Drug Addiction I

Section I Problems of Drug Dependence.- 1 General Problems of Drug Abuse and Drug Dependence.- A. Introduction.- B. Cost of Abuse of Major Drugs (Economic, Social, and Health).- I. Narcotic Analgesics.- II. Sedative/Hypnotics and Minor Tranquilizers (Depressants).- III. Alcohol.- IV. Amphetaminelike Agents (Stimulants).- V. Hallucinogens.- VI. Cannabis, Marihuana, Hashish.- VII. Summary and Conclusions.- C. Legal and Regulatory Approaches to Minimizing Drug Abuse.- I. Forces Influencing Federal Legislation.- II. Summary of Laws of the United States Regulating Drugs of Abuse.- D. Medical Treatment and Research Efforts.- I. National Research Council.- II. The Federal Government.- 1. Treatment.- 2. Research.- III. Medical and Psychiatric Concepts of Addiction.- 1. Psychopathology.- 2. Sociologic Theories.- 3. Tolerance, Dependence, and Conditioning.- 4. Heredity.- E. Conclusions.- Most Usual Abbreviations.- References.- Section II Morphine Dependence.- 1 Neuropharmacology and Neurochemistry of Subjective Effects, Analgesia, Tolerance, and Dependence Produced by Narcotic Analgesics.- A. Introduction.- B. Subjective States and Their Correlates.- I. Introduction.- II. Subjective Effects in Man.- 1. Single Doses.- 2. Effects of Chronic Administration and Withdrawal.- III. Mouse.- IV. Rat.- V. Cat.- VI. Protracted Abstinence.- VII. EEG Effects.- VIII. Discussion and Conclusions.- C. Analgesia and Pain.- I. Introduction.- II. Neuropharmacology of Pain and the Narcotic Analgesics.- 1. Peripheral Nerve and the Myoneural Junction.- 2. Spinal Cord.- a) Segmental and Spinal Cord Reflexes.- ?) Cat.- ?) Dog.- ?) Rat.- b) Spinal Cord Inhibitory Processes.- 3. Supraspinal Influences.- 4. Sensory Pathways.- 5. Discussion and Conclusions.- III. Neurochemical and Neurohumoral Changes Associated with Analgesia.- 1. Introduction.- 2. Acetylcholine.- a) Analgesia.- b) Guinea Pig Ileum and Other Isolated Tissues.- c) Brain ACh Release.- d) Brain ACh Metabolism.- 3. Serotonin.- Analgesia.- 4. NE and E.- a) Analgesia.- b) Interactions with Narcotic Analgesics.- c) Metabolism.- ?) Dopamines ?-Hydroxylase.- ?) Tyrosine Hydroxylase.- ?) Reserpine.- ?) 6-OHDA.- ?) Pyragallol.- ?) Isolated Tissue.- 5. Dopamine (DA).- 6. Other Drugs Which Affect Indole and Catecholamine Metabolism.- 7. Cyclic AMP, Prostaglandins, and Polypeptides.- 8. Discussion and Conclusions.- D. Tolerance and Physical Dependence.- I. Introduction.- II. Definitions.- III. Description of Tolerance and Dependence.- 1. Mouse.- 2. Rat.- 3. Guinea Pig.- 4. Rabbit.- 5. Dog.- 6. Monkey.- 7. Man.- IV. Problems of Quantitating Tolerance and Physical Dependence.- 1. Tolerance.- a) Baseline Problem.- b) The Syndrome Problem.- c) Change in Effect.- d) Quantitation of Tolerance.- 2. Physical Dependence.- a) Baseline Problem.- b) Syndrome Problem.- V. Neurophysiology.- 1. Isolated Tissues.- 2. Spinal Cord and Brain.- VI. Neurochemical and Neurohumoral Changes.- 1. ACh.- 2. E and NE.- a) Adrenal Medulla.- ?) Single Doses (Cat, Dog, Rat, Mouse, Rabbit).- ?) Chronic Administration.- ?) Abstinence (Rat, Dog, Rabbit, Man).- b) Brain.- ?) Single Doses (Cat, Dog, Rat, Mouse).- ?) Chronic Administration (Monkey, Cat, Dog, Rat, Mouse).- ?) Abstinence.- 3. DA.- a) Single Doses (Cat, Monkey, Rabbit, Mouse, Rat).- b) Chronic Administration (Rat, Mouse, Dog, Monkey, Man).- c) Abstinence (Rat, Dog, Mouse).- 4. Serotonin.- a) Single Doses (Cat, Dog, Rat, Mouse).- b) Chronic Administration (Dog, Rat, Mouse, Rabbit, Man).- c) Abstinence.