METHODS AND COMPOSITIONS FOR TREATING DISTRESS DYSFUNCTION AND ENHANCING SAFETY AND EFFICACY OF SPECIFIC MEDICATIONS

• US 20110159048A1
• Filed: 12/20/2010
• Published: 06/30/2011
• Est. Priority Date: 12/22/2009
• Status: Active Grant

• Current Assignee: Pondera Biotechnologies, LLC
• Original Assignee: Pondera Biotechnologies, LLC
• Inventors: Crain, Stanley M., Crain, Michael, Crain, William E., Crain, Steven
• Granted Patent: US 8,202,525 B2
• Time in Patent Office: Days
• US Class Current: 424/400
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/10 Sulfides; Sulfoxides; Sulfones
• CPC Class Codes: A61K 31/138 Aryloxyalkylamines, e.g. propranolol, tamoxifen, phenoxybenzamine atenolol A61K31/165; pindolol A61K31/404; timolol A61K31/5377
• CPC Class Codes: A61K 31/167 having the nitrogen of a carboxamide group directly attached to the aromatic ring, e.g. lidocaine, paracetamol
• CPC Class Codes: A61K 31/198 Alpha-amino acids, e.g. alanine or edetic acid [EDTA] betaine A61K31/205; proline A61K31/401; tryptophan A61K31/405; histidine A61K31/4172; peptides not degraded to individual amino acids A61K38/00
• CPC Class Codes: A61K 31/4015 having oxo groups directly attached to the heterocyclic ring, e.g. piracetam, ethosuximide
• CPC Class Codes: A61K 31/437 the heterocyclic ring system containing a five-membered ring having nitrogen as a ring hetero atom, e.g. indolizine, beta-carboline
• CPC Class Codes: A61K 31/439 the ring forming part of a bridged ring system, e.g. quinuclidine 8-azabicyclo [3.2.1] octanes A61K31/46
• CPC Class Codes: A61K 31/44 Non condensed pyridines; Hydrogenated derivatives thereof
• CPC Class Codes: A61K 31/46 8-Azabicyclo [3.2.1] octane; Derivatives thereof, e.g. atropine, cocaine
• CPC Class Codes: A61K 31/485 Morphinan derivatives, e.g. morphine, codeine
• CPC Class Codes: A61K 31/522 having oxo groups directly attached to the heterocyclic ring, e.g. hypoxanthine, guanine, acyclovir
• CPC Class Codes: A61K 31/60 Salicylic acid; Derivatives thereof
• CPC Class Codes: A61K 33/06 Aluminium, calcium or magnesium; Compounds thereof , e.g. clay
• CPC Class Codes: A61K 36/16 Ginkgophyta, e.g. Ginkgoaceae (Ginkgo family)
• CPC Class Codes: A61K 36/76 Salicaceae (Willow family), e.g. poplar
• CPC Class Codes: A61K 36/77 Sapindaceae (Soapberry family), e.g. lychee or soapberry
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 15/10 : for impotence
• CPC Class Codes: A61P 25/00 : Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 : Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 25/14 : for treating abnormal movements, e.g. chorea, dyskinesia
• CPC Class Codes: A61P 25/18 : Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 : Anxiolytics
• CPC Class Codes: A61P 25/24 : Antidepressants
• CPC Class Codes: A61P 25/32 : Alcohol-abuse
• CPC Class Codes: A61P 25/34 : Tobacco-abuse
• CPC Class Codes: A61P 25/36 : Opioid-abuse
• CPC Class Codes: A61P 37/08 : Antiallergic agents antiasthmatic agents A61P11/06; ophthalmic antiallergics A61P27/14
• CPC Class Codes: A61P 5/24 : of the sex hormones

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 distress 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 anxiety, depression, anger, insomnia, mood disorders, eating disorders, sexual problems, pain, substance and behavioral addictions, gastrointestinal disorders, autistic spectrum disorders, attention-deficit and hyperactivity disorders, and other emotional and physical distress disorders. The foundation of this discovery is the power of Receptor Switchers, such as ultra-low-dose and very-low-dose opioid antagonists and GM1 ganglioside attenuators, in blocking acute and protracted excitatory opioid receptor signaling. Co-administration of Receptor Switchers with Endorphin Enhancers, such as 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 emotional and physical distress, and through synergistic and homeostatic processes, restoring positive hedonic tone. The addition of Synergistic Enhancers, such as amino acids, SSRI and SNRI agents, and non-opioid analgesics, as well as Exogenous Opioids, enhances and prolongs these therapeutic benefits. The novel principles discovered by this invention also teach a new generation of safe and effective formulations for the treatment of respiratory conditions, neuropathy, and nociceptive pain.

