Opiate Receptors and Antagonists (eBook)

Preface 5
Foreword 7
Opiate Receptors and Antagonists 7
References 9
Contents 11
Contributors 16
Ultra-Low-Dose Opioid Antagonists Enhance Opioid Analgesia and Reduce Tolerance 23
1.1 Introduction 24
1.2 Preclinical Evidence of Enhanced Opioid Analgesia and Reduced Tolerance 24
1.3 Dose Effects and Dependency on Strain and Sex 26
1.4 Ultra-Low-Dose Naltrexone Effects on Neuropathic Pain and Cannabinoid Analgesia 28
1.5 Clinical Studies of Ultra-Low-Dose Opioid Antagonist Effects in Analgesia 29
1.6 Mechanism of Ultra-Low-Dose Opioid Antagonists 32
1.7 Conclusions 34
References 34
Upregulation of Opioid Receptors 38
2.1 Introduction 39
2.2 Opioid Receptor Upregulation Following Opioid Receptor Antagonist Administration 39
2.2.1 In Vivo Studies 39
2.2.2 In Vitro Studies 44
2.3 Functional Supersensitivity 45
2.4 Studies of the Molecular Mechanisms Involved in Antagonist-Induced Opioid Receptor Upregulation 46
2.5 Opioid Receptor Upregulation Induced by Nonopioid Drugs 52
2.6 Summary and Conclusions 56
References 58
Imaging Human Brain Opioid Receptors: Applications to Substance Use Disorders 64
3.1 Introduction 64
3.2 Mu Receptors 65
3.2.1 Ligands with muOR Affinity 65
3.2.2 Clinical Studies 66
3.2.2.1 Studies of Antagonists to Block Receptors in Healthy Humans 66
3.2.2.2 Opioid Dependence 67
3.2.2.3 Nonopioid Substance Use Disorders 71
Nicotine 71
Alcohol 71
Cocaine 73
3.3 Kappa Receptors 74
3.3.1 Ligands with kappaOR Affinity 74
3.3.2 Clinical Studies 74
3.4 Delta Receptors 75
3.4.1 Ligands with deltaOR Affinity 76
3.4.2 Clinical Studies 76
3.5 Conclusions 76
References 77
Opioid Receptor Antagonist-Mediated Signaling in the Immune System 85
4.1 Introduction 85
4.2 Opioid Receptor Expression in the Immune System 86
4.2.1 Opioid Receptors on Lymphocytes 87
4.2.2 Opioid Receptors on Granulocytes, Monocytes, and Macrophages 87
4.3 Opioid Receptor Antagonists: Effects on Immune Functions 88
4.3.1 Effects on T Cell Growth and Proliferation 88
4.3.2 Role in Thymocytes and Effect on Cellular Apoptosis 88
4.3.3 Effects on Cytokine Signaling 89
4.3.4 Effects on Phagocytic Functions 90
4.3.5 Effects on NK Function 90
4.3.6 Effects on Antibody Production 90
4.4 The Central Nervous System-Immune System Link 91
4.5 Opioid Receptor Signaling and Infection 92
4.6 Conclusions and Perspectives 92
References 93
The Chemistry and Pharmacology of Mu-Opioid Antagonists 99
5.1 Introduction 99
5.1.1 Opioid Background 100
5.1.2 Mu Opioid-Related Side Effects 100
5.2 When Is an Antagonist Called an Antagonist 101
5.2.1 The [35S]GTPGammaS Binding Assay 101
5.2.2 From In Vitro Antagonist Characterization to an In Vivo Model 101
5.3 Nalorphine, Naloxone, and Naltrexone: A History Lesson 103
5.3.1 Clinical Applications for Naltrexone 105
5.3.1.1 Alcohol 105
5.3.1.2 Opioid Detoxification 105
5.3.1.3 Feeding Behaviors 105
5.4 Irreversible Antagonists 105
5.4.1 Beta-Funaltrexamine 106
5.4.2 Dihydromorphinone and Dihydrocodeinone Derivatives 106
5.5 Reversible Antagonists 107
5.5.1 Quarternary Antagonists 107
5.5.1.1 Methylnaltrexone 108
5.5.1.2 Alvimopan 108
