more effective treatment for asthma.  This finding with asthma sufferers suggests that this increased therapeutic efficacy and safety would also occur when using this cotreatment formula for COPD patients.

More recently, these subjects were transitioned to roflumilast (500 mg) and n-acetyl-cysteine (1200 mg).  The results have been even more compelling, especially over time.  Asthma has been consistently controlled, with an increased sense of calm and well being, and an absence of side effects.  A clear synergistic effect has been discovered between these two agents, both regarding their respiratory benefits, but also their ability to resolve symptoms of Distress Dysfunction that are both a function of the asthmatic condition as well as a side effect of the medications.

 

Summary of Validation Studies

In summary, a series of studies have been conducted in order to validate the science and formulations contained in this patent.  This research has consisted of two primary forms of investigation:  induced pain and clinical case studies.

 

Induced Pain Trials

 

More than 100 subjects have participated in hot and cold water induced pain trials. In addition to the hot-water finger immersion studies described above, two Jeio Tech cold-pressor testing units have been purchased since this methodology represents the state-of-the art in induced pain research.  Consensus in the research literature, as well as our own findings, suggest that over-the-counter analgesics, such as acetaminophen, aspirin, and ibuprofen, have no greater analgesic effect than placebo in cold-pressor pain tolerance testing.  Only exogenous opioid drugs, such as oxycodone, have been shown to have a significant analgesic effect, making the cold-pressor the “gold standard” for moderate-to-severe pain assessment.

 

Our studies have included a variety of formulations, based on the discoveries made in this patent.  Receptor Switchers have included ultra-low-dose naltrexone (1-10 microgram), N-Acetyl-Cysteine (NAC), and Magnesium Sulfate.  Endorphin Enhancers have included roflumilast, theophylline, caffeine, ginkgo biloba, glutamic acid, MSG, and DLPA. All of the subjects were given a variety of formulations over time from single agents to up to four agents, as well as placebo, in order to assess intra-subject differences and controls. When administered alone in blinded trials, these agents were shown to be no better than placebo.  In fact, many of the Endorphin Enhancers, such as roflumilast, theophylline, and glutamic acid, when given alone, tended to result in shorter pain tolerance latencies, indicating hyperalgesic effects.  On the other hand, when a Receptor Switcher was combined with an Endorphin Enhancer, these formulations were generally more effective than placebo and non-opioid analgesics (including acetaminophen, ibuprophen, aspirin).  In fact, several formulations were found to be as effective as exogenous opioids, such as oxycodone.  The addition of Synergistic Enhancers, such as low-dose non-opioid analgesics (including acetaminophen, aspirin, and white willow bark) were found to potentiate the basic co-treatment formula, and resulted in greater analgesia than the agents administered alone.  All of these results have been consistent for both single dose and multi-day trials, with a clear tendency toward increased pain relief with repeated dosing.

 

Therefore, these novel non-opioid formulations were able to reduce moderate-to-severe pain at levels consistent with opioid analgesics, such as oxycodone, without any of the noxious side effects typical of exogenous opioids.  A trial using very-low-doses of Exogenous Opioids (e.g., tramadol and oxycodone), combined with a Receptor Balancer (e.g., ULDN and NAC) and an Endorphin Enhancer (e.g., roflumilast and glutamic acid), showed particularly dramatic analgesia, as reflected in increased pain tolerance on the cold-pressor test, demonstrating a marked synergistic potentiation when using very-low-doses of Exogenous Opioids, which when administered alone, were no different than placebo.  This cotreatment formulation eliminated nearly all of the typical side effects of the Exogenous Opioids, in part, we hypothesized, because of the very-low doses used.

 

Subjects in these induced pain trials consistently reported an absence of side effects using our formulations (in contrast to the typical side effect profile reported when normal dose exogenous opioids were administered, including constipation, itching, emotional and cognitive disorientation, and yearnings to take more of the opioid). Normal acute reflexive pain was always maintained, with no changes in cognitive abilities (again, in contrast to the “conventional dose” opioids, often characterized by blurred judgment and logic, and interference with adaptive acute reflexive pain). Moreover, subjects frequently reported many remarkable therapeutic benefits, consistent with a reduction in Distress Dysfunction, including an increased sense of calm and well being, and a significant decrease in anxiety, worries, obsessions, anger, irritability, distractibility, cravings, GI symptoms, and general aches and pains.  Therefore, these novel formulations were able to simultaneously reduce emotional and physical distress and pain, with no side effects.  While similar in pain relief, the cognitive and emotional differences between our formulations and exogenous opioids were quite remarkable.

 

Clinical Case Studies

 

More than 85 patients with various forms of Distress Dysfunction have participated in clinical case studies using these formulations, using remarkably low doses of all agents, from a few days to more than one year.  Many of these patients (35) suffered from emotional distress, including anxiety, obsessive-compulsive symptoms, panic, social fears, depression, dysthymia, anger, irritability, and emotional agitation and outbursts.  Another group of patients (18) suffered from pain, including fibromyalgia, neuropathic pain, arthritis, headaches as well as back, shoulder, and neck pain.  Many of these patients also suffered from anxiety and depression.  Another group of patients suffered from alcohol (7) and opioid (3) dependence, which lasted for several years with daily abuse.  Another group of patients (6) suffered from eating disorders.  Another group (4) suffered from IBS, primarily diarrhea.  Finally, three patients were diagnosed with adult Autistic Spectrum Disorder, particularly Asperger’s Syndrome.  A number of these patients also had co-existing problems, including sexual dysfunction, behavioral addictions, premenstrual syndrome, seasonal affective disorder, and social and relationship conflicts.  The same cotreatment formulations used in the induced pain trials were generally used within this clinical population, with the exception of Exogenous Opioids and the addition of certain Synergistic Enhancers (e.g., SSRIs, SNRIs, 5HTP).  Approximately 25% of these patients were already on an SSRI or SNRI, so either a Receptor Switcher alone, or a Receptor Switcher plus an Endorphin Enhancer, were simply added to the ongoing treatment.  A majority of these patients were in concurrent psychotherapy.  Most of the case studies involved full disclosure with no blinding.  Nearly all of the patients were given more than one cotreatment formulation over time to assess the differential benefits, using intra-subject comparisons.

 

Although placebo factors must always be considered, the results of these case studies were, nevertheless, remarkable.  All but three patients, all of whom suffered from Major Depressive Disorder and were not on an SSRI or SNRI, reported clear, and at times dramatic, improvements in their emotional and physical distress, including pain and GI symptoms.  Therapeutic benefits of this novel treatment were only observed when at least on Receptor Switcher was included in the formulation.  All of these patients had been suffering from significant symptoms for over a year, and many for more than a decade.  For those on an SSRI and/or in psychotherapy, prior benefits were compared to those obtained with the addition of our novel cotreatment formulations.  The most reliable therapeutic benefit our formulations provided for these patients was a dramatic reduction in emotional distress, particularly a remarkable decrease in anxiety, irrational fears and worries, panic, obsessions, compulsions, anger and irritability, and depression. Increased attention, concentration, productivity, and overall social and emotional functioning were consistently reported.  Nearly all patients experienced a greater calm and sense of well being than they felt in years, a benefit that was maintained consistently during the entire course of treatment.  One 87-year-old female, with severe arthritis, chronic worries, and depression, remarked that “I felt for the first time in years that life is worth living.”

 

Patient with obsessive-compulsive symptoms that were not controlled by psychotherapy or medication, including SSRIs and SNRIs, experienced a dramatic reduction in symptoms, which had previously controlled their lives.  SSRI treatment was clearly enhanced using Receptor Switchers and Endorphin Enhancers.  Other Synergistic Enhancers also increased therapeutic benefits.  IBS symptoms were reduced for the first time in years for several patients.  Eating disorder symptoms (that had remained unchanged despite years of psychotherapy and conventional medication) were remarkably reduced, including a decrease in food cravings, binging, purging, and general sense of emptiness often experienced by many of these patients. Increased sexual functioning, including a reduction in premature ejaculation was reported by several patients. Several patients with Asperger’s Syndrome were able to relax and become more social, as well as less irritable with a great reduction in emotional outbursts.  All patients with alcohol and opioid dependence were able to completely eliminate their substance abuse after years of unsuccessful treatment, and also experienced a greater sense of well being and reduction in cravings and anxieties.

 

Overall, physical distress was dramatically reduced, with benefits increasing significantly over time.  Complaints about moderate-to-severe pain, regardless of the etiology, were generally reduced, without use of opioid analgesics.  No tolerance was ever experienced so that the remarkably low doses of formulations were maintained throughout all case studies.  No side effects were reported, with all cognitive and emotional functions improved, in contrast to the experience reported by patients when they have used conventional medications, especially exogenous opioid drugs.  If anything, cognitive and emotional functions were significantly improved, with greater clarity, judgment, attention, mood, and motivation.

 

Therefore, while placebo factors and concurrent psychotherapy were potential confounding factors, these case studies offer compelling evidence of meaningful therapeutic benefits for a wide variety of Dysfunctional Distress disorders, conditions, and symptoms, using these remarkably safe pharmaceutical formulations.  Specifically, these case studies, which always included a Receptor Switcher (ULDN, NAC, or magnesium sulfate) combined with an Endorphin Enhancer (roflumilast, theophylline, ginkgo biloba, caffeine, glutamic acid, MSG, or DLPA) and/or a Synergistic Enhancer (SSRI, SNRI, white willow bark, acetaminophen, aspirin, 5HTP), provide validation for the remarkable safety and clinical effectiveness for our pharmaceutical formulations.