Claims

1. A method to safely and effectively treat Distress Dysfunction conditions, symptoms and/or disorders in a subject in need comprising:

(a) administering at least one Receptor Switcher to the subject; and

(b) administering at least one compound to the subject selected from the group consisting of an Endorphin Enhancer, an Exogenous Opioid, a Synergistic Enhancer, and any combination thereof.

2. The method of claim 1, wherein the Distress Dysfunction conditions, symptoms and/or disorders are selected from the group consisting of:

(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, but not limited to, distressing, neuropathic, migraine psychogenic, and nociceptive 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, cAMP enhancers, opioid and non-opioid analgesics, stimulants, SSRIs, SNRIs, amino acids, and nerve growth factor;

(34) Respiratory disorders including, but not limited to asthma, COPD, and neonatal apnea;

(35) Nerve damage and neuropathic disorders, including, but not limited to, HIV-induced and Diabetic Neuropathy;

(36) Inflammatory disorders;

(37) Allergic and non-allergic glutamate and mono-sodium glutamate related disorders, including “

Chinese Food Syndrome”

, and (38) 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. The method of claim 2, wherein:

(a) the Anxiety Disorder is selected from the group consisting of 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;

(b) the Mood Disorder is selected from the group consisting of 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;

(c) the Somatoform Disorder is selected from the group consisting of 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;

(d) the Factitious Disorder is selected from the group consisting of 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;

(e) the Sexual Dysfunction is selected from the group consisting of 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;

(f) the Eating Disorder is selected from the group consisting of 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;

(g) the Gastrointestinal Disorder is selected from the group consisting of 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;

(h) the Movement Disorder is Restless Leg Syndrome;

(i) the Sleep Disorder is selected from the group consisting of Insomnia, Dyssomnias Parasomnias as well as signs and symptoms of sleep problems that are not classified as a Sleep Disorder;

(j) the Impulse-Control Disorder is selected from the group consisting 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;

(k) the Alcohol-Related Disorder is selected from the group consisting of 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;

(l) the Opioid-Related Disorder is selected from the group consisting of 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;

(m) the Caffeine-Related Disorder is selected from the group consisting of 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;

(n) the Cannabis-Related Disorder is selected from the group consisting of Cannabis Dependence, Cannabis Addiction, Cannabis Abuse, Cannabis-Induced Disorders, and Cannabis-Related Disorder NOS;

(o) the Amphetamine (or Amphetamine-Like)-Related Disorder is selected from the group consisting of Amphetamine Dependence, Amphetamine Addiction, Amphetamine Abuse, Amphetamine-Induced Disorders, and Amphetamine-Related Disorder NOS;

(p) the Cocaine-Related Disorder is selected from the group consisting of Cocaine Dependence, Cocaine Addiction, Cocaine Abuse, Cocaine-Induced Disorders, and Cocaine-Related Disorder NOS;

(q) the Nicotine-Related Disorder is selected from the group consisting of Nicotine Dependence, Nicotine Addiction, Nicotine Abuse, Nicotine-Induced Disorders, and Nicotine-Related Disorder NOS;

(r) the Inhalant-Related Disorder is selected from the group consisting of Inhalant Dependence, Inhalant Addiction, Inhalant Abuse, Inhalant-Induced Disorders, and Inhalant-Related Disorder NOS;

(s) the Phencyclidine-Related Disorder is selected from the group consisting of Phencyclidine Dependence, Phencyclidine Addiction, Phencyclidine Abuse, Phencyclidine-Induced Disorders, and Phencyclidine-Related Disorder NOS;

(t) the Sedative-, Hypnotic-, or Anxiolytic-Related Disorder is selected from the group consisting of Sedative-, Hypnotic-, or Anxiolytic Dependence, Addiction, and/or Abuse, Sedative-, Hypnotic-, or Anxiolytic-Induced Disorders, and Sedative-, Hypnotic-, or Anxiolytic-Related Disorder NOS;