5.6 Other Structural Motifs as Mu Antagonists 108
5.6.1 Dmt-Tic Analogues 108
5.6.2 Somatostatin Analogues 109
5.6.3 Morphinans 109
5.6.4 Benzomorphans 109
5.6.5 Oripavines 110
5.7 Summary 110
References 111
Medicinal Chemistry of Kappa Opioid Receptor Antagonists 114
6.1 Introduction 114
6.2 SAR of Selective Nonpeptidic KOR Antagonists 116
6.2.1 SAR of norBNI 117
6.2.2 SAR of JDTic 125
6.2.3 SAR of MTHQ 125
6.3 Unusually Long Duration of Action of Current Selective KOR Antagonists 127
6.4 Future Directions 128
References 129
The Chemistry and Pharmacology of Delta Opioid Antagonists 134
7.1 Introduction 134
7.2 Classical delta-Opioid Antagonists 135
7.2.1 N,N-diallyl-Tyr-Aib-Aib-Phe-Leu-OH 135
7.2.2 Naltrindole 136
7.2.3 H-Tyr-Tic-Phe-Phe-OH 136
7.2.4 [D-Ala2, Leu5, Cys6]enkephalin and [D-Ala2, Leu5, Ser6]enkephalin 138
7.2.5 5'-Isothiocyanate 139
7.2.6 Naltriben 139
7.2.7 7-Benzylidenenaltrexone 140
7.3 New delta-Opioid Antagonists 140
7.3.1 [(±)-KF4] 140
7.3.2 Fluorescent delta-Antagonists 141
7.4 Clinical Applications of delta-Antagonists 142
7.4.1 Prevention of Morphine-Induced Antinociceptive Tolerance 142
7.4.2 Antitussive Properties 142
7.4.3 Ethanol Addiction 143
7.4.4 Cardiovascular Effects 145
7.5 Conclusion 146
References 146
Novel Opioid Antagonists with Mixed/Dual Selectivity 167
8.1 Introduction 168
8.2 Peptide Ligands Possessing Mixed Mu Agonist/Delta Antagonist Activity 169
8.3 Nonpeptide Ligands that Possess Mixed Agonist/Antagonist Activity 170
8.4 Conclusions 179
References 179
Experimental Utility and Clinical Potential of Irreversible Opioid Antagonists 182
9.1 Introduction 183
9.2 Insurmountable Antagonists Available for Mu-Opioid Receptors 184
9.2.1 Beta-Chlornaltrexamine 185
9.2.2 Beta-Funaltrexamine 185
9.2.3 Buprenorphine 185
9.2.4 Clocinnamox 186
9.2.5 Others 186
9.3 Experimental Utility 187
9.3.1 In Vitro Binding Parameters 187
9.3.2 Agonist Affinity and Efficacy Estimates 187
9.3.2.1 Agonist Affinity 188
9.3.2.2 Antagonist Affinities 190
9.3.2.3 Measures of Agonist Efficacy 190
9.3.2.4 Special Considerations 191
9.3.3 Receptor Turnover 192
9.3.4 Underlying Mechanisms of Tolerance and Dependence 193
9.4 Implications for Clinical Use 195
9.4.1 Clinical Experimental Utility 195
9.4.2 Implications for Therapeutics 197
9.5 Conclusions 198
References 198
Methylnaltrexone: A Peripherally Acting Opioid Antagonist 204
10.1 Introduction 204
10.2 Physical and Chemical Properties 205
10.3 Preclinical Development 205
10.3.1 Receptor Binding Activities 205
10.3.2 Acute Toxicity and Demethylation Studies 205
10.3.3 Opioid-Induced Emesis 206
10.3.4 Gut Motility and Opioids 207
10.4 Clinical Development 207
10.4.1 Safety and Tolerability 207
10.4.2 Absorption, Elimination, and Metabolism 208
10.4.3 Activity of Parenteral Methylnaltrexone in Healthy Volunteers 209
10.4.4 Activity of Oral Methylnaltrexone in Healthy Volunteers 210
10.4.5 Activity of Methylnaltrexone in Chronic Opioid Users 212
10.4.6 Methylnaltrexone in Long-Term Opioid Users with Advanced Medical Illness (44) 214
10.4.7 Methylnaltrexone for Post-operative Ileus 216
10.4.8 First Phase III Trial: Methylnaltrexone in Chronic Opioid Users with Advanced Medical Illness 217