 

Therefore, a series of clinical trials and case studies have been conducted  which surprisingly and dramatically support the emotional and physical health restoring benefits of these novel formulations.  Over 200 subjects and patients have been given one or more of these novel formulations.  There have been no side effects or any adverse events observed in any of these individuals.  In addition, all reports indicate that these formulations do not produce any feeling of “taking a drug,” in contrast to the “drugged” experience typically seen in most medications currently available for the treatment of symptoms of Distress Dysfunction, such as tranquillizers and opioid drugs.  At the same time, the therapeutic benefits of these novel formulations have been extremely positive, and dramatically more effective that any of the agents when taken alone, or in combinations within each functional category of agents, thereby validating the surprising synergistic healing power of this invention’s unique formulations.  Using this invention’s principles, new formulations, using different agents with similar functional properties, have reliably been effective, validating these principles and the entire invention.  Furthermore, since these formulations clearly are safer and more effective than conventional treatment, they provide validation for both the existence of Distress Dysfunction, as defined in this patent, and for a revolutionary line of pharmaceutical formulations, which literally restore healthy homeostatic balance to the neurotransmitter systems within the nervous system.

 

 

 

 

 

 

CLAIMS

What is claimed is:

1. A method to safely and effectively treat DISTRESS DYSFUNCTION by the administration of at least one RECEPTOR SWITCHER (CLASS I AGENTS), together with at least one ENDORPHIN ENHANCER (CLASS II AGENTS) and/or EXOGENOUS OPIOID (CLASS III AGENTS) and/or SYNERGISTIC ENHANCER (CLASS IV AGENTS), as defined in this patent.
2. A method of treatment for one or more of the following DISTRESS DYSFUNCTION conditions, symptoms and/or disorders:  (1) Anxiety Disorders, including, but not limited to, Panic Disorders, Agoraphobia, Specific Phobias, Social Phobias, Obsessive-Compulsive Disorder, Post-Traumatic Stress Disorder, Acute Stress Disorder, Generalized Anxiety Disorder, Substance-Induced Anxiety, Anxiety Related to Medical Disorders, Anxiety Disorder Not Otherwise Specified (NOS), as well as signs and symptoms of anxiety, stress, agitation, and worry that are not classified as an Anxiety Disorder; (2) Mood Disorders, including, but not limited to, Depressive Disorders, Dysthymic Disorder, Bipolar I Disorder, Bipolar II Disorder, Bipolar Disorder NOS, Cyclothymic Disorder, Mood Disorders Related to Medical Conditions, Seasonal Affective Disorder, Mood Disorders NOS, as well as signs and symptoms of depressed mood, anhedonia, despair, anhedonia, hypomania, mania, and negative hedonic tone that are not classified as a Mood Disorder; (3) Somatoform Disorders, including, but not limited to, Somatization Disorder, Somatoform Disorder, Conversion Disorder, Pain Disorder Associated with Psychological Factors, Pain Disorder Associated with Medical Conditions, Hypochondriasis, Body Dysmorphic Disorder, and Somatoform Disorder NOS; (4)  Factitious Disorders, including but not limited to, Factitious Disorders with Psychological Signs and Symptoms, Factitious Disorders with Physical Signs and Symptoms Factitious Disorders with Combined Psychological and Physical Signs and Symptoms, and Factitious Disorder NOS; (5) Dissociative Disorders; (6) Sexual Dysfunction, including, but not limited to, Sexual Desire Disorders, Sexual Arousal Disorders, Orgasmic Disorders, Premature Ejaculation, Erectile Dysfunction, Sexual Pain Disorder, Sexual Dysfunction to a General Medical Condition, Substance-Induced Sexual Dysfunction, Sexual Dysfunction NOS, as well as signs and symptoms of sexual dissatisfaction and dysfunction that are not classified as a Sexual Dysfunction disorder; (7) Eating Disorders, including, but not limited to, Bulimia Nervosa, Anorexia Nervosa, Binge Eating, Eating Disorder NOS, as well as signs and symptoms of eating and appetite problems that are not classified as an Eating Disorder; (8) Gastrointestinal Disorders, including, but not limited to, Irritable Bowel Syndrome (IBS) with Predominately Diarrhea, IBS with Predominately Constipation, and IBS Mixed Type, Crohn’s Disease, as well as GI distress including, but not limited to, nausea, vomiting, diarrhea, constipation, and bloating; (9) Pre-Menstrual Syndrome (PMS) and other hormonally-related distress signs and symptoms; (9) Movement Disorders, including, but not limited to, Restless Leg Syndrome; (10) Fibromyalgia; (11) Sleep Disorders, including, but not limited to, Insomnia, Dyssomnias  Parasomnias as well as signs and symptoms of sleep problems that are not classified as a Sleep Disorder; (12) Impulse-Control Disorders, including, but not limited to, Intermittent Explosive Disorder, Kleptomania, Pyromania, Pathological Gambling, Trichotillomania, Impulse Control Disorder NOS as well as signs and symptoms of impulsivity that are not classified as an Impulse-Control Disorder; (13) Psychological Factors Affecting Medical Conditions; (14) Medication-Induced Movement Disorders; (15) Alcohol-Related Disorders, including, but not limited to, Alcohol Dependence, Alcohol Abuse, Alcohol Addiction, Alcohol-Induced Disorders, Alcohol-Related Disorder NOS as well as alcohol-related problems that are not classified as an Alcohol-Related Disorder; (16) Opioid-Related Disorders, including, but not limited to, Opioid Dependence, Opioid Addiction, Opioid Abuse, Opioid-Induced Disorders, Opioid-Related Disorder NOS, as well as opioid-related problems that are not classified as an Opioid-Related Disorder;  (17) Caffeine-Related Disorders, including, but not limited to, Caffeine Dependence, Caffeine Addiction, Caffeine Abuse, Caffeine-Induced Disorders, Caffeine-Related Disorders NOS as well as caffeine-related problems that are not classified as a Caffeine-Related Disorder; (18) Cannabis-Related Disorders, including, but not limited to, Cannabis Dependence, Cannabis Addiction, Cannabis Abuse, Cannabis-Induced Disorders, and Cannabis-Related Disorder NOS; (19) Amphetamine (or Amphetamine-Like)-Related Disorders, including but not limited to, Amphetamine Dependence, Amphetamine Addiction, Amphetamine Abuse, Amphetamine-Induced Disorders, and Amphetamine-Related Disorder NOS; (20) Cocaine-Related Disorders, including, but not limited to, Cocaine Dependence, Cocaine Addiction, Cocaine Abuse, Cocaine-Induced Disorders, and Cocaine-Related Disorder NOS; (21) Nicotine-Related Disorders, including, but not limited to, Nicotine Dependence, Nicotine Addiction, Nicotine Abuse, Nicotine-Induced Disorders, and Nicotine-Related Disorder NOS; (22) Inhalant-Related Disorders, including, but not limited to, Inhalant Dependence, Inhalant Addiction, Inhalant Abuse, Inhalant-Induced Disorders, and Inhalant-Related Disorder NOS; (23) Phencyclidine-Related Disorders, including, but not limited to, Phencyclidine Dependence, Phencyclidine Addiction, Phencyclidine Abuse, Phencyclidine-Induced Disorders, and Phencyclidine- Related Disorder NOS; (24) Sedative-, Hypnotic-, or Anxiolytic-Related Disorders, including, but not limited to, Sedative-, Hypnotic-, or Anxiolytic Dependence, Addiction, and/or Abuse, Sedative-, Hypnotic-, or Anxiolytic-Induced Disorders, and Sedative-,Hypnotic-, or Anxiolytic-Related Disorder NOS; (25) Polysubstance-Related Disorders;(26)  Pervasive Developmental Disorders, including, but not limited to, Autism Disorder, Rhett’s Disorder, Aspberger’s Disorder, or Pervasive Developmental Disorder NOS; (27) Attention-Deficit and Disruptive Behavior Disorders, including, but not limited to Attention-Deficit/Hyperactivity Disorder, Conduct Disorder, Oppositional Disorder, Disruptive Behavior Disorder NOS as well as attentional and concentration problems that are not classified as an Attention-Deficit Disorder; (28) Chronic Fatigue Disorder, (29) Psychotic Disorders, (30) Behavioral addictions, compulsions, and dysfunctions, including, but not limited to, sex, pornography, gambling, shopping, eating, drinking, smoking, computer use, and cleaning, (31) Pain disorders, including, nociceptive, neuropathic, migraine and psychogenic pain, (32)  Psychotic disorders, including, but not limited to, schizophrenia; (33) Unpleasant or deleterious side effects of CLASS II,III, or IV agents when such agents are administered alone (i.e., without co-administration with an CLASS I agent) which may, or may not, interfere with the potential therapeutic benefits of CLASS II, III, or IV agents, including, but not limited to PDE inhibitors, opioid and non-opioid analgesics, stimulants, SSRIs, SNRIs, and amino acids; (34) Respiratory, inflammatory, and pain disorders including, but not limited to, asthma and COPD; (35) Allergic and non-allergic glutamate and mono-sodium glutamate related disorders, including “Chinese Food Syndrome”, and (36) Emotional and physical malaise, distress, discomfort, pain, restlessness, irritability, worries, cravings, compulsions, obsessions, agitation, addictions, and other related complaints and signs of protracted negative hedonic tone that may, or may not, be part of a traditional medical or psychiatric disorder. Distress Dysfunction is not limited to these conditions and diagnoses and is best defined by a variety of symptoms, conditions, syndromes, and disorders, characterized by dysfunctional emotional and physical distress and pain.
3. A method to treat DISTRESS DYSFUNCTION, as defined in claims 1-2, that includes at least one RECEPTOR SWITCHER (CLASS I AGENT) that is functionally defined such that, when co-administered with CLASS II, III, and/or IV AGENTS, reduce and/or resolve one or more Distress Dysfunction symptoms.  CLASS I AGENTS include, but are not limited to:  agents that selectively block and/or inhibit opioid receptor excitatory signaling, ultra-low-dose and very-low-dose opioid antagonists, ultra-low-dose and very-low-dose naltrexone, naloxone, diprenorphine, nalmefene, and norbinaltorphimine, agents that inhibit synthesis or activity of GM1 ganglioside, neuraminidase inhibitors, magnesium sulfate, chondroitin sulfate, sodium sulfate, n-acetyl-cysteine (NAC), oseltamivir, zanamivir, laninamivir, peramivir,, scutellaria, and 5,7,4′-trihydroxy-8-methoxyflavone.
4. A method to treat DISTRESS DYSFUNCTION, as defined in claims 1-2, that can include one or more ENDORPHIN ENHANCERS (CLASS II AGENTS) that are functionally defined such that, when co-administered with at least one RECEPTOR SWITCHER (CLASS I AGENT), reduce and/or resolve one or more Distress Dysfunction symptoms.  CLASS II AGENTS include, but are not limited to: agents that enhance the release, production, and/or functioning of endogenous opioids (i.e., endorphins), cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE) inhibitors or agents that directly enhance cAMP, a cAMP phosphodiesterase (PDE) inhibitor, an agent that directly enhances cAMP, a specific or non-specific cAMP PDE inhibitor, a specific cAMP PDE-4 inhibitor, theophylline, roflumilast, ibudilast, cilomilast, ardenafil, tadalafil, sildenafil, zaprinast, rolipram, methylxanthine, milrinone, inamrinone, cilostazol, caffeine, forskolin, excitatory amino acids, a salt of an excitatory amino acid, all forms of excitatory amino acids, glutamic acid, aspartic acid, glutamine, mono-sodium glutamate (MSG), and N-methyl-D-asparate (NMDA), phenylalanine, and dl-phenylalanine (DLPA).
5. A method to treat DISTRESS DYSFUNCTION, as defined in claims 1-2, that can include one or more EXOGENOUS OPIOIDS (CLASS III AGENTS) that are functionally defined such that, when co-administered with at least one RECEPTOR SWITCHER (CLASS I AGENT), reduce and/or resolve one or more DISTRESS DYSFUNCTION symptoms.  CLASS III AGENTS include, but are not limited to:  exogenous opioid agonist (full, partial, mixed) agents, tramadol, morphine, oxycodone, hydrocodone, papaverine, codeine, dihydrocodeine, fentanyl, hydromorphone, buprenorphine, butorphanol, methadone, alfentanil, levorphanol, meperidine, nalbuphine, oxymorphone, pentazocine, pentazocine, propoxyphene, remifentanil, and sufenta.
6. A method to treat DISTRESS DYSFUNCTION, as defined in claims 1-2, that can include one or more SYNERGISTIC ENHANCERS (CLASS IV AGENTS) that are functionally defined such that, when co-administered with at least one RECEPTOR SWITCHER (CLASS I AGENT), reduce and/or resolve one or more DISTRESS DYSFUNCTION symptoms.   CLASS IV AGENTS include, but are not limited to, agents that enhance the release, production and/or functioning of serotonin, dopamine, epinephrine, norepinephrine, and glutamate neurotransmitters, non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, white willow bark, acetylsalicylic acid, salicin, ibuprofen, naproxen, ketoprofen, indomethacin, fenoprofen, tolmetin, sulindac, meclofenamate, piroxicam, flurbiprofen, diclofenac, stimulants, selective serotonin reuptake inhibitors (SSRI), serotonin agonists, antagonists and modulators, selective norepinephrine reuptake inhibitors (SNRIs), citalopram, dapoxetine, escitalopram, fluoxetine fluvoxamine, paroxetine, sertraline, fluvoxamine, zimelidine, dapoxetine, alosetron, ondansetron, granisetron, bemesetron, eplivanserine, deramciclane, agomelatine, elazasonan, pruvanserin, asenapine, zomari, valazodone, bifeprunox, buspirone, ritanseron, geperone, paliperidone, clomipram, doxepin, haloperidol, risperidone, amino acids, a salt of an inhibitory amino acid, all forms of  amino acids, gamma-aminobutrynic acid (GABA), glycine, taurine, tryptophan, 5HTP,phenylalanine, dl-phenylalanine (DLPA), valine, threonine, methionine, lysine, leucine, isoleucine, tyrosine, alanine, arginine, histidine, serine, selenocfysteine, proline, glycine, cysteine, aspargine, alanine, L-DOPA, vitamins and minerals, luteolin, quercetin, qercetin-3-O-methylether (3-MQ, 2), quercetin-3,7,4′-O-trimethylether, ayanin, quercetin-3,7,3′,4′-O- tetramethylether, quercetin-3,5,7,3′,4′-O-petamethylether, quercetin-3,5,7,3′,4′-O-pentaacetate, quercetin-3-O-methyl-5,7,3′,4′-O-tetraacetate, methylcobalamin, vitamin C, vitamin D, vitamin D-3,, vitamins B1, B2, B3, B6, and B12, folic acid, niacin, or niacinamide, folinic acid, calcium folinate, methylcobalamin, pyridoxal-5′-phosphate (P5P), alkaloids, flavonoids, and saponins, hesperetin, hesperidin, naringin, naringenin, epigallocatechin-3-gallate (EGCG), dioclein, genistein, daidzein, eriodictyol, prunetin, biochanin A, apigenin, myricetin, liquiritigenin, liquiritin, kaempferol, isoliquiritigenin, chrysin, rutin, cyanidin, delphinidin, pelargonidin, isorhamnetin, vitamin C, St. John’s Wort, passion flower, hyperforin, hypericin, biotin, vitamin B5 (pantothenic acid), magnesium, alpha-ketoglutarate, copper, zinc, L-theanine, iron, california poppy, ginseng (Panax spp.), licorice, night-blooming cereus (Selenicereus grandiflorus; Cactus grandiflorus), hordenine, nutmeg, myristicin, tyramine, scotch broom, green tea, ephedra, and yohimbe.
7. The method for claims 1-2, comprising the step of administering to a subject at least one RECEPTOR SWITCHER co-administered with at least one ENDORPHIN ENHANCER.
8. The method for claims 1-2, comprising the step of administering to a subject at least one RECEPTOR SWITCHER co-administered with at least one EXOGENOUS OPIOID.
9. The method for claims 1-2, comprising the step of administering to a subject at least one RECEPTOR SWITCHER co-administered with at least one SYNERGISTIC ENHANCER.