(u) the Pervasive Developmental Disorder is selected from the group consisting of Autism Disorder, Rhett'"'"'s Disorder, Asperger'"'"'s Syndrome, or Pervasive Developmental Disorder NOS;

(v) the Attention-Deficit and Disruptive Behavior Disorder is selected from the group consisting of Attention-Deficit Disorder, 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;

(w) the Behavioral addiction, compulsion, and/or dysfunction is selected from the group consisting of sex, pornography, gambling, shopping, eating, drinking, smoking, computer use, and cleaning;

(x) the Pain disorder is selected from the group consisting of distressing, nociceptive, neuropathic, migraine and psychogenic pain;

(z) the Psychotic disorder is schizophrenia;

(aa) the Respiratory disorder is selected from the group consisting of asthma, COPD, and neonatal apnea,

(bb) the Nerve damage or Neuropathy is selected from the group consisting of HIV-induced and Diabetic Neuropathy;

or

(cc) any combination thereof.

4. The method of claim 1, wherein the RECEPTOR SWITCHER(CLASS I AGENT):

(a) when co-administered with CLASS II, III, and/or IV AGENTS, reduces and/or resolves one or more Distress Dysfunction symptoms; and

(b) is selected from the group consisting of agents that selectively block and/or inhibit opioid receptor excitatory signaling, ultra-low-dose, very-low-dose and 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, agents that increase sulfates in the body, methylsulfonylmethane (MSM), magnesium sulfate, sodium sulfate, chondroitin sulfate, n-acetyl-cysteine (NAC), zanamivir, laninamivir, peramivir, oseltamivir, scutellaria, and 5,7,4′

-trihydroxy-8-methoxyflavone.

5. The method of claim 1, wherein the ENDORPHIN ENHANCER(CLASS II AGENT):

(a) when co-administered with at least one RECEPTOR SWITCHER, reduces and/or resolves one or more Distress Dysfunction symptoms; and

(b) is selected from the group consisting of 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, inaminone, cilostazol, caffeine, guarana, ginkgo biloba, forskolin, celecoxib, 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, dl-phenylalanine (DLPA), and nerve growth factor (NGF).

6. The method of claim 1, wherein the EXOGENOUS OPIOID (CLASS III AGENT):

(a) when co-administered with at least one RECEPTOR SWITCHER, reduces and/or resolves one or more DISTRESS DYSFUNCTION symptoms;

(b) is selected from the group consisting of exogenous opioid agonist (full, partial, mixed) agents, tramadol, morphine, oxycodone, hydrocodone, papaverine, codeine, dihydrocodeine, fentanyl, hydromorphone, buprenorphine, butorphanol, methadone, alfentanil, loperamide, levorphanol, menthol, meperidine, nalbuphine, oxymorphone, pentazocine, pentazocine, propoxyphene, remifentanil, and sufenta.

7. The method of claim 1, wherein the SYNERGISTIC ENHANCER(CLASS IV AGENT):

(a) when co-administered with at least one RECEPTOR SWITCHER, reduces and/or resolves one or more DISTRESS DYSFUNCTION symptoms; and

(b) is selected from the group consisting of 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, celecoxib, 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, venlafaxine, duloxetine, desvenlafaxine, alosetron, ondansetron, granisetron, bemesetron, eplivanserine, deramciclane, agomelatine, elazasonan, pruvanserin, asenapine, zomari, valazodone, bifeprunox, buspirone, ritanseron, geperone, paliperidone, clomipram, doxepin, haloperidol, risperidone, methylphenidate, amino acids, a salt of an inhibitory amino acid, all forms of amino acids, gamma-aminobutrynic acid (GABA), pharmaGABA, glycine, taurine, tryptophan, 5HTP, phenylalanine, dl-phenylalanine (DLPA), s-adenosylmethionine (SAMe), acetyl-L-carinitine (ALC), valine, threonine, methionine, lysine, leucine, isoleucine, tyrosine, alanine, arginine, histidine, serine, selenocfysteine, proline, glycine, cysteine, aspargine, alanine, cannabis, all formas and derivatives of cannabis, 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, yohimbe, myhhr, myhhr gum, boswellia, peppermint oil, and menthol.

