Ebook: Drug Addiction I: Morphine, Sedative/Hypnotic and Alcohol Dependence

This volume addresses the general problem of drug addiction from several points of view, which are in some ways quite unique and different from other areas of pharmacology. Drug addiction is closely associated with criminal behavior. One of the great and noble edifices of civilization is the philosophic and ethical view that man is perfectible, and some believe that this can be achieved by providing the appropriate circumstance or environment in which man can mature and be educated. Some have postulated that drug abuse is a consequence of an inadequate or pathologic set of socializing experiences or is a consequence of basic conflicts between the values and accepted patterns of behavior of a subculture and that of a larger culture. The degree to which man is malleable and perfectible by social forces is not known nor do we know the true desirability of socializing individuals to the extent that their behavior does not deviate from social norms. Some deviancy is essential for innovation and creativity, and at times there may be difficulties in determining whether an innovator or creator is exhibiting sociopathic behavior or not. This aspect of drug addiction is inherently a matter of social values and ethics.

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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.
Content:
Front Matter....Pages I-XXIII
Front Matter....Pages 1-1
General Problems of Drug Abuse and Drug Dependence....Pages 3-40
Front Matter....Pages 41-41
Neuropharmacology and Neurochemistry of Subjective Effects, Analgesia, Tolerance, and Dependence Produced by Narcotic Analgesics....Pages 43-158
Assessment of the Abuse Potential of Narcotic Analgesics in Animals....Pages 159-196
Assessment of the Abuse Potentiality of Morphinelike Drugs (Methods Used in Man)....Pages 197-258
Psychiatric Treatment of Narcotic Addiction....Pages 259-278
Chemotherapy of Narcotic Addiction....Pages 279-318
Detection of Drugs of Abuse in Biological Fluids....Pages 319-409
Front Matter....Pages 411-411
The Pharmacology of Sedative/Hypnotics, Alcohol, and Anesthetics: Sites and Mechanisms of Action....Pages 413-587
The Assessment of the Abuse Potentiality of Sedative/Hypnotics (Depressants) (Methods Used in Animals and Man)....Pages 589-612
Clinical Aspects of Alcohol Dependence....Pages 613-666
Abuse of Non-Narcotic Analgesics....Pages 667-672
Back Matter....Pages 673-750