- 5. Proteins, Polypeptides, Cyclic AMP, Prostaglandins, and GABA.- VII. Theories of Tolerance and Physical Dependence.- 1. Neuronal and Neurohumoral Factors.- 2. General Theories.- a) Homeostasis.- b) Learning and Adaptation.- c) Reversible Changes.- d) Persisting Changes.- Single Cells.- VIII. Summary and Conclusions.- Abbreviations.- References.- 2 Assessment of the Abuse Potential of Narcotic Analgesics in Animals.- A. Introduction.- B. Reinforcing Properties.- C. Pharmacologic Equivalence.- I. Autonomic, Somatomotor, and Behavioral Effects in Nondependent and Dependent Animals.- II. Tolerance and Cross-Tolerance.- III. Suppression Studies.- IV. Direct Addiction and Precipitation Studies.- D. Mouse.- I. Pharmacologic Profile.- II. Direct Addiction, Suppression and Precipitated Abstinence Studies.- E. Rat.- I. Pharmacologic Profile.- II. Self-Administration.- III. Suppression Studies.- IV. Direct Addiction and Precipitation Studies.- F. Dog.- I. Pharmacologic Profile.- II. Self-Administration.- III. Suppression Studies.- IV. Direct Addiction and Precipitation Studies.- G. Monkey.- I. Pharmacologic Profile.- II. Self-Administration.- III. Suppression Studies.- IV. Direct Addiction and Precipitation Studies.- Direct Addiction.- H. Critique of Certain Critical Drugs.- I. Meperidine and Ketobemidone.- II. Dextrorphan and Dextromethorphan.- III. Phenazocine, GPA-1657 (Beta-[-]-5-phenyl-9-methyl-2?-hydroxy-2-methyl-6,7-benzomorphan) and GPA-2087 (l-alpha-5,9-diethyl-2?-hydroxy-2-methyl-6,7-benzomorphan; l-etazocine).- IV. Profadol and Propiram.- J. Discussion and Conclusions.- I. Species.- II. Sensitivity of Measures and Experimental Design.- III. Validity of Tests.- 1. Pharmacologic Profile.- 2. Self-Administration.- 3. Suppression Studies.- a) Partial Agonists.- b) Species.- 4. Direct Addiction and Precipitation Studies.- IV. Conclusions.- References.- 3 Assessment of the Abuse Potentiality of Morphinelike Drugs (Methods Used in Man).- A. Introduction.- I. Rationale for Assessment.- II. Origin of Assessment.- 1. Development of Morphine Substitutes.- 2. Protection of the Public Health.- B. Origin of Methods.- I. Physical Dependence.- 1. Substitution Hypothesis.- 2. Experimental Procedures.- II. Euphoria and Subjective Effects.- 1. Initial Definition.- 2. Experimental Procedures.- C. Current Methods.- I. Physical Dependence.- 1. Substitution Tests.- 2. Direct Addiction.- II. Euphoria and Subjective Effects.- D. Narcotic Antagonists.- I. Nalorphine and Cyclazocinelike Antagonists.- II. Antagonists Lacking Agonist Effects (Naloxone).- III. Partial Agonists of the Morphine Type.- E. Validity.- I. Subjective Effects and Euphoria.- II. Physical Dependence.- III. Indication of Abuse Potential.- F. Pentazocine and Related Compounds.- G. Summary and Conclusions.- References.- 4 Psychiatric Treatment of Narcotic Addiction.- A. Introduction.- B. Psychoanalytic Treatment.- C. Institutional Treatment.- D. Community Treatment Efforts.- I. Psychiatrically Oriented Programs.- II. Synanon.- E. Civil Commitment Programs.- F. Conclusions.- References.- 5 Chemotherapy of Narcotic Addiction.- A. Introduction.- B. Diagnosis of Narcotic Addiction.- I. Diagnosis of Psychopathy.- II. Diagnosis of Tolerance and Physical Dependence.- C. Natural History of Narcotic Addiction.- D. Assessment of Efficacy.- I. Relevant Outcome Variables and Goals of Therapy.- II. Experimental Design.- 1. Controls.- 2. Dropouts.- 3. Use of a Blind Design.- 4. Random Selection of Patients.- E. Detoxification.