10.4.9 Second Phase III Trial: Methylnaltrexone in Chronic Opioid Users with Advanced Medical Illness 218
10.5 Other Potential Roles of Methylnaltrexone in Clinical Practice 221
10.5.1 Opioid-Induced Delay in Gastric Emptying 221
10.5.2 Opioid-Induced Urinary Retention 221
10.5.3 Opioid-Induced Subjective Effects 222
10.5.4 Maintaining the Cough Reflex After Opioids 222
10.5.5 Opioid-Induced Immunosuppression 222
10.5.6 Constipation Associated with Functional Bowel Disorders 223
10.5.7 Inhibition of Angiogenesis 223
10.6 Summary 223
Conflict of Interest Disclaimer 224
References 224
Opioid Antagonist Effects in Animal Models Related to Opioid Abuse: Drug Discrimination and Drug Self-Administration 228
11.1 Introduction 229
11.2 Animal Models of Abuse-Related Drug Effects 229
11.2.1 The 3-Term Contingency 229
11.2.2 Drug Discrimination Procedures 230
11.2.3 Drug Self-Administration Procedures 231
11.2.4 Procedures to Study Drug Dependence and Withdrawal 232
11.3 Effects of Opioid Antagonists in Assays of Drug Discrimination 233
11.3.1 Discriminative Stimulus Effects of Opioid Agonists 233
11.3.2 Antagonism of the Discriminative Stimulus Effects of Opioid Agonists 233
11.3.3 Discriminative Stimulus Effects of Opioid Antagonists 236
11.4 Effects of Opioid Antagonists in Assays of Drug Self-Administration 237
11.4.1 Effects of Opioid Agonists As Consequent Stimuli 237
11.4.2 Effects of Opioid Antagonists on Opioid Agonist Self-Administration 237
11.4.3 Effects of Opioid Antagonists as Consequent Stimuli 239
11.5 Effects of Opioid Antagonists in Opioid-Dependent Subjects 240
11.5.1 Dependence Associated with Opioid Agonist Treatment 240
11.5.2 Effects of Antagonists in Dependent Subjects: Drug Discrimination Studies 240
11.5.3 Effects of Antagonists in Dependent Subjects: Drug Self-Administration Studies 242
11.5.3.1 Effects on Self-Administration of Opioid Agonists 242
11.5.3.2 Effects As Consequent Stimuli 244
11.6 Summary and Implications for Clinical Studies 245
References 246
Naltrexone for Initiation and Maintenance of Opiate Abstinence 254
12.1 Overview of Opiate Dependence Pharmacotherapy 254
12.2 Opiate Detoxification 255
12.2.1 Range of Pharmacotherapies 255
12.2.2 Rapid Opiate Detoxification 255
12.2.2.1 Naltrexone Combined with Alpha-2 Agonists 255
12.2.2.2 Naltrexone Combined with Buprenorphine 256
12.2.3 Ultrarapid Opiate Detoxification 257
12.3 Naltrexone Maintenance of Opiate Abstinence 258
12.3.1 Opiate Receptor Antagonists 258
12.3.2 Naltrexone Maintenance 259
12.3.2.1 Naloxone Challenge, Naltrexone Induction, and Naltrexone Maintenance Dosing 259
12.3.2.2 Safety and Side Effect Profile 259
12.3.2.3 Efficacy in Clinical Use 260
12.3.2.4 Depot Naltrexone 261
12.3.2.5 Pharmacological Adjuncts to Improve Compliance (Lofexidine/Fluoxetine) 263
12.3.2.6 Behavioral Platforms to Improve Compliance 264
12.3.2.7 Patient Selection 265
12.4 Conclusion 266
References 266
Ultra-Low-Dose Naltrexone Decreases Dependence and Addictive Properties of Opioids 273
13.1 Introduction 274
13.2 Ultra-Low-Dose Naltrexone or Naloxone Reduces Somatic Withdrawal in Rodents 274