8. The method of claim 1, wherein the subject has previously taken an ENDORPHIN ENHANCER, an EXOGENOUS OPIOID, a SYNERGISTIC ENHANCER, or any combination thereof.

10. The method of claim 1, wherein the RECEPTOR SWITCHER:

(a) is an ultra-low-dose, very-low-dose, or low-dose opioid antagonist;

or

(b) is ultra-low-dose, very-low-dose, or low-dose naltrexone or naloxone.

11. The method of claim 10, wherein:

(a) naltrexone is administered in the ultra-low-dose amount of about 125 micrograms or less;

(b) naltrexone is administered in the very-low-dose range of about 125-about 500 micrograms;

(c) naltrexone is administered in the low-dose range of about 500-about 1000 micrograms;

(d) naloxone is administered at an ultra-low-dose of about 0.15 nanagrams·

kg<sup>−

1</sup>·

h<sup>−

1</sup> to 0.25 μ

g·

kg<sup>−

1</sup>·

h<sup>−

1</sup>;

(e) naloxone is administered at about 400 micrograms naloxone in 1000 ml crystalloid given in 24 h to a patient weighing 70 kg;

(f) naloxone is administered at a low-dose of about 0.25 μ

g·

kg<sup>−

1</sup>·

h<sup>−

1</sup> to 1.0 μ

g·

kg<sup>−

1</sup>·

h<sup>−

1</sup>;

or

(g) naloxone is administered at as dose of about 1 μ

g·

kg<sup>−

1</sup>·

h<sup>−

1</sup> to about 5 μ

g·

kg<sup>−

1</sup>·

h<sup>−

1</sup>.

12. The method of claim 1, wherein the RECEPTOR SWITCHER is selected from the group consisting of a neuraminidase inhibitor, n-acetyl-cysteine, magnesium sulfate, sodium sulfate, scutellaria, and methylsulfonylmethane (MSM).

13. The method of claim 1, wherein the ENDORPHIN ENHANCER is selected from the group consisting of a cAMP enhancing agent, a cAMP PDE inhibitor, roflumilast, theophylline, ginkgo biloba, caffeine, guarana, ibudilast, celecoxib, an excitatory amino acid, glutamic acid, mono-sodium-glutamate, DL-Phenylalanine (DLPA), or nerve growth factor (NGF).

14. The method of claim 1, wherein the EXOGENOUS OPIOID is selected from the group consisting of tramadol, oxycodone, hydrocodone, loperamide, buprenorphine, methadone, menthol, codeine, and morphine.

15. The method of claim 1, wherein the SYNERGISTIC ENHANCER is a(n):

(a) selective serotonin reuptake inhibitor (SSRI) or a selective norepinephrine reuptake inhibitor (SNRI);

(b) non-opioid analgesic;

(c) non-steroidal anti-inflammatory agent (NSAID);

(d) cannabis, in any form or derivative;

(e) stimulant;

(f) acetaminophen;

(g) aspirin;

(h) white willow bark;

(i) ibuprofen;

(j) an amino acid in any form or derivative, including a salt;

(k) 5HTP;

(l) tryptophan;

(m) S-adenosylmethionine (SAMe);

(n) GABA;

(o) tyrosine;

(p) taurine;

(q) arginine;

(r) celecoxib;

(s) methylphenidate;

(t) acetyl-L-carinitine;

or

(u) any combination thereof.

16. The method of claim 15, wherein the SSRI or SNRI is selected from the group consisting of citalopram, escitalopram oxalate, fluoxetine, venlaflafaxine, and duloxetine.

17. The method of claim 1, wherein the SYNERGISTIC ENHANCER is selected from the group consisting of acetaminophen, celecoxib, aspirin, white willow bark, ibuprofen, methylphenidate, an amino acid in any form or derivative, including a salt, 5HTP, tryptophan, S-adenosylmethionine (SAMe), GABA in any form, pharmaGABA, tyrosine, taurine, acetyl-L-carinitine (ALC), menthol, myhhr gum, boswellia, and arginine.

18. The method of claim 1, wherein:

(a) the RECEPTOR SWITCHER is naloxone, the SYNERGISTIC ENHANCER is ibuprofen, and the co-administration further includes administering arginine;

or

(b) the RECEPTOR SWITCHER is naloxone, the SYNERGISTIC ENHANCER is ibuprofen, the EXOGENOUS OPIOID is morphine, and the co-administration further includes administering arginine.