10. The method for claims 1-2, comprising the step of administering to a subject at least one RECEPTOR SWITCHER co-administered with at least one ENDORPHIN ENHANCER and at least one EXOGENOUS OPIOID.

11. The method for claims 1-2, comprising the step of administering to a subject at least one RECEPTOR SWITCHER co-administered with at least one ENDORPHIN ENHANCER and at least one SYNERGISTIC ENHANCER.

12. The method for claims 1-2, comprising the step of administering to a subject at least one RECEPTOR SWITCHER co-administered with at least one EXOGENOUS OPIOID and at least one SYNERGISTIC ENHANCER.

13. The method for claims 1-2, comprising the step of administering to a subject at least one RECEPTOR SWITCHER co-administered with at least one ENDORPHIN ENHANCER and at least one SYNERGISTIC ENHANCER and at least one EXOGENOUS OPIOID.

14. The method for claims 1-2, comprising the step of administering at least one RECEPTOR SWITCHER to a subject already taking an ENDORPHIN BALANCER.

15. The method for claims 1-2, comprising the step of administering at least one RECEPTOR SWITCHER to a subject already taking an EXOGENOUS OPIOID.

16. The method for claims 1-2, comprising the step of administering at least one RECEPTOR SWITCHER to a subject already taking a SYNERGISTIC ENHANCER.

17. A method to enhance the therapeutic benefit and/or reduce the side effects of an ENDORPHIN ENHANCER by co-administering to a subject at least one RECEPTOR SWITCHER.

18. A method to enhance the therapeutic benefit and/or reduce the side effects of an EXOGENOUS OPIOID by co-administering to a subject at least one RECEPTOR SWITCHER.

19. A method to enhance the therapeutic benefit and/or reduce the side effects of a SYNERGISTIC ENHANCER by co-administering to a subject at least one RECEPTOR SWITCHER.