13.3 Ultra-Low-Dose Naltrexone Reduces Affective Withdrawal in Rodents 276
13.4 Reduced Physical Dependence in Clinical Trial of Oxytrex Versus Oxycodone 277
13.5 Ultra-Low-Dose Naltrexone Reduces the Rewarding Properties of Opioids 278
13.6 Ultra-Low-Dose Naltrexone Reduces the Rewarding Potency of Intravenous Oxycodone and Blocks Relapse to Oxycodone Seeking in Rats 281
13.7 Conclusions 283
References 285
Can a Combination Formulation Containing a Neutral Opiate Antagonist Decrease the Abuse of mu-Agonist Opiates 288
14.1 Prescription Opiate Abuse in the United States – An Emerging Epidemic 289
14.1.1 US Trends in Ambulatory Care Opioid Prescribing from 1993 to 2003 291
14.1.2 Opioid Basal Signaling, Inverse Agonists, and Neutral Antagonists 292
14.2 Potential Advantages of 6beta-naltrexol in Decreasing Abuse of Prescription Opiates 294
14.3 Assessing the Neutral Antagonist Propertiesof 6beta-Naltrexol 295
References 296
Effects of Opioid Antagonists on the Abuse-Related Effects of Psychomotor Stimulants and Nicotine 298
15.1 Introduction 299
15.2 Pharmacology of Psychomotor Stimulants 299
15.3 Influence of Psychomotor Stimulants on Opioid Gene Expression 300
15.4 Animal Models of Addiction 300
15.4.1 Drug Self-Administration 300
15.4.2 Reinstatement of Drug Seeking 301
15.4.3 Conditioned Place Preference 301
15.4.4 Intracranial Self-Stimulation 302
15.5 Nonselective Opioid Receptor Antagonists 302
15.5.1 Drug Self-Administration 302
15.5.2 Conditioned Place Preference 304
15.5.3 Intracranial Self-Stimulation 306
15.5.4 Neurochemistry 307
15.6 Selective MOPr Antagonists 309
15.6.1 Drug Self-Administration 309
15.6.2 Neurochemistry 310
15.7 Selective DOPr Antagonists 311
15.7.1 Drug Self-Administration 311
15.7.2 Conditioned Place Preference 312
15.7.3 Intracranial Self-Stimulation 313
15.7.4 Neurochemistry 313
15.8 Selective KOPr Antagonists 313
15.8.1 Drug Self-Administration 314
15.8.2 Conditioned Place Preference 314
15.8.3 Intracranial Self-Stimulation 315
15.8.4 Neurochemistry 315
15.9 Conclusions 316
References 317
Potential Use of Opioid Antagonists in the Treatment of Marijuana Abuse and Dependence 324
16.1 Introduction 325
16.2 Historical Evolution of Research on Cannabinoids 325
16.3 Effects of Opioid Antagonists in Animal Models of cap delta 9-THC Abuse and Dependence 326
16.3.1 Effects of Opioid Antagonists on cap delta 9-THC-Induced Changes in Dopamine Neurotransmission 326
16.3.2 Effects of Opioid Antagonists on THC Discrimination 328
16.3.3 Effects of Opioid Antagonists on the Cannabinoid Withdrawal Syndrome 329
16.3.4 Effects of Opioid Antagonists on THC-Induced CPPs 329
16.3.5 Effects of Opiates Antagonists on Intravenous Drug Self-Administration 331
16.4 Research in Human Subjects 332
16.4.1 Current Clinical Research with Humans 332
16.4.2 Future Directions for Clinical Research 334
16.5 Conclusions 334
References 335
Naltrexone in Smoking Cessation: A Review of the Literature and Future Directions 340
17.1 Introduction 340
17.1.1 Opioid Mediation of Smoking Behavior 341
17.2 Human Laboratory Studies of Naltrexone and Acute Smoking 341
17.3 Clinical Trials 346