19. The method of claim 1, wherein:

(a) the mode of administration is selected from the group consisting of oral, pulmonary, nasal, sublingual, parenteral, and transdermal;

(b) the pharmaceutical formulation is delivered in a pharmaceutically-acceptable carrier that is rapid release, immediate-release, slow-release, delayed-released, controlled release, a combination of immediate release and controlled release, a nano-encapsulation formulations, and an abuse and/or tamper-resistant delivery system;

or

(c) any combination thereof.

20. The method of claim 1, wherein:

(a) the ENDORPHIN ENHANCER is a glutamate or glutamine, such as monosodium glutamate (MSG); and

(b) the RECEPTOR SWITCHER is magnesium sulfate, NAC, or a combination thereof;

wherein the combination of the ENDORPHIN ENHANCER with a RECEPTOR SWITCHER provides an effective treatment for the allergic and other noxious side effects of MSG, and wherein by preserving the flavor enhancing characteristics of MSG and attenuating and eliminating the noxious side effects of MSG, the formulation is appropriate and useful as a food additive, condiment, and flavor enhancer.

21. The method of claim 1, wherein:

(a) the ENDORPHIN ENHANCER is a PDE inhibitor selected from the group consisting of methyxanthines, roflumilast, ibudilast, rolipram, ginkgo biloba, caffeine, and theophylline, and

(b) by combining the PDE inhibitors with a RECEPTOR SWITCHER, including, but not limited to, ultra-low-dose opioid antagonists, n-acetyl cysteine, methylsulfonylmethane, magnesium sulfate, and neurominidase inhibitors, wherein the formulation (i) reduces side effects that would occur when the PDE inhibitor is administered alone;

(ii) reduces hyperalgesia that would occur when the PDE inhibitor is administered alone;

(iii) improves the therapeutic efficacy of the PDE inhibitor when administered alone; and

/or (iv) improves the therapeutic benefit of the PDE inhibitor in the treatment of respiratory conditions including, but not limited to, COPD, asthma, and neonatal apnea, as compared to the administration of the PDE inhibitor alone.

22. The method of claim 21, wherein:

(a) the ENDORPHIN ENHANCER is a specific cAMP PDE-4 inhibitor, and the RECEPTOR SWITCHER is ultra-low-dose or very-low-dose naltrexone;

(b) the ENDORPHIN ENHANCER is roflumilast, ibudilast, theophylline, or ginkgo biloba, and the RECEPTOR SWITCHER is ultra-low-dose or very-low-dose naltrexone or naloxone;

(c) the ENDORPHIN ENHANCER is a specific cAMP PDE-4 inhibitor, and the RECEPTOR SWITCHER is n-acetyl-cysteine;

(d) the ENDORPHIN ENHANCER is roflumilast, ibudilast, or theophylline, and the RECEPTOR SWITCHER is n-acetyl-cysteine;

(e) the ENDORPHIN ENHANCER is ginkgo biloba, and the RECEPTOR SWITCHER is n-acetyl-cysteine;

or

(f) the ENDORPHIN ENHANCER is a roflumilast, ibudilast, theophylline, guarana, or ginkgo biloba, and the RECEPTOR SWITCHER is magnesium sulfate.

23. The method of claim 1, wherein the ENDORPHIN ENHANCER is nerve growth factor (NGF), and by combining NGF with one or more RECEPTOR SWITCHERS, including, but not limited to, ultra-low-dose, very-low-dose, or low-dose opioid antagonists and neurominidase inhibitors, the resultant formulation:

(a) reduces side effects that would occur when NGF is administered alone;

(b) reduces hyperalgesia and pain that would occur when NGF is administered alone;

(c) improves the therapeutic efficacy of NGF when administered alone;

(d) improves the therapeutic benefit of NGF in the treatment of HIV-induced and diabetic neuropathy (DN) and/or Distress Dysfunction, including stress, anxiety, and depression, as compared to the administration of NGF alone;

or

(e) any combination thereof.

24. The method of claim 23, wherein nerve growth factor is combined with:

(a) ultra-low-dose, very-low-dose, or low-dose naltrexone or naloxone;

(b) n-acetyl-cysteine;

(c) methylsulfonylmethane;

or

(d) magnesium sulfate.