20. The method of Claims 1-19, wherein the RECEPTOR SWITCHER is an low dose opioid antagonist.

21. The method of Claims 1-19, wherein the RECEPTOR SWITCHER is low dose naltrexone.

22. The method of Claims 1-19, wherein the naltrexone is administered in the most preferred ultra low dose range of about 25 micrograms or less.

23. The method of Claims 1-19, wherein the naltrexone is administered in the very low dose range of about 25-250 micrograms.

24. The method of Claims 1-19 wherein the naltrexone is administered in the low dose range of about 250-1000 micrograms.

25. The method of Claims 1-1, wherein the OSD1 is naloxone.

26. The method of Claims 1-19, wherein the most preferred dosing of naloxone is an ultra low dosing of about 0.25 µg · kg^-1 · h^-1 .

27. The method of Claims 1-19 wherein an exemplary dosing of naloxone would be about 400 micrograms naloxone in 1000 ml crystalloid given in 24 h to a patient weighing 70 kg.

28. The method of Claims 1-19, wherein the next preferred dosing of naloxone is a very-low-dosing of about 1.0 µg · kg^-1 · h^-1 .

29. The method of Claims 1-19, wherein the dosing range of naloxone is .01 µg · kg^-1 · h^-1 to 5 µg · kg^-1 · h^-1.

30. The method of Claims 1-19, wherein the RECEPTOR SWITCHER is a neuramindase inhibitor.

31. The method of Claims 1-19, wherein the RECEPTOR SWITCHER is n-acetyl-cysteine.

32. The method of Claims 1-19, wherein the RECEPTOR SWITCHER is magnesium sulfate.

33. The method of Claims 1-19, wherein the ENDORPHIN ENHANCER is a cAMP PDE inhibitor.

34. The method of Claims 1-19, wherein the ENDORPHIN ENHANCER is roflumilast.

35. The method of Claims 1-19, wherein the ENDORPHIN ENHANCER is theophylline.

36. The method of Claims 1-19, wherein the ENDORPHIN ENHANCER is ginkgo biloba.

37. The method of Claims 1-19, wherein the ENDORPHIN ENHANCER is caffeine.

38. The method of Claims 1-19, wherein the ENDORPHIN ENHANCER is ibudilast.

39. The method of Claims 1-19, wherein the ENDORPHIN ENHANCER is an excitatory amino acid.

40. The method of Claims 1-19, wherein the ENDORPHIN ENHANCER is glutamic acid or mono-sodium-glutamate.

41. The method of Claims 1-19, wherein the ENDORPHIN ENHANCER is DLPA.

42. The  method of Claims 1-19, wherein the EXOGENOUS OPIOID is tramadol.

43. The  method of Claims 1-19, wherein the EXOGENOUS OPIOID is oxycodone.

44. The  method of Claims 1-19, wherein the EXOGENOUS OPIOID is hydrocodone.

45. The  method of Claims 1-19, wherein the EXOGENOUS OPIOID is morphine.

46. The method of Claims 1-19, wherein the SYNERGISTIC ENHANCER is a selective serotonin reuptake inhibitor or a selective norepinephrine reuptake inhibitor.

47. The method of Claims 1-19, wherein the SYNERGISTIC ENHANCER is a non-opioid analgesic.

48. The method of Claims 1-19, wherein the SYNERGISTIC ENHANCER is non-steroidal anti-inflammatory agent.

49. The method of Claims 1-19, wherein the SYNERGISTIC ENHANCER is a acetaminophen.

50. The method of Claims 1-19, wherein the SYNERGISTIC ENHANCER is aspirin.

51. The method of Claims 1-19, wherein the SYNERGISTIC ENHANCER is white willow bark.

52. The method of Claims 1-19, wherein the SYNERGISTIC ENHANCER is ibuprofen.

53. The method of Claims 1-19, wherein the SYNERGISTIC ENHANCER is an amino acid in any form or derivative, including a salt.

54. The method of Claims 1-19, wherein the SYNERGISTIC ENHANCER is 5HTP or tryptophan.

55. The method of Claims 1-19, wherein an additional agent is arginine.

56. The method of Claims 1-19, wherein the RECEPTOR SWITCHER is naloxone, the SYNERGISTIC ENHANCER is ibuprofen, and the co-administration further includes administering arginine.

57. The method of Claims 1-19, wherein the RECEPTOR SWITCHER is naloxone, the SYNERGISTIC ENHANCER is ibuprofen, the EXOGENOUS OPIOID is morphine, and the co-administration further includes administering arginine.

58. The method of Claims 1-19, wherein the mode of administration is selected from the group consisting of oral, nasal, sublingual, parenteral, or transdermal.

59. The method of Claims 1-19, wherein the pharmaceutical formulation is delivered in a pharmaceutically-acceptable carrier that is rapid release, immediate-release, slow-release, or delayed-released, including nano-encapsulation formulations that allows for extended and slow release of the pharmaceutical formulation.

60. The method of Claims 1-19, wherein the pharmaceutical formulation is delivered in an abuse-resistant delivery system.

61. The method of Claims 1-19, wherein the pharmaceutical formulation is combined with appropriate agents to improve delivery and effectiveness.

62. The method of Claims 1-19, wherein the dose, frequency, and administration method of the agents are chosen in order to maximize the therapeutic effectiveness of each formulation.

63. The method of Claims 1-19, wherein the ENDORPHIN ENHANCER is a glutamate or glutamine, including monosodium glutamate (MSG), and by combining these ENDORPHIN ENHANCERS with a RECEPTOR SWITCHER, including, but not limited to magnesium sulfate and NAC, (a) This formulation provides an effective treatment for the allergic and other noxious side effects of MSG, and (b) By preserving the flavor enhancing characteristics of MSG and attenuating and eliminating the noxious side effects of MSG, this formulation is appropriate and useful as a food additive, condiment, and flavor enhancer.

64. The method of Claims 1-19, wherein the ENDORPHIN ENHANCER is a PDE inhibitor including, but not limited to roflumilast, ibudilast, rolipram, and theophylline, and by combining these PDE inhibitors with a RECEPTOR SWITCHER, including, but not limited to, ultra-low-dose opioid antagonists and neurominidase inhibitors, (a) This formulation reduces side effects, that would occur when the PDE inhibitor is administered alone, and/or (b) This formulation reduces hyperalgesia that would occur when the PDE inhibitor is administered alone, and/or (c) This formulation improves the therapeutic efficacy of the PDE inhibitor when administered alone, and/or (d) This formulation improves the therapeutic benefit of the PDE inhibitor in the treatment of respiratory conditions including, but not limited to, COPD and asthma, as compared to the administration of the PDE inhibitor alone.

65. A method of Claim 64, wherein the ENDORPHIN ENHANCER is a specific cAMP PDE-4 inhibitor, and the RECEPTOR SWITCHER is ultra-low-dose or very-low-dose naltrexone

66. A method of Claim 64, wherein the ENDORPHIN ENHANCER is rofllumilast, ibudilast, theophylline, or ginkgo biloba, and the RECEPTOR SWITCHER is ultra-low-dose or very-low-dose naltrexone.

67. A method of Claim 64, wherein the ENDORPHIN ENHANCER is a specific cAMP PDE-4 inhibitor, and the RECEPTOR SWITCHER is n-acetyl-cysteine.

68. A method of Claim 64, wherein the ENDORPHIN ENHANCER is rofllumilast, ibudilast, or theophylline, and the RECEPTOR SWITCHER is n-acetyl-cysteine.

69. A method of Claim 64, wherein the ENDORPHIN ENHANCER is ginkgo biloba, and the RECEPTOR SWITCHER is n-acetyl-cysteine

70. These and other embodiments of this invention that will readily occur to those skillful in the art are covered by this patent, in view of the disclosures contained in this patent.

71. A composition to safely and effectively treat DISTRESS DYSFUNCTION by the administration of at least one RECEPTOR SWITCHER (CLASS I AGENTS), together with at least one ENDORPHIN ENHANCER (CLASS II AGENTS) and/or EXOGENOUS OPIOID (CLASS III AGENTS) and/or SYNERGISTIC ENHANCER (CLASS IV AGENTS), as defined in this patent.