17.4 Sources of Individual Differencesin Response to Naltrexone 350
17.4.1 Sex Differences 350
17.4.2 Depression History and Symptoms 351
17.4.3 Cessation-Related Weight Gain 351
17.4.4 Alcohol Drinking Patterns 352
17.4.5 Genetic Variants 352
17.5 Future Directions and Ongoing Research 353
References 353
Opioid Antagonists and Ethanol’s Ability to Reinforce Intake of Alcoholic Beverages: Preclinical Studies 358
18.1 Introduction: Alcoholism is a Problem with a Long History 358
18.2 A Scientific Revolution in Theory of Addictions 362
18.3 The Revolution and Alcoholism 363
18.4 Tolerance to Naltrexone’s Effects 369
18.5 Secondary Reinforcers That Strengthen the Habit to Drink and Their Opioid Involvement 372
18.6 Specificity of Naltrexone 377
18.6.1 Overlap with Eating Disorders 377
18.6.2 Overlap with Analgesia 379
18.6.3 Kind of Opioid Receptors 379
18.7 Opioids and Sex of the Drinker 381
18.8 Combining Drugs to Achieve Better Outcomes of Treatments 382
18.9 Theory Incorporating the Lessons of the Revolution 383
References 384
Clinical Use of Opioid Antagonists in the Treatment of Alcohol Dependence 393
19.1 Introduction 394
19.2 Evidence for the Clinical Use of Opioid Antagonists in the Treatment of Alcohol Dependence 395
19.2.1 Translation from Basic Science to Clinical Utility 395
19.2.2 Human Laboratory Models of Heavy Drinking 395
19.3 Opiate Antagonist Clinical Trials 398
19.3.1 Early Clinical Trials – Initial Efficacy and Questions 398
19.3.2 The COMBINE Study in the US 400
19.4 Factors that Affect Naltrexone Efficacy 402
19.4.1 Treatment Adherence 402
19.4.2 Long Acting Injectable Naltrexone 403
19.5 Longer-Term Follow-up of Individuals Treated with Naltrexone 404
19.6 Patient Variables Affecting Response 404
19.7 Side Effects and Clinical Use 405
19.8 Summary 405
References 406
Preclinical Effects of Opioid Antagonists on Feeding and Appetite 409
20.1 Introduction 409
20.2 Opioid Antagonist Effects upon Palatable and Hedonic Aspects of Food Intake 410
20.2.1 Behavioral Role of General and Specific Opioid Antagonists 410
20.2.1.1 General Opioid Antagonist Effects 410
20.2.1.2 Opioid Receptor Subtype Antagonist Effects 411
20.2.1.3 Central Sites of Action of General and Specific Opioid Antagonists 411
20.2.2 Molecular Role of General and Specific Opioid Antagonists 412
20.3 Opioid Antagonist Effects upon Homeostatic Regulatory Challenges 412
20.3.1 Behavioral Role of General and Specific Opioid Antagonists 412
20.3.1.1 General Opioid Antagonist Effects 412
20.3.1.2 Opioid Receptor Subtype Antagonist Effects 412
20.3.1.3 Central Sites of Action of General and Specific Opioid Antagonists 413
20.3.2 Molecular Role of General and Specific Opioid Antagonists 413
20.3.2.1 Neurochemical Changes 413
20.3.2.2 Knockout and Antisense Effects 414
20.4 Opioid Antagonist Effects upon Body Weight Regulation 414
20.4.1 Behavioral Role of General and Specific Opioid Antagonists in Chronic and Obesity Studies 414
20.4.1.1 General Opioid Antagonist Effects 414
20.4.1.2 Opioid Receptor Subtype Antagonist Effects 415
20.4.2 Molecular Role of General and Specific Opioid Antagonists in Chronic and Obesity Studies 415