25. The method of claim 1, wherein a safe and effective treatment for nociceptive pain comprises:

(a) administering at least one Receptor Switcher to the subject; and

(b) administering at least one compound to the subject selected from the group consisting of an Endorphin Enhancer, an Exogenous Opioid, a Synergistic Enhancer, and any combination thereof.

26. The method of claim 1, wherein a safe and effective method to produce pain relief and/or analgesia in a subject experiencing nociceptive pain comprises:

(a) administering (i) at least one Receptor Switcher to the subject with (ii) at least one Endorphin Enhancer in combination with (iii) one or more Exogenous Opioids and/or Synergistic Enhancers;

or

(b) administering at least one Receptor Switcher to the subject in combination with at least one Synergistic Enhancer.

27. The method of claim 1, wherein a safe and effective method to produce pain relief and/or analgesia in a subject experiencing nociceptive pain comprises:

(a) administering one or more of the following agents to the subject;

methylsulfonylmethane (MSM), n-acetyl-cysteine (NAC), scutellaria, and 5,7,4′

-trihydroxy-8-methoxyflavone, in combination with

(b) at least one compound selected from the group consisting of at least one Endorphin Enhancer, at least one Exogenous Opioid, at least one Synergistic Enhancer, and any combination, thereof.

28. The method of claim 1, wherein a safe and effective method to produce pain relief and/or analgesia in a subject experiencing nociceptive pain comprises:

(a) administering one or more Receptor Switchers, in combination with

(b) one or more of the following agents;

guarana, ginkgo biloba, phenylalanine, dl-phenylalanine (DLPA), and celecoxib.

9. A method to enhance the therapeutic benefit and/or reduce the side effects of an ENDORPHIN ENHANCER, EXOGENOUS OPIOID, a SYNERGISTIC ENHANCER, or any combination thereof, in a subject comprising:

(a) co-administering to a subject at least one RECEPTOR SWITCHER;

or

(b) co-administering to a subject at least one RECEPTOR SWITCHER combined with at least one ENDORPHIN ENHANCER and/or a SYNERGISTIC ENHANCER.

29. A composition useful in safely and effectively treating DISTRESS DYSFUNCTION comprising:

(a) at least one RECEPTOR SWITCHER; and

(b) at least one compound selected from the group consisting of an ENDORPHIN ENHANCER, an EXOGENOUS OPIOID, a SYNERGISTIC ENHANCER, and any combination thereof.

30. The composition of claim 29, wherein the RECEPTOR SWITCHER:

(a) when co-administered with CLASS II, III, and/or IV AGENTS, reduces and/or resolves one or more Distress Dysfunction symptoms; and

(b) is selected from the group consisting of agents that selectively block and/or inhibit opioid receptor excitatory signaling, ultra-low-dose, very-low-dose, and low-dose opioid antagonists, ultra-low-dose, very-low-dose, and low-dose naltrexone, naloxone, diprenorphine, nalmefene, and norbinaltorphimine, agents that inhibit synthesis or activity of GM1 ganglioside, neuraminidase inhibitors, agents that increase sulfates in the body, methylsulfonylmethane (MSM), magnesium sulfate, sodium sulfate, chondroitin sulfate, n-acetyl-cysteine (NAC), zanamivir, oseltamivir, laninamivir, peramivir, scutellaria, and 5,7,4′

-trihydroxy-8-methoxyflavone.

31. The composition of claim 29, wherein the ENDORPHIN ENHANCER:

(a) when co-administered with at least one RECEPTOR SWITCHER, reduces and/or resolves one or more Distress Dysfunction symptoms; and

(b) is selected from the group consisting of 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, inaminone, cilostazol, caffeine, guarana, ginkgo biloba, forskolin, celecoxib, 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, dl-phenylalanine (DLPA), and nerve growth factor (NGF).