72.  A composition of treatment for one or more of the following DISTRESS DYSFUNCTION conditions, symptoms and/or disorders:  (1) Anxiety Disorders, including, but not limited to, Panic Disorders, Agoraphobia, Specific Phobias, Social Phobias, Obsessive-Compulsive Disorder, Post-Traumatic Stress Disorder, Acute Stress Disorder, Generalized Anxiety Disorder, Substance-Induced Anxiety, Anxiety Related to Medical Disorders, Anxiety Disorder Not Otherwise Specified (NOS), as well as signs and symptoms of anxiety, stress, agitation, and worry that are not classified as an Anxiety Disorder; (2) Mood Disorders, including, but not limited to, Depressive Disorders, Dysthymic Disorder, Bipolar I Disorder, Bipolar II Disorder, Bipolar Disorder NOS, Cyclothymic Disorder, Mood Disorders Related to Medical Conditions, Seasonal Affective Disorder, Mood Disorders NOS, as well as signs and symptoms of depressed mood, anhedonia, despair, anhedonia, hypomania, mania, and negative hedonic tone that are not classified as a Mood Disorder; (3) Somatoform Disorders, including, but not limited to, Somatization Disorder, Somatoform Disorder, Conversion Disorder, Pain Disorder Associated with Psychological Factors, Pain Disorder Associated with Medical Conditions, Hypochondriasis, Body Dysmorphic Disorder, and Somatoform Disorder NOS; (4)  Factitious Disorders, including but not limited to, Factitious Disorders with Psychological Signs and Symptoms, Factitious Disorders with Physical Signs and Symptoms Factitious Disorders with Combined Psychological and Physical Signs and Symptoms, and Factitious Disorder NOS; (5) Dissociative Disorders; (6) Sexual Dysfunction, including, but not limited to, Sexual Desire Disorders, Sexual Arousal Disorders, Orgasmic Disorders, Premature Ejaculation, Erectile Dysfunction, Sexual Pain Disorder, Sexual Dysfunction to a General Medical Condition, Substance-Induced Sexual Dysfunction, Sexual Dysfunction NOS, as well as signs and symptoms of sexual dissatisfaction and dysfunction that are not classified as a Sexual Dysfunction disorder; (7) Eating Disorders, including, but not limited to, Bulimia Nervosa, Anorexia Nervosa, Binge Eating, Eating Disorder NOS, as well as signs and symptoms of eating and appetite problems that are not classified as an Eating Disorder; (8) Gastrointestinal Disorders, including, but not limited to, Irritable Bowel Syndrome (IBS) with Predominately Diarrhea, IBS with Predominately Constipation, and IBS Mixed Type, Crohn’s Disease, as well as GI distress including, but not limited to, nausea, vomiting, diarrhea, constipation, and bloating; (9) Pre-Menstrual Syndrome (PMS) and other hormonally-related distress signs and symptoms; (9) Movement Disorders, including, but not limited to, Restless Leg Syndrome; (10) Fibromyalgia; (11) Sleep Disorders, including, but not limited to, Insomnia, Dyssomnias  Parasomnias as well as signs and symptoms of sleep problems that are not classified as a Sleep Disorder; (12) Impulse-Control Disorders, including, but not limited to, Intermittent Explosive Disorder, Kleptomania, Pyromania, Pathological Gambling, Trichotillomania, Impulse Control Disorder NOS as well as signs and symptoms of impulsivity that are not classified as an Impulse-Control Disorder; (13) Psychological Factors Affecting Medical Conditions; (14) Medication-Induced Movement Disorders; (15) Alcohol-Related Disorders, including, but not limited to, Alcohol Dependence, Alcohol Abuse, Alcohol Addiction, Alcohol-Induced Disorders, Alcohol-Related Disorder NOS as well as alcohol-related problems that are not classified as an Alcohol-Related Disorder; (16) Opioid-Related Disorders, including, but not limited to, Opioid Dependence, Opioid Addiction, Opioid Abuse, Opioid-Induced Disorders, Opioid-Related Disorder NOS, as well as opioid-related problems that are not classified as an Opioid-Related Disorder;  (17) Caffeine-Related Disorders, including, but not limited to, Caffeine Dependence, Caffeine Addiction, Caffeine Abuse, Caffeine-Induced Disorders, Caffeine-Related Disorders NOS as well as caffeine-related problems that are not classified as a Caffeine-Related Disorder; (18) Cannabis-Related Disorders, including, but not limited to, Cannabis Dependence, Cannabis Addiction, Cannabis Abuse, Cannabis-Induced Disorders, and Cannabis-Related Disorder NOS; (19) Amphetamine (or Amphetamine-Like)-Related Disorders, including but not limited to, Amphetamine Dependence, Amphetamine Addiction, Amphetamine Abuse, Amphetamine-Induced Disorders, and Amphetamine-Related Disorder NOS; (20) Cocaine-Related Disorders, including, but not limited to, Cocaine Dependence, Cocaine Addiction, Cocaine Abuse, Cocaine-Induced Disorders, and Cocaine-Related Disorder NOS; (21) Nicotine-Related Disorders, including, but not limited to, Nicotine Dependence, Nicotine Addiction, Nicotine Abuse, Nicotine-Induced Disorders, and Nicotine-Related Disorder NOS; (22) Inhalant-Related Disorders, including, but not limited to, Inhalant Dependence, Inhalant Addiction, Inhalant Abuse, Inhalant-Induced Disorders, and Inhalant-Related Disorder NOS; (23) Phencyclidine-Related Disorders, including, but not limited to, Phencyclidine Dependence, Phencyclidine Addiction, Phencyclidine Abuse, Phencyclidine-Induced Disorders, and Phencyclidine- Related Disorder NOS; (24) Sedative-, Hypnotic-, or Anxiolytic-Related Disorders, including, but not limited to, Sedative-, Hypnotic-, or Anxiolytic Dependence, Addiction, and/or Abuse, Sedative-, Hypnotic-, or Anxiolytic-Induced Disorders, and Sedative-,Hypnotic-, or Anxiolytic-Related Disorder NOS; (25) Polysubstance-Related Disorders;(26)  Pervasive Developmental Disorders, including, but not limited to, Autism Disorder, Rhett’s Disorder, Aspberger’s Disorder, or Pervasive Developmental Disorder NOS; (27) Attention-Deficit and Disruptive Behavior Disorders, including, but not limited to Attention-Deficit/Hyperactivity Disorder, Conduct Disorder, Oppositional Disorder, Disruptive Behavior Disorder NOS as well as attentional and concentration problems that are not classified as an Attention-Deficit Disorder; (28) Chronic Fatigue Disorder, (29) Psychotic Disorders, (30) Behavioral addictions, compulsions, and dysfunctions, including, but not limited to, sex, pornography, gambling, shopping, eating, drinking, smoking, computer use, and cleaning, (31) Pain disorders, including, nociceptive, neuropathic, migraine and psychogenic pain, (32)  Psychotic disorders, including, but not limited to, schizophrenia; (33) Unpleasant or deleterious side effects of CLASS II,III, or IV agents when such agents are administered alone (i.e., without co-administration with an CLASS I agent) which may, or may not, interfere with the potential therapeutic benefits of CLASS II, III, or IV agents, including, but not limited to PDE inhibitors, opioid and non-opioid analgesics, stimulants, SSRIs, SNRIs, and amino acids; (34) Respiratory, inflammatory, and pain disorders including, but not limited to, asthma and COPD; (35) Allergic and non-allergic glutamate and mono-sodium glutamate related disorders, including “Chinese Food Syndrome”, and (36) Emotional and physical malaise, distress, discomfort, pain, restlessness, irritability, worries, cravings, compulsions, obsessions, agitation, addictions, and other related complaints and signs of protracted negative hedonic tone that may, or may not, be part of a traditional medical or psychiatric disorder. Distress Dysfunction is not limited to these conditions and diagnoses and is best defined by a variety of symptoms, conditions, syndromes, and disorders, characterized by dysfunctional emotional and physical distress and pain.

73. A composition to treat DISTRESS DYSFUNCTION, as defined in claims 1-2, that includes at least one RECEPTOR SWITCHER (CLASS I AGENT) that is functionally defined such that, when co-administered with CLASS II, III, and/or IV AGENTS, reduce and/or resolve one or more Distress Dysfunction symptoms.  CLASS I AGENTS include, but are not limited to:  agents that selectively block and/or inhibit opioid receptor excitatory signaling, ultra-low-dose and very-low-dose opioid antagonists, ultra-low-dose and very-low-dose naltrexone, naloxone, diprenorphine, nalmefene, and norbinaltorphimine, agents that inhibit synthesis or activity of GM1 ganglioside, neuraminidase inhibitors, magnesium sulfate, chondroitin sulfate, sodium sulfate, n-acetyl-cysteine (NAC), oseltamivir, zanamivir, laninamivir, peramivir,, scutellaria, and 5,7,4′-trihydroxy-8-methoxyflavone.

74. A composition to treat DISTRESS DYSFUNCTION, as defined in claims 1-2, that can include one or more ENDORPHIN ENHANCERS (CLASS II AGENTS) that are functionally defined such that, when co-administered with at least one RECEPTOR SWITCHER (CLASS I AGENT), reduce and/or resolve one or more Distress Dysfunction symptoms.  CLASS II AGENTS include, but are not limited to: agents that enhance the release, production, and/or functioning of endogenous opioids (i.e., endorphins), cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE) inhibitors or agents that directly enhance cAMP, a cAMP phosphodiesterase (PDE) inhibitor, an agent that directly enhances cAMP, a specific or non-specific cAMP PDE inhibitor, a specific cAMP PDE-4 inhibitor, theophylline, roflumilast, ibudilast, cilomilast, ardenafil, tadalafil, sildenafil, zaprinast, rolipram, methylxanthine, milrinone, inamrinone, cilostazol, caffeine, forskolin, excitatory amino acids, a salt of an excitatory amino acid, all forms of excitatory amino acids, glutamic acid, aspartic acid, glutamine, mono-sodium glutamate (MSG), and N-methyl-D-asparate (NMDA), phenylalanine, and dl-phenylalanine (DLPA).