20.4.2.1 Neurochemical Changes 415
20.4.2.2 Knockout and Antisense Effects 416
20.5 Opioid Antagonist Effects upon Pharmacologically Elicited Feeding Responses 416
20.5.1 Behavioral Role of General and Specific Opioid Antagonists 416
20.5.1.1 General Opioid Antagonist Effects 416
20.5.1.2 Opioid Receptor Subtype Antagonist Effects 416
20.5.1.3 Central Sites of Action of General and Specific Opioid Antagonists 417
20.5.2 Molecular Role of General and Specific Opioid Antagonists 418
20.6 Conclusions 418
References 419
CNS Opiate Systems and Eating Disorders 429
21.1 Definitions 429
21.2 Incidence and Prevalence 430
21.3 Diagnostic Criteria 430
21.3.1 Anorexia Nervosa 430
21.3.2 Bulimia Nervosa 430
21.4 Anorexia Versus Starvation 431
21.5 Clinical Research on Anorexia and Opioids 431
21.6 Anorexia Nervosa: An Addictive Disorder? 432
21.7 Metabolic Response to Caloric Restriction 433
21.8 Case Studies and Clinical Trials 437
21.9 Summary 440
References 441
Potential Utility of Kappa Ligands in the Treatment of Mood Disorders 444
22.1 Background 444
22.2 Kappa Antagonists 446
22.2.1 History 446
22.2.2 Mechanisms 448
22.2.3 Complexities 449
22.2.4 Clinical Studies 450
22.2.5 Summary 451
22.3 Kappa Agonists 451
22.3.1 History 451
22.3.2 Mechanisms 453
22.3.3 Complexities 453
22.3.4 Clinical Studies 454
22.3.5 Summary 455
22.4 The Future of Kappa Ligands in the Study and Treatment of Mood Disorders 456
References 458
Opioid Antagonists in the Treatment of Pathological Gambling and Kleptomania 464
23.1 Introduction 464
23.2 Clinical Presentation 465
23.2.1 Pathological Gambling 465
23.2.2 Kleptomania 465
23.3 Addiction Model and Etiological Issues 466
23.3.1 Addiction Model 466
23.3.2 Genetics of Addiction 466
23.4 Neurobiology 467
23.4.1 Dopamine 467
23.4.2 Opioid System 468
23.4.3 Neuroimaging Studies 468
23.5 Treatment 469
23.5.1 Opioid Antagonists 470
23.5.2 Safety of Opioid Anatgonists 471
23.6 Conclusions 472
References 472
Efficacy of Opioid Antagonists in Attentuating Self-Injurious Behavior 476
24.1 Introduction 477
24.2 Overview 479
24.2.1 The Biological Stress System Pain, Pleasure, and SIB 479
24.2.2 Pain and the Endogenous Opioid System 479
24.2.3 Pleasure (Addiction) and the Endogenous Opioid System 479
24.2.4 Stress and the Endogenous Opioid System 480
24.3 Efficacy of Opiate Blockers in the Treatment of SIB 480
24.3.1 Acute Effects of Naltrexone 480
24.3.2 Long-Term Effects of Naltrexone Treatments 483
24.4 Endogenous Opioid Levels Predict Response to Opiate Blockers 484
24.5 Conclusions 486
References 487
Pharmacotherapeutic Effects of Opioid Antagonists in Alcohol-Abusing Patients with Schizophrenia 492
25.1 Introduction 492
25.2 Opioid Antagonist Use in Schizophrenia 493
25.3 Opioid Antagonist Treatment in Alcohol Dependence 494
25.4 Opiate Antagonist Treatment in Patients with Alcohol Dependence and Psychiatric Comorbidity 495
25.5 Opiate Antagonist Treatment in Patients with Alcohol Dependence and Schizophrenia 497
25.6 Conclusions 499
References 500
Current Issues in the Use of Opioid Antagonists (Naltrexone for Opiate Abuse: A Re-Educational Tool as Well as an Effective Drug) 503