- F. Maintenance Therapy.- I. Introduction.- II. Acceptance and Retention Rates.- III. Efficacy.- 1. New York City Methadone Maintenance Program (NYCMMP).- 2. Illinois Drug Abuse Program (IDAP).- 3. Santa Clara County Methadone Program (SCCMP).- 4. California Department of Corrections Methadone Maintenance Program (CDCMMP).- 5. Pittsburgh Black Action Methadone Program (PBAMP).- 6. Drug Abuse Reporting Program (DARP).- 7. Summary.- IV. Toxicity.- V. Types of Maintenance Therapy.- 1. High Dose Maintenance.- 2. Low Dose Maintenance.- 3. Levomethadyl (LAAM, dl-?-acetylmethadol, l-?-acetylmethadol).- 4. Heroin.- VI. Rationale and Critique.- G. Narcotic Antagonists.- I. Pharmacology.- Agonistic and Antagonistic Actions of Narcotic Antagonists.- a) Cyclazocine and Nalorphine.- b) Naloxone.- c) Naltrexone.- d) Oxilorphan (1-BC-2605).- e) Diprenorphine.- II. Pharmacologic and Therapeutic Rationales.- 1. Pharmacologic.- 2. Therapeutic.- III. Therapeutic Trials.- 1. Cyclazocine.- 2. Naloxone.- 3. Naltrexone.- IV. Discussion.- H. Summary.- Abbreviations.- References.- 6 Detection of Drugs of Abuse in Biological Fluids.- A. Introduction.- B. General Principles.- I. Uses of Biological Fluid Screening.- II. Test Parameters.- 1. Socioeconomic Parameters.- 2. Chemical Parameters.- a) Sensitivity.- b) Specificity.- 3. Pharmacologic Parameters.- Validity.- 4. Other Terms.- III. Interpretation of Screening Tests.- IV. Other Factors.- 1. Confirmation of Test Results.- 2. Frequency of Testing.- 3. Proficiency Testing of Laboratories.- 4. Urine Sampling.- C. Methods.- I. Thin-Layer Chromatography (TLC).- 1. Extraction Methods.- a) Organic Solvent Extraction.- b) Ion Exchange Resin Impregnated Paper Extraction.- c) Nonionic Resin Extraction, Amberlite XAD-2.- d) Other.- 2. Thin-Layer Chromatography (TLC).- 3. Sensitivity.- a) Hydrolysis.- 4. Specificity.- 5. Socioeconomic Parameters.- 6. Special TLC Procedures.- a) Mini-TLC.- b) Specific Drug Problems.- II. Gas Chromatography (GC).- 1. Methods.- a) General Screening Methods.- b) Confirmation Methods.- c) Methods for Specific Drugs or Drug Groups.- 2. Sensitivity.- 3. Specificity.- 4. Socioeconomic Parameters.- III. Fluorometry.- 1. Methods.- 2. Sensitivity.- 3. Specificity.- 4. Socioeconomic Parameters.- IV. Immunoassay.- 1. Methods.- a) Radioimmunoassay (RIA).- b) Homogeneous Enzyme Immunoassay (EMIT).- c) Hemagglutination-Inhibition (HI).- d) Free Radical Assay Technique (FRAT).- 2. Sensitivity.- 3. Specificity.- 4. Socioeconomic Parameters.- V. Other Techniques.- 1. Paper Chromatography.- 2. Colorimetry.- 3. Ultraviolet (UV) Spectrophotometry.- 4. Microcrystallography.- 5. Mass Spectrometry (MS) and Gas Chromatography/Mass Spectrometry (GC/MS).- 6. Infrared (IR) Spectrophotometry.- 7. High Pressure Liquid Chromatography (HPLC).- D. Validity.- I. Narcotic Analgesics and Antagonists.- 1. Heroin and Morphine.- 2. Other Drugs.- II. Sedative/Hypnotics.- III. Stimulants.- IV. Other Drugs.- E. Summary.- References.- Section III Sedative/Hypnotics and Alcohol Dependence.- 1 The Pharmacology of Sedative/Hypnotics, Alcohol, and Anesthetics: Sites and Mechanisms of Action.- A. Introduction: Sedative/Hypnotics of Interest.- B. Patterns of Nonmedical Use of Sedative/Hypnotic Agents.- I. Characteristics of Dependency on Sedative/Hypnotic Agents.- II. Mechanisms of Dependence.- 1. Drug Effects Subjectively Perceived.- 2. Conditioning or Learning Theories.- 3. Drug Taking or Intoxication as Part of a Psychological Reaction.- 4. Drug-Induced Drug Dependence.