32. The composition of claim 29, wherein the EXOGENOUS OPIOID:

(a) when co-administered with at least one RECEPTOR SWITCHER, reduces and/or resolves one or more DISTRESS DYSFUNCTION symptoms; and

(b) is selected from the group consisting of exogenous opioid agonist (full, partial, mixed) agents, tramadol, morphine, oxycodone, hydrocodone, papaverine, codeine, dihydrocodeine, fentanyl, hydromorphone, buprenorphine, butorphanol, methadone, alfentanil, loperamide, buprenorphine, menthol, codeine, levorphanol, meperidine, nalbuphine, oxymorphone, pentazocine, pentazocine, propoxyphene, remifentanil, and sufenta.

33. The composition of claim 29, wherein the SYNERGISTIC ENHANCER:

(a) when co-administered with at least one RECEPTOR SWITCHER, reduces and/or resolves one or more DISTRESS DYSFUNCTION symptoms; and

(b) is selected from the group consisting of 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, celecoxib, 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, venlaflafaxine, duloxetine, desvenlafaxine, zimelidine, dapoxetine, alosetron, ondansetron, granisetron, bemesetron, eplivanserine, deramciclane, agomelatine, elazasonan, pruvanserin, asenapine, zomari, valazodone, bifeprunox, buspirone, ritanseron, geperone, paliperidone, clomipram, doxepin, haloperidol, risperidone, methylphenidate, amino acids, a salt of an inhibitory amino acid, all forms of amino acids, gamma-aminobutrynic acid (GABA), all forms of GABA, PharmaGABA, glycine, taurine, tryptophan, 5HTP, phenylalanine, dl-phenylalanine (DLPA), acetyl-L-carinitine (ALC), sadenosylmethionine (SAMe), valine, threonine, methionine, lysine, leucine, isoleucine, tyrosine, alanine, arginine, histidine, serine, selenocfysteine, proline, glycine, cysteine, aspargine, alanine, cannabis, all forms and derivatives of cannabis, 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, yohimbe, myhhr, myhhr gum, boswellia, peppermint oil, and menthol.

34. The composition of claim 29, wherein the RECEPTOR SWITCHER:

(a) is an ultra-low-dose, very-low-dose, or low-dose opioid antagonist; and

/or

(b) is ultra-low-dose, very-low-dose, or low-dose naltrexone; and

/or

(c) is ultra-low-dose, very-low-dose, or low-dose naloxone.

35. The composition of claim 34, wherein:

(a) naltrexone is administered in the ultra-low-dose amount of about 125 micrograms or less;

(b) naltrexone is administered in the very-low-dose range of about 125-about 500 micrograms;

(c) naltrexone is administered in the low-dose range of about 500-about 1000 micrograms;

(d) naloxone is administered at an ultra-low-dose of about 0.15 nanagrams·

kg<sup>−

1</sup>·

h<sup>−

1</sup> to 0.25 μ

g·

kg<sup>−

1</sup>·

h<sup>−

1</sup>;

(e) naloxone is administered at about 400 micrograms naloxone in 1000 ml crystalloid given in 24 h to a patient weighing 70 kg;

(f) naloxone is administered at a low-dose of about 0.25 μ

g·

kg<sup>−

1</sup>·

h<sup>−

1</sup> to 1.0 μ

g·

kg<sup>−

1</sup>·

h<sup>−

1</sup>;

or

(g) naloxone is administered at as dose of about 1 μ

g·

kg<sup>−

1</sup>·

h<sup>−

1</sup> to about 5 μ

g·

kg<sup>−

1</sup>·

h<sup>−

1</sup>.

36. The composition of claim 29, wherein:

(a) the RECEPTOR SWITCHER is selected from the group consisting of a neuramindase inhibitor, n-acetyl-cysteine (NAC), magnesium sulfate, sodium sulfate, and methylsulfonylmethane (MSM);

(b) the ENDORPHIN ENHANCER is selected from the group consisting of a cAMP PDE inhibitor, methylxanthine, roflumilast, theophylline, ginkgo biloba, guarana, caffeine, ibudilast, an excitatory amino acid, glutamic acid, mono-sodium-glutamate, DL-Phenylalanine (DLPA), celecoxib, and nerve growth factor (NGF);

(c) the EXOGENOUS OPIOID is selected from the group consisting of tramadol, oxycodone, oxycodone, hydrocodone, morphine loperamide, buprenorphine, methadone, menthol, and codeine;

(d) the SYNERGISTIC ENHANCER is selected from the group consisting of;