26.1 Introduction 504
26.2 Overview and History 504
26.3 Testing-Out and Other Aspects of Naltrexone’s Ability to Block Opiates 507
26.4 Breakthrough and Pseudo-Breakthrough 511
26.5 Toxicity and Side Effects: The Myth of Serious Hepatotoxicity 512
26.6 Side Effects or Withdrawal Effects? 513
26.7 Receptor Up-Regulation and Supersensitivity After Naltrexone Discontinuation 514
26.8 Local Tissue Reactions 515
26.9 Scheduled and Unscheduled Removal of Implants and Dealing with Severe Pain in Patients with Active Depot Naltrexone 516
26.10 Compliance 517
26.11 Comparisons with Disulfiram 518
26.12 Special Techniques for Maximising Success and Minimising Distress and Drop-Out in the Transition from Opiates to Naltrexone 519
26.13 Psychological Aspects of Treatment with Naltrexone Implants 520
26.14 Naltrexone Politics 521
26.15 The Future 522
References 522
Emergency Room Use of Opioid Antagonists in Drug Intoxication and Overdose 527
27.1 Introduction 527
27.2 Naloxone 530
27.2.1 Pharmacology 530
27.2.2 Therapeutic Uncertainties 531
27.2.2.1 Receptor Binding 531
27.2.2.2 Acute Complications 532
27.2.2.3 Acute Withdrawal Symptoms 542
27.2.2.4 Renarcotization 542
27.2.2.5 Summary 542
27.2.3 Effect of Dose and Route of Naloxone on Response Rate 543
27.2.4 Effect of Dose and Route of Naloxone on AWS 544
27.2.5 Effect of Dose and Route of Naloxone on Recurrence of Toxicity 545
27.2.6 Timing of Complications 546
27.2.7 Research Difficulties 546
27.2.8 Summary 547
27.3 The Long-Acting Opioid Antagonists: Nalmefene and Naltrexone 549
References 550
Kappa-Opioid Antagonists as Pruritogenic Agents 556
28.1 Introduction 556
28.2 Effects of Kappa Antagonists on Overt Behavior 557
28.2.1 Initial Observations with norBNI 557
28.2.2 Findings with GNTI 557
28.3 Experimental Protocol 558
28.4 Results 560
28.5 Perspective 561
References 562
Clinical Effect of Opioid Antagonists on Clinical Pruritus 565
29.1 Introduction 565
29.1.1 The Sensation of Pruritus 565
29.1.2 Neurophysiology of Pruritus 566
29.1.3 Pathophysiology of Pruritus 566
29.1.4 Is Central Sensitization for Itch a Common Pathway in Diseases Characterized by this Symptom 567
29.2 Opioidergic Neurotransmission and Pruritus 568
29.2.1 Etiology of the Pruritus of Cholestasis 568
29.2.2 Opioidergic Neurotransmission in Cholestasis 568
29.2.3 The Liver as a Source of Endogenous Opioids in Hepatic Disease 569
29.3 Fundamental Studies Towards Clinical Trials of Opiate Antagonists for the Treatment of the Pruritus of Cholestasis 569
29.3.1 Behavioral Methodology to Study Scratching 570
29.3.2 Instruments to Study Scratching Behavior 570
29.3.3 Insight from Behavioral Studies in Pruritus 571
29.3.4 Behavioral Studies from Animal Models of Scratching 572
29.4 Clinical Trials of Opiate Antagonists for the Treatment of Pruritus 573
29.4.1 Opiate Antagonists for the Treatment of the Pruritus of Cholestasis 573
29.4.2 Opiate Antagonists for the Treatment of the Pruritus of Uremia 574
29.4.3 Opiate Antagonists for the Treatment of the Pruritus of Skin Diseases 575
29.5 Summary 575
References 578
Effects of Opioid Antagonists on L-DOPA-Induced Dyskinesia in Parkinson’s Disease 582