- C. Mechanisms and Sites of Action of Barbiturates, Ethanol and General Anesthetics.- I. Introduction: Origin of Selectivity and Specificity of Action.- II. Mechanisms.- 1. Selectivity Due to Differential Distribution.- 2. Alterations in Axonal Excitation and Conductance; ATPase as a Site of Action.- 3. Alterations in Synaptic Transmission: Excitatory Transmission; Presynaptic Inhibition; Postsynaptic Depression.- a) Depression of Central Excitatory Synaptic Transmission by Barbiturates and General Anesthetics.- b) Presynaptic Sites of Action to Reduce Transmitter Synthesis or Release.- c) Effects on Inhibitory Postsynaptic Potential (IPSP).- 4. Evidence from Invertebrate Nervous Systems.- 5. Evidence from the Skeletal Neuromuscular Junction.- 6. Alterations in Putative Central Neurotransmitters.- a) Serotonergic Systems.- b) Adrenergic Systems.- c) Cholinergic Systems.- d) GABA Systems.- e) Dopaminergic Systems.- f) Histamine.- g) Tryptamine.- h) Cyclic AMP.- 7. Nonspecific Membrane Actions.- 8. Stereo- and Chemical Specificity.- 9. Mechanisms of Action Other than those Directly on Excitable Membranes and Synapses.- a) Direct Action on Oxidation.- b) Free Intracellular Ca++ Changes and Mitochondrial Respiration.- c) Ethanol on Uptake of Other Drugs.- 10. Alterations in Microcirculation.- 11. Interactions with Hormones, Antagonists, and Metabolic Products.- a) Hormonal Interactions.- b) Evidence Derived from Antagonism and Interaction Studies.- c) Actions Due to Metabolic and Condensation Products of Ethanol and Barbiturates.- 12. Evidence from Genetic Differences.- 13. Differences in Neural Organization.- a) Effects of Drugs Following Brain Damage.- b) Patterns of Neuronal Discharge and Sensitivity of Drug Depression.- c) Interactions Among Sites, Mechanisms, and Agents. Other Possibilities.- III. Sites of Action.- 1. Motor Systems and Incoordination.- 2. Specificity of Site and Mechanism of Action on Cerebral Cortex, Reticular and Limbic Systems.- a) Cortical Activity and Evoked Potentials-Barbiturates, Anesthetics, Ethanol.- b) Summary and Comment.- 3. Consideration of a Variety of Purported Clinical Effects of Sedative/Hypnotic Agents.- a) Antianxiety Action.- b) Sedation vs. Antianxiety or Antiepileptic Effects.- c) Amnesia.- d) Impairment of Judgement, Increased Risk-taking Behavior, Release of Inhibitions.- e) Analgesia.- f) Mood.- g) Psychedelic Actions of Hypnotics, Anesthetics, and Volatile Solvents.- h) Conclusions.- IV. Mechanisms and Sites of Action of Benzodiazepines.- 1. Sites of Detectable Effects.- 2. Mechanisms of Action.- 3. Subjective Effects.- D. Tolerance and Dependence.- I. Characterization of Acute and Chronic Acquired Functional Tolerance.- 1. Introduction.- 2. Ethanol.- 3. Barbiturates.- 4. Meprobamate.- 5. Benzodiazepines.- 6. General Anesthetics.- II. Mechanisms of Functional Tolerance to Depressant Drugs.- 1. Introduction.- 2. Feedback Compensatory Systems.- 3. Localization of Site of Tolerance.- 4. Receptor Desensitization.- 5. Disuse Supersensitivity.- 6. Tolerance Involving Adaptation in Small and Large Neuronal Networks.- 7. Neurotropic Processes.- 8. Acquired Functional Tolerance Not Due to Homeostatic or Compensatory Functions.- 9. Rate Theory of Drug Action.- 10. Depletion of Transmitter, Substrate or Mediators.- 11. Learned Responses and Tolerance; Related Subjective Phenomena.- III. Benzodiazepine Tolerance and Dependence.- 1. Introduction.- 2. Cross-tolerance and Dependence.- E. Conclusions and Postulates.- I. Sites of Action.