(i) a selective serotonin reuptake inhibitor (SSRI) or a selective norepinephrine reuptake inhibitor (SNRI);

(ii) a non-opioid analgesic;

(iii) a non-steroidal anti-inflammatory agent (NSAID);

(iv) acetaminophen;

(v) aspirin;

(vi) white willow bark

(vii) ibuprofen;

(viii) an amino acid in any form or derivative, including a salt;

(ix) 5HTP;

(x) tryptophan;

(xi) S-adenosylmethionine (SAMe);

(xii) GABA;

(xiii) tyrosine;

(xiv) taurine;

(xv) arginine;

(xvi) celecoxib;

(xvii) methylphenidate;

(xviii) acetyl-L-carinitine;

(ixx) cannabis in any form or derivative;

or

(xx) any combination thereof.

37. The composition of claim 36, wherein the SSRI or SNRI is selected from the group consisting of citalopram, escitalopram oxalate, fluoxetine, venlaflafaxine, or duloxetine.

38. The composition of claim 29, wherein:

(a) the RECEPTOR SWITCHER is naloxone, the SYNERGISTIC ENHANCER is ibuprofen, and the co-administration further includes administering arginine;

or

(b) the RECEPTOR SWITCHER is naloxone, the SYNERGISTIC ENHANCER is ibuprofen, the EXOGENOUS OPIOID is morphine, and the co-administration further includes administering arginine.

39. The composition of claim 29, wherein the ENDORPHIN ENHANCER:

(a) is a PDE inhibitor selected from the group consisting of methylxanthine, roflumilast, ibudilast, guarana, caffeine, rolipram, ginkgo biloba, and theophylline;

(b) is a specific cAMP PDE-4 inhibitor, and the RECEPTOR SWITCHER is ultra-low-dose, very-low-dose, or low-dose naltrexone;

(c) is rofllumilast, ibudilast, theophylline, or ginkgo biloba, and the RECEPTOR SWITCHER is ultra-low-dose, very-low-dose, or low-dose naltrexone;

(d) is a specific cAMP PDE-4 inhibitor, and the RECEPTOR SWITCHER is n-acetyl-cysteine;

(e) is rofllumilast, ibudilast, or theophylline, and the RECEPTOR SWITCHER is n-acetyl-cysteine;

(f) is ginkgo biloba, and the RECEPTOR SWITCHER is n-acetyl-cysteine; and

/or

(g) is roflumilast, ibudilast theophylline or ginkgo biloba, and the RECEPTOR SWITCHER is magnesium sulfate;

or

(h) is nerve growth factor (NGF), and the RECEPTOR SWITCHER is selected from the group consisting of ultra-low-dose, very-low-dose, or low-dose opioid antagonists, neurominidase inhibitors, n-acetyl-cysteine, methylsulfonylmethane, magnesium sulfate, and any combination thereof.

40. The composition of claim 29, useful in a safe and effective method to produce pain relief and/or analgesia in a subject experiencing nociceptive pain, wherein the composition comprises:

(a) (i) at least one Receptor Switcher; and

(ii) at least one compound selected from the group consisting of an Endorphin Enhancer, an Exogenous Opioid, a Synergistic Enhancer, and any combination thereof;

(b) (i) at least one Receptor Switcher, (ii) at least one Endorphin Enhancer, and (iii) at least one Exogenous Opioid, at least one Synergistic Enhancer, or any combination thereof;

(c) at least one Receptor Switcher in combination with at least one Synergistic Enhancer;

(d) (i) a compound selected from the group consisting of methylsulfonylmethane (MSM), n-acetyl-cysteine (NAC), scutellaria, and 5,7,4′

-trihydroxy-8-methoxyflavone, and any combination thereof; and

(ii) at least one Endorphin Enhancer and/or Exogenous Opioid and/or Synergistic Enhancer or any combination thereof;

or

(e) (i) at least one Receptor Switcher, in combination with (ii) at least one agent selected from the group consisting of guarana, ginkgo biloba, phenylalanine, dl-phenylalanine (DLPA), celecoxib, and nerve growth factor (NGF).

41. The composition of claim 29 formulated into a dosage form selected from the group consisting of rapid release, immediate-release, slow-release, delayed-released, controlled release, a combination of controlled release and immediate release, nano-encapsulation formulations, and an abuse-resistant delivery system.