75. A composition to treat DISTRESS DYSFUNCTION, as defined in claims 1-2, that can include one or more EXOGENOUS OPIOIDS (CLASS III AGENTS) that are functionally defined such that, when co-administered with at least one RECEPTOR SWITCHER (CLASS I AGENT), reduce and/or resolve one or more DISTRESS DYSFUNCTION symptoms.  CLASS III AGENTS include, but are not limited to:  exogenous opioid agonist (full, partial, mixed) agents, tramadol, morphine, oxycodone, hydrocodone, papaverine, codeine, dihydrocodeine, fentanyl, hydromorphone, buprenorphine, butorphanol, methadone, alfentanil, levorphanol, meperidine, nalbuphine, oxymorphone, pentazocine, pentazocine, propoxyphene, remifentanil, and sufenta.

76. A composition to treat DISTRESS DYSFUNCTION, as defined in claims 1-2, that can include one or more SYNERGISTIC ENHANCERS (CLASS IV AGENTS) that are functionally defined such that, when co-administered with at least one RECEPTOR SWITCHER (CLASS I AGENT), reduce and/or resolve one or more DISTRESS DYSFUNCTION symptoms.   CLASS IV AGENTS include, but are not limited to, agents that enhance the release, production and/or functioning of serotonin, dopamine, epinephrine, norepinephrine, and glutamate neurotransmitters, non-opioid analgesics, non-steroidal anti-inflammatory drugs (NSAIDs), acetaminophen, white willow bark, acetylsalicylic acid, salicin, ibuprofen, naproxen, ketoprofen, indomethacin, fenoprofen, tolmetin, sulindac, meclofenamate, piroxicam, flurbiprofen, diclofenac, stimulants, selective serotonin reuptake inhibitors (SSRI), serotonin agonists, antagonists and modulators, selective norepinephrine reuptake inhibitors (SNRIs), citalopram, dapoxetine, escitalopram, fluoxetine fluvoxamine, paroxetine, sertraline, fluvoxamine, zimelidine, dapoxetine, alosetron, ondansetron, granisetron, bemesetron, eplivanserine, deramciclane, agomelatine, elazasonan, pruvanserin, asenapine, zomari, valazodone, bifeprunox, buspirone, ritanseron, geperone, paliperidone, clomipram, doxepin, haloperidol, risperidone, amino acids, a salt of an inhibitory amino acid, all forms of  amino acids, gamma-aminobutrynic acid (GABA), glycine, taurine, tryptophan, 5HTP,phenylalanine, dl-phenylalanine (DLPA), valine, threonine, methionine, lysine, leucine, isoleucine, tyrosine, alanine, arginine, histidine, serine, selenocfysteine, proline, glycine, cysteine, aspargine, alanine, L-DOPA, vitamins and minerals, luteolin, quercetin, qercetin-3-O-methylether (3-MQ, 2), quercetin-3,7,4′-O-trimethylether, ayanin, quercetin-3,7,3′,4′-O- tetramethylether, quercetin-3,5,7,3′,4′-O-petamethylether, quercetin-3,5,7,3′,4′-O-pentaacetate, quercetin-3-O-methyl-5,7,3′,4′-O-tetraacetate, methylcobalamin, vitamin C, vitamin D, vitamin D-3,, vitamins B1, B2, B3, B6, and B12, folic acid, niacin, or niacinamide, folinic acid, calcium folinate, methylcobalamin, pyridoxal-5′-phosphate (P5P), alkaloids, flavonoids, and saponins, hesperetin, hesperidin, naringin, naringenin, epigallocatechin-3-gallate (EGCG), dioclein, genistein, daidzein, eriodictyol, prunetin, biochanin A, apigenin, myricetin, liquiritigenin, liquiritin, kaempferol, isoliquiritigenin, chrysin, rutin, cyanidin, delphinidin, pelargonidin, isorhamnetin, vitamin C, St. John’s Wort, passion flower, hyperforin, hypericin, biotin, vitamin B5 (pantothenic acid), magnesium, alpha-ketoglutarate, copper, zinc, L-theanine, iron, california poppy, ginseng (Panax spp.), licorice, night-blooming cereus (Selenicereus grandiflorus; Cactus grandiflorus), hordenine, nutmeg, myristicin, tyramine, scotch broom, green tea, ephedra, and yohimbe.

77. The composition for claims 1-2, comprising the step of administering to a subject at least one RECEPTOR SWITCHER co-administered with at least one ENDORPHIN ENHANCER.

78. The composition for claims 1-2, comprising the step of administering to a subject at least one RECEPTOR SWITCHER co-administered with at least one EXOGENOUS OPIOID.

79. The composition for claims 1-2, comprising the step of administering to a subject at least one RECEPTOR SWITCHER co-administered with at least one SYNERGISTIC ENHANCER.

80. The composition for claims 1-2, comprising the step of administering to a subject at least one RECEPTOR SWITCHER co-administered with at least one ENDORPHIN ENHANCER and at least one EXOGENOUS OPIOID.

81. The composition for claims 1-2, comprising the step of administering to a subject at least one RECEPTOR SWITCHER co-administered with at least one ENDORPHIN ENHANCER and at least one SYNERGISTIC ENHANCER.

82. The composition for claims 1-2, comprising the step of administering to a subject at least one RECEPTOR SWITCHER co-administered with at least one EXOGENOUS OPIOID and at least one SYNERGISTIC ENHANCER.

83. The composition for claims 1-2, comprising the step of administering to a subject at least one RECEPTOR SWITCHER co-administered with at least one ENDORPHIN ENHANCER and at least one SYNERGISTIC ENHANCER and at least one EXOGENOUS OPIOID.

84. The composition for claims 1-2, comprising the step of administering at least one RECEPTOR SWITCHER to a subject already taking an ENDORPHIN BALANCER.

85. The composition for claims 1-2, comprising the step of administering at least one RECEPTOR SWITCHER to a subject already taking an EXOGENOUS OPIOID.

86. The composition for claims 1-2, comprising the step of administering at least one RECEPTOR SWITCHER to a subject already taking a SYNERGISTIC ENHANCER.

87. A composition to enhance the therapeutic benefit and/or reduce the side effects of an ENDORPHIN ENHANCER by co-administering to a subject at least one RECEPTOR SWITCHER.

88. A composition to enhance the therapeutic benefit and/or reduce the side effects of an EXOGENOUS OPIOID by co-administering to a subject at least one RECEPTOR SWITCHER.

89. A composition to enhance the therapeutic benefit and/or reduce the side effects of a SYNERGISTIC ENHANCER by co-administering to a subject at least one RECEPTOR SWITCHER.

90. The composition of Claims 71- 89, wherein the RECEPTOR SWITCHER is an low dose opioid antagonist.

91. The composition of Claims 71- 89, wherein the RECEPTOR SWITCHER is low dose naltrexone.

92. The composition of Claims 71- 89, wherein the naltrexone is administered in the most preferred ultra low dose range of about 25 micrograms or less.

93. The composition of Claims 71- 89, wherein the naltrexone is administered in the very low dose range of about 25-250 micrograms.

94. The composition of Claims 71- 89 wherein the naltrexone is administered in the low dose range of about 250-1000 micrograms.

95. The composition of Claims 1-1, wherein the OSD1 is naloxone.

96. The composition of Claims 71- 89, wherein the most preferred dosing of naloxone is an ultra low dosing of about 0.25 µg · kg^-1 · h^-1 .

97. The composition of Claims 71- 89 wherein an exemplary dosing of naloxone would be about 400 micrograms naloxone in 1000 ml crystalloid given in 24 h to a patient weighing 70 kg.

98. The composition of Claims 71- 89, wherein the next preferred dosing of naloxone is a very-low-dosing of about 1.0 µg · kg^-1 · h^-1 .

99. The composition of Claims 71- 89, wherein the dosing range of naloxone is .01 µg · kg^-1 · h^-1 to 5 µg · kg^-1 · h^-1.

100.  The composition of Claims 71- 89, wherein the RECEPTOR SWITCHER is a neuramindase inhibitor.

101.  The composition of Claims 71- 89, wherein the RECEPTOR SWITCHER is n-acetyl-cysteine.

102.  The composition of Claims 71- 89, wherein the RECEPTOR SWITCHER is magnesium sulfate.

103.  The composition of Claims 71- 89, wherein the ENDORPHIN ENHANCER is a cAMP PDE inhibitor.

104.  The composition of Claims 71- 89, wherein the ENDORPHIN ENHANCER is roflumilast.

105.  The composition of Claims 71- 89, wherein the ENDORPHIN ENHANCER is theophylline.

106.  The composition of Claims 71- 89, wherein the ENDORPHIN ENHANCER is ginkgo biloba.

107.  The composition of Claims 71- 89, wherein the ENDORPHIN ENHANCER is caffeine.

108.  The composition of Claims 71- 89, wherein the ENDORPHIN ENHANCER is ibudilast.

109.  The composition of Claims 71- 89, wherein the ENDORPHIN ENHANCER is an excitatory amino acid.

110.  The composition of Claims 71- 89, wherein the ENDORPHIN ENHANCER is glutamic acid or mono-sodium-glutamate.

111.  The composition of Claims 71- 89, wherein the ENDORPHIN ENHANCER is DLPA.

112.  The composition of Claims 71- 89, wherein the EXOGENOUS OPIOID is tramadol.

113.  The composition of Claims 71- 89, wherein the EXOGENOUS OPIOID is oxycodone.

114.  The composition of Claims 71- 89, wherein the EXOGENOUS OPIOID is hydrocodone.

115.  The composition of Claims 71- 89, wherein the EXOGENOUS OPIOID is morphine.

116.  The composition of Claims 71- 89, wherein the SYNERGISTIC ENHANCER is a selective serotonin reuptake inhibitor or a selective norepinephrine reuptake inhibitor.