- II. Mechanisms of Action.- III. Subjective Phenomena.- IV. Tolerance.- V. Dependence.- VI. Incidence and Selection of Agent.- VII. A Classification of the Potential Hazards of Self-ingestion of Psychoactive Agents with Sedative and Hypnotic Actions.- 1. The Individual and the Drug.- a) Hazards from Other than the Central/Primary, Predictable Drug Actions.- b) Hazards Associated with Intoxicant (Psychoactive) Drug Administration in an Acute or Single Dose.- c) Hazards Associated with Repeated Administration.- 2. Hazards of Intoxicant Drug Use in the Context of the Society and Social Setting, as Well as the Individual and the Drug.- Abbreviations.- References.- 2 The Assessment of the Abuse Potentiality of Sedative/Hypnotics (Depressants). (Methods Used in Animals and Man).- A. Definitions and Scope of Review.- B. Assessment of Barbituratelike Agents.- I. Tests for Physical Dependence in Animals.- 1. Dog.- 2. Monkey.- 3. Rat.- 4. Mouse.- 5. Cat.- II. Tests for Psychic Dependence on Barbiturates in Animals.- 1. Rat.- 2. Monkey.- III. Evaluation of Physical and Psychic Dependence Tests Conducted in Animals for their Capacity to Predict Abuse Potential of Barbiturates in Man.- IV. Tests for Physical Dependence in Man.- V. Tests for Psychic Dependence in Man.- VI. Evaluation of Physical and Psychic Tests in Man for Predicting the Abuse Potential of Barbituratelike Drugs.- C. Assessment of Minor Tranquilizers.- I. Tests for Physical Dependence in Animals.- 1. Dog.- 2. Monkey.- II. Tests for Psychic Dependence in Animals.- Monkey.- III. Evaluation of Physical and Psychic Dependence Tests in Animals of Minor Tranquilizers for their Capacity to Predict Abuse Potential in Man.- IV. Tests for Physical Dependence in Man.- V. Tests for Psychic Dependence in Man.- VI. Evaluation of Experimental Tests in Man of Physical and Psychic Dependence for their Capacity to Predict the Abuse Potential of the Minor Tranquilizers.- D. Assessment of Major Tranquilizers.- I. Assessment in Animals.- II. Assessment in Man.- E. Summary.- References.- 3 Clinical Aspects of Alcohol Dependence.- A. Introduction.- I. Toward a Definition of Alcoholism.- II. The Concept of Addiction.- B. Tolerance.- I. Behavioral Tolerance.- II. Pharmacologic Tolerance.- III. Cross Tolerance.- C. Physical Dependence.- I. The Alcohol Withdrawal Syndromes in Historical Perspective.- II. Basic Phenomenology of the Alcohol Withdrawal Syndrome.- 1. Clinical Description.- 2. Temporal Development of Alcohol Dependence.- III. Some Attempts to Account for the Alcohol Withdrawal Syndrome.- D. Theoretical Models of Withdrawal Syndromes.- I. The Disuse Supersensitivity Hypothesis.- II. Receptor Induction.- III. Enzyme De-Repression.- IV. Conclusions.- E. Experimental Animal Models of Alcohol Withdrawal.- I. Oral and Intragastric Administration.- II. Intravenous Alcohol Administration.- III. Alcohol Administration via Inhalation.- F. Treatment of the Alcohol Withdrawal Syndrome.- I. The Natural History of the Alcohol Withdrawal Syndrome.- II. Intercurrent Illness.- III. Disorders of Electrolyte Acid Base and Water Balance.- IV. The Use of Psychotropic Agents in the Treatment of the Alcohol Withdrawal Syndrome.- V. Nonspecific Pharmacotherapies in the Treatment of Alcohol Withdrawal.- Appendix Social and Drinking History Questionnaire.- References.- 4 Abuse of Non-Narcotic Analgesics.- A. Incidence of the Abuse of Non-Narcotic Analgesics.- B. Symptomatology and Etiology of the Abuse of Non-Narcotic Analgesics.- References.- Author Index.