117.  The composition of Claims 71- 89, wherein the SYNERGISTIC ENHANCER is a non-opioid analgesic.

118.  The composition of Claims 71- 89, wherein the SYNERGISTIC ENHANCER is non-steroidal anti-inflammatory agent.

119.  The composition of Claims 71- 89, wherein the SYNERGISTIC ENHANCER is a acetaminophen.

120.  The composition of Claims 71- 89, wherein the SYNERGISTIC ENHANCER is aspirin.

121.  The composition of Claims 71- 89, wherein the SYNERGISTIC ENHANCER is white willow bark.

122.  The composition of Claims 71- 89, wherein the SYNERGISTIC ENHANCER is ibuprofen.

123.  The composition of Claims 71- 89, wherein the SYNERGISTIC ENHANCER is an amino acid in any form or derivative, including a salt.

124.  The composition of Claims 71- 89, wherein the SYNERGISTIC ENHANCER is 5HTP or tryptophan.

125.  The composition of Claims 71- 89, wherein an additional agent is arginine.

126.  The composition of Claims 71- 89, wherein the RECEPTOR SWITCHER is naloxone, the SYNERGISTIC ENHANCER is ibuprofen, and the co-administration further includes administering arginine.

127.  The composition of Claims 71- 89, wherein the RECEPTOR SWITCHER is naloxone, the SYNERGISTIC ENHANCER is ibuprofen, the EXOGENOUS OPIOID is morphine, and the co-administration further includes administering arginine.

128.  The composition of Claims 71- 89, wherein the mode of administration is selected from the group consisting of oral, nasal, sublingual, parenteral, or transdermal.

129.  The composition of Claims 71- 89, wherein the pharmaceutical formulation is delivered in a pharmaceutically-acceptable carrier that is rapid release, immediate-release, slow-release, or delayed-released, including nano-encapsulation formulations that allows for extended and slow release of the pharmaceutical formulation.

130.  The composition of Claims 71- 89, wherein the pharmaceutical formulation is delivered in an abuse-resistant delivery system.

131.  The composition of Claims 71- 89, wherein the pharmaceutical formulation is combined with appropriate agents to improve delivery and effectiveness.

132.  The composition of Claims 71- 89, wherein the dose, frequency, and administration composition of the agents are chosen in order to maximize the therapeutic effectiveness of each formulation.

133.  The composition of Claims 71- 89, wherein the ENDORPHIN ENHANCER is a glutamate or glutamine, including monosodium glutamate (MSG), and by combining these ENDORPHIN ENHANCERS with a RECEPTOR SWITCHER, including, but not limited to magnesium sulfate and NAC, (a) This formulation provides an effective treatment for the allergic and other noxious side effects of MSG, and (b) By preserving the flavor enhancing characteristics of MSG and attenuating and eliminating the noxious side effects of MSG, this formulation is appropriate and useful as a food additive, condiment, and flavor enhancer.

134.  The composition of Claims 71- 89, wherein the ENDORPHIN ENHANCER is a PDE inhibitor including, but not limited to roflumilast, ibudilast, rolipram, and theophylline, and by combining these PDE inhibitors with a RECEPTOR SWITCHER, including, but not limited to, ultra-low-dose opioid antagonists and neurominidase inhibitors, (a) This formulation reduces side effects, that would occur when the PDE inhibitor is administered alone, and/or (b) This formulation reduces hyperalgesia that would occur when the PDE inhibitor is administered alone, and/or (c) This formulation improves the therapeutic efficacy of the PDE inhibitor when administered alone, and/or (d) This formulation improves the therapeutic benefit of the PDE inhibitor in the treatment of respiratory conditions including, but not limited to, COPD and asthma, as compared to the administration of the PDE inhibitor alone.

135.  A composition of Claim 134, wherein the ENDORPHIN ENHANCER is a specific cAMP PDE-4 inhibitor, and the RECEPTOR SWITCHER is ultra-low-dose or very-low-dose naltrexone

136.  A composition of Claim 134, wherein the ENDORPHIN ENHANCER is rofllumilast, ibudilast, theophylline, or ginkgo biloba, and the RECEPTOR SWITCHER is ultra-low-dose or very-low-dose naltrexone.

137.  A composition of Claim 134, wherein the ENDORPHIN ENHANCER is a specific cAMP PDE-4 inhibitor, and the RECEPTOR SWITCHER is n-acetyl-cysteine.

138.  A composition of Claim 134, wherein the ENDORPHIN ENHANCER is rofllumilast, ibudilast, or theophylline, and the RECEPTOR SWITCHER is n-acetyl-cysteine.

139.  A composition of Claim 134, wherein the ENDORPHIN ENHANCER is ginkgo biloba, and the RECEPTOR SWITCHER is n-acetyl-cysteine

140.  These and other embodiments of this invention that will readily occur to those skillful in the art are covered by this patent, in view of the disclosures contained in this patent.

 

ABSTRACT

The present invention relates to methods and compositions for reducing Distress Dysfunction by restoring and maintaining homeostatic balance in the neurotransmitter systems underlying the Stress Response and the experience of pain and hedonic tone.  Distress Dysfunction refers to the experience of dysfunctional emotional and physical distress that interferes with the individual’s quality of life and functioning.  A novel understanding of the bimodal opioid modulation of pain, and its impact, through serotonergic, dopaminergic, epinephrinergic, and norepinephrinergic processes, on hedonic tone, leads directly to new generation pharmaceutical formulations that are remarkably safe and effective for the treatment of a wide variety of Distress Dysfunctions, including chronic pain, addiction, anxiety, depression, anger, eating disorders, IBS, and other emotional and physical distress disorders.  The foundation of this discovery is the power of Receptor Switchers, such as ultra-low-dose opioid antagonists and GM1 ganglioside attenuators, in blocking acute and protracted excitatory receptor signaling.  Co-administration of Receptor Switchers with Endorphin Enhancers, such specific cAMP PDE inhibitors and excitatory amino acids, is an excellent formulation for restoring healthy homeostatic balance to the endogenous opioid system, using the body’s endorphins to reduce pain as well as emotional and physical distress, and through synergistic and homeostatic processes, restoring positive hedonic tone. In this homeostatic condition, acute reflexive pain is experienced, through non-opioid systems, in response to injury or stress, but quickly is reduced when endorphins trigger inhibitory signaling. The addition of Synergistic Enhancers, such as non-opioid analgesics and SSRIs, as well as Exogenous Opioids, enhances and prolongs these therapeutic benefits.  In addition, this invention teaches a new generation of enhanced anti-depressant and anti-anxiety medications that are developed by combining Receptor Switchers with SSRIs and SNRIs, which are remarkably effective in creating positive hedonic tone, including calm, well being, and pain relief.  Finally, this invention teaches the surprising discovery of a new set of pharmaceutical formulations for the treatment of respiratory disorders that combine Receptor Swiitchers, such as ULDN and NAC, with certain Endorphin Enhancers, such as roflumilast and theophylline, such that the therapeutic benefits and/or side effect profile of the cotreatment formulation are improved as compared to the use of these drugs alone.

 

 

APPENDIX

BIMODAL OPIOID MODULATION OF PAIN AND HEDONIC TONE[1]

 

Healthy Homeostatic Balance

Normal homeostasis maintains an adaptive balance between the Excitatory and Inhibitory Modes in the Bimodally-Acting Opioid Receptors.  In the absence of injury or stress, Opioid Receptors are generally in the Inhibitory Mode.  Normal levels of Endogenous Opioids, (i.e., endorphins), are homeostatically maintained, producing a generally positive Hedonic Tone, including a sense of calm and well being

Normal Acute Pain

Acute injury or stress triggers Acute Reflexive Pain Signals mediated by non-opioid systems, leading to the adaptive reflexive experience of immediate pain and distress.  Simultaneously, acute injury or stress set Opioid Receptors in the Excitatory Mode and Endogenous Opioids (i.e., endorphins) are released.  The Endogenous Opioids bind with the Opioid Receptors, triggering excitatory signaling. Through G_s, excitatory signals enhance the release of cAMP, which by increasing Protein Kinase A (which increases Ca² conductance and decreases K⁺ conductance), excites Pain-Sensory Neurons, which trigger the sensation of pain as well as increased sensitivity toward pain (hyperalgesia).  The increased cAMP also enhances the release of Endogenous Opioids, maintaining the pain and distress cycle, leading to an extended adaptive response to the noxious stimuli. However, as soon as the acute danger is reduced, in part as a result of an adaptive response to pain and distress, the Opioid Receptors are switched to Inhibitory Mode.  The Endogenous Opioids then trigger inhibitory signaling and, through G_o, (which decreases Ca²⁺ conductance and increases K⁺ conductance), inhibit Pain-Sensory Neurons, which triggers reduced sensation of pain and produces analgesia.  At the same time, the Opioid Receptor inhibitory signaling, through G_i, inhibits cAMP, which in turn reduces Endogenous Opioids, which tunes down the entire endogenous opioid pain response system, restoring normal homeostatic balance and positive Hedonic Tone.

 

Protracted Excitatory Mode

Chronic stress, injury, exogenous opioids, drugs, alcohol, and various medical and genetic factors can set Opioid Receptors in a protracted excitatory mode.  In this condition, Endogenous Opioids trigger mostly excitatory signaling, which results in chronic pain and hyperalgesia.  Any factor that triggers the release of Endogenous Opioids, including injury or stress and even reward states and various drugs, can potentiate pain.  This protracted condition triggers homeostatic processes in related Serotonin, Dopamine, and other neurotransmitter systems, which produces a variety of signs and symptoms of emotional and physical distress.  This negative Hedonic Tone state may be reflected by the experience of anxiety, irritability, depression, cravings, addictive tendencies and physical distress, including pain and gastrointestinal symptoms.  Protracted opioid receptor excitatory mode conditions are a major component of a wide variety of Distress Dysfunction disorders, syndromes, and symptoms.  Unfortunately, typical coping patterns, including the use of drugs and alcohol, perpetuate and exacerbate protracted excitatory signaling and its negative impact on Hedonic Tone.

 

Exogenous Opioids

Exogenous Opioid analgesic drugs, such as tramadol, oxycodone, and morphine, clearly have a dramatic impact on the endogenous opioid system.  Exogenous Opioids act like Endogenous Opioids, binding with Opioid Receptors, and their impact depends on the mode of the Bimodally-Acting Opioid Receptors.  In a balanced system, their impact initially leads to inhibitory signaling, resulting in analgesia and even a sense of well being.  However, fairly quickly, this increased inhibitory signaling results in a homeostatic balancing response that includes, through cAMP, a reduction in Endogenous Opioid levels as well as a receptor shift to the Excitatory Mode.  Over time, this leads to a protracted excitatory receptor mode and diminished Endogenous Opioid levels, producing chronic pain, hyperalgesia, tolerance, dependence, and addiction as well as emotional and physical distress. These iatrogenic problems are greatly exacerbated when the endogenous opioid system is already in a protracted excitatory mode, resulting more immediately in excitatory signaling, leading to an exacerbation of pain and hyperalgesia, tolerance, as well as negative hedonic mode.  Thus, while at times initially therapeutic, Exogenous Opioids can rapidly lead to the development of serious and Distress Dysfunction, even long after the Exogenous Opioids are discontinued.

 

Receptor Switching Agents

Opioid Receptor Switchers, including ultra-low-dose opioid antagonists, such as ultra-low-dose naltrexone and naloxone, and  GM1 ganglioside attenuators, such as neuraminidase inhibitors (e.g., magnesium sulfate and N-Acetyl-Cysteine), selectively block the Opioid Receptor Excitatory Mode. Therefore, protracted excitatory signaling is eliminated, and inhibitory receptor signaling is enhanced. As a result, when Endogenous Opioids (or Exogenous Opioids) bind with the Opioid Receptor, the result is increased inhibitory signaling, producing analgesia and a sense of well being.  These agents have the potential to reverse both acute and protracted excitatory mode imbalances, helping to restore normal homeostatic functioning.  However, since protracted excitatory conditions lead to diminished Endogenous Opioids, Receptor Switchers alone may be insufficient to produce analgesia and a sense of well being.  Therefore, Receptor Switchers are most effective with co-adminstered with an agent that boosts the level of Endogenous Opioids.  Alternatively, by administering a Receptor Switcher with an Exogenous Opioid, excitatory signaling is minimized, resulting in enhanced analgesia as well as a dramatic reduction in protracted excitatory mode conditions, reducing and/or eliminating many of the noxious effects of Exogenous Opioids, including tolerance, dependence, addiction, and other side effects.

 

Cyclic AMP Enhancing Agents

Cyclic AMP Enhancers, particularly specific cAMP PDE-4 inhibitors, such as roflumilast, as well as non-specific cAMP PDE Inhibitors, such as theophylline, caffeine,  and ginkgo biloba, enhance the release of cAMP, which, in turn, enhances the release of Endogenous Opioids (i.e., endorphins). In addition to cAMP PDE inhibitors, less potent cAMP Enhancers include excitatory amino acids, such as glutamic acid.  When cAMP Enhancers are administered alone, the resulting increase in cAMP can directly trigger an increase in pain and hyperalgesia.  Furthermore, excitatory signaling is likely if Opioid Receptors are set in the protracted excitatory mode and/or if injury or stress is present, resulting in a further increase in pain and hyperalgesia as well as emotional and physical distress. This mechanism explains the typical side effects seen with these agents. However, when co-administered with an agent that switches opioid receptors from an excitatory state to an inhibitory state, Receptor Switchers, the increase in Endogenous Opioids produced by cAMP PDE inhibitors leads to enhanced inhibitory signaling, resulting in analgesia and positive hedonic tone. Therefore, combining a Receptor Switcher and a cAMP Enhancer creates a remarkable non-opioid pharmaceutical formulation for the treatment of a wide variety of Distress Dysfunctions.  Moreover, by adding a Receptor Balancer to cAMP PDE inhibitors, such as roflumilast and theophylline, enhanced formulations for the treatment of COPD and asthma are discovered with dramatically reduced side effects and increased pain relief and positive hedonic tone.

 

Synergistic Enhancing Agents

A variety of agents have a synergistic effect with the endogenous opioid system through the G_i –mediated metabolic processes that trigger the inhibition of pain-sensory neurons.  There is evidence to suggest that higher levels of Gi that are produced by enhanced inhibitory signaling potentiate the pain-relieving effects of non-opioid analgesics, such as NSAIDs and acetaminophen.  Therefore, there is a synergistic potentiation produced by the combination of non-opioid analgesics plus Receptor Switchers, such as ultra-low-dose naltrexone and neuraminidase inhibitors, creating a new generation of enhanced non-opioid analgesics.  Similarly, synergistic potentiation occurs with serotonin reuptake inhibitors (SSRIs), suggesting increased pain relief as well as calm and well being is produced by the combination of SSRIs and Receptor Switchers. Therefore, a new generation of enhanced SSRIs for depression and anxiety are created by this discovery. In addition to SSRIs, inhibitory serontonergic and adrenergic agents can function as Synergistic Enhancers.  Specific amino acids that enhance release of serotonin and dopamine, such as tryptophan and 5HTP, can also act as Synergistic Enhancers in cotreatment formulations.  Finally, there is evidence to suggest that ultra-low-dose naltrexone (ULDN) has a synergistic effect through this G_i metabolic process in addition to its function as a Receptor Switcher, making ULDN a particularly powerful agent in all cotreatment formulations.

 

Endogenous Opioid Reuptake Inhibitors

Agents, such as DLPA, both enhance the release of Endogenous Opioids as well as block the enzymes that reuptake them, providing an enhanced level of Endogenous Opioids (i.e., endorphins) for longer periods of time.  When administered alone, these agents have the potential for increased inhibitory signaling, but may also produce excitatory signaling when injuries or stress are present, as well as when the receptors are set in an excitatory mode.  However, when co-administered with agents that switch the receptors from an excitatory to inhibitory mode, Receptor Switchers, these agents are more likely to trigger inhibitory signaling, leading to enhanced and prolonged analgesia and well being.  Therefore, DLPA is an excellent agent to complement all cotreatment formulations.

 

Clinical Implications

This novel understanding of the Bimodal Opioid Modulation of Pain and Hedonic Tone leads directly to new generation pharmaceutical formulations that are remarkably safe and effective for the treatment of a wide variety of Distress Dysfunctions, including chronic pain, addiction, anxiety, depression, anger, eating disorders, IBS, and other emotional and physical distress disorders.  The foundation of this discovery is the power of Receptor Switchers, especially ultra-low-dose naltrexone, in blocking acute and protracted excitatory signaling.  Therefore, co-administration of Receptor Switchers with cAMP Enhancing Agents is an excellent formulation for restoring healthy homeostatic balance to the endogenous opioid system, using the body’s endorphins to reduce pain as well as emotional and physical distress, restoring positive hedonic tone. In this homeostatic condition, acute reflexive pain is experienced, through non-opioid systems, in response to injury or stress, but quickly is reduced when endorphins trigger inhibitory signaling. The addition of Endorphin Enhancers, such as DLPA, can enhance and prolong these therapeutic benefits.  While opioid and non-opioid analgesics can potentiate these therapeutic effects when used in co-treatment with Receptor Switchers (and cAMP and Endorphin Enhancers), the evidence suggests that they can produce serious dysfunctional imbalances in the endogenous opioid system when used alone.  Therefore, it is critical to co-administer Receptor Switchers whenever using opioid and non-opioid analgesic drugs in order to maximize their analgesic potency and to reduce noxious side effects including tolerance and dependence produced by protracted excitatory signaling.  Finally, a new generation of enhanced anti-depressant and anti-anxiety medications is created by these discoveries by combining Receptor Switchers with SSRIs, which are remarkably effective in creating positive hedonic tone, including calm, well being, and pain relief.