30.1 Introduction 583
30.1.1 L-DOPA-Induced Dyskinesia 583
30.2 Enhanced Opioid Neurotransmission is Associated with l-DOPA-Induced Dyskinesia 583
30.2.1 PPE-B Expression 584
30.2.2 PPE-A Expression 584
30.3 A Role for Opioid Transmission in the Expression of Established LID 586
30.4 Preclinical Studies Using Opioid Receptor Antagonists to Suppress the Expression of l-DOPA-Induced Dyskinesia in Animal Models of PD 587
30.5 Clinical Studies of Potential of Opioid Receptor Antagonists to Reduce Expression of LID in PD Patients 588
30.6 Role of Opioid Peptides in Development (‘Priming’) of LID 588
30.7 The Future for Opioid Receptor Antagonists in LID? 589
References 589
Endocrine Effects of Opioid Antagonists 594
31.1 Introduction 594
31.2 Opioid Antagonist Effects on the HPG Axis 596
31.2.1 Naltrexone Stimulates Release of LH 596
31.2.1.1 Clinical Studies of the HPG Axis 596
31.2.1.2 Preclinical Studies of the HPG Axis 601
31.3 Opioid Antagonist Effects on the HPA Axis 602
31.3.1 Clinical Studies of Opioid Effects on the HPA Axis 604
31.3.2 Preclinical Studies of Opioid Effects on the HPA Axis 605
31.4 Opioid Effects on Prolactin 606
31.4.1 Clinical Studies of Opioid Effects on Prolactin 607
31.4.2 Preclinical Studies of Opioid Effects on Prolactin 608
31.5 Summary of the Effects of Opioid Agonists and Antagonists on the HPG and HPA Axis and Prolactin 609
References 610
Opioid Antagonists in Traumatic Shock:Animal and Human Studies 618
32.1 Introduction 618
32.2 Role of Beta-Endorphin in Cardiovascular Function and Immune Depression Following Traumatic Shock 619
32.2.1 Role of Beta-Endorphin in Cardiovascular Depression Following Traumatic Shock 619
32.2.2 Role of Beta-Endorphin in Immune Depression Following Traumatic Shock in Rats 620
32.3 Opioid Receptors Associated with Traumatic Shock 622
32.4 Antishock Effects of Opioid Antagonists 626
32.4.1 Nonselective Opioid Receptor Antagonists 626
32.4.2 Specific Opioid Receptor Antagonists 630
32.4.2.1 Effects of TRH on Traumatic Shock 630
32.4.2.2 Effects of Delta- and Kappa-Opioid Receptor Antagonists on Traumatic Shock 630
32.5 Conclusion and Perspective 632
References 633
The Efficacy of Opioid Antagonists Against Heatstroke-Induced Ischemia and Injury in Rats 637
33.1 Introduction 637
33.2 Materials and Methods 638
33.2.1 Experimental Animals 638
33.2.2 Induction of Heatstroke 639
33.2.3 Experimental Group 639
33.2.4 Physiological and Biochemical Parameter Monitoring 639
33.2.5 Measurement of Extracellular Glutamate, Glycerol, Lactate/Pyruvate, NOx , and DHBA in the Striatum 640
33.2.6 Measurement of CBF, Brain O2, and Brain Temperature 640
33.2.7 Measurement of Baroreflex Sensitivity 641
33.2.8 Neuronal Damage Score 641
33.2.9 Statistical Analysis 641
33.3 Experimental Results 641
33.3.1 CTAP or Naltrexone Increases both Latency and Survival Time During Heatstroke 641
33.3.2 CTAP or Naltrexone Attenuates Heatstroke-Induced Cerebrovascular Dysfunction During Heatstroke 642
33.3.3 CTAP Attenuates Heatstroke-Induced Hypercoagulable State 642
33.3.4 CTAP Attenuates Heatstroke-Induced Cellular Injury and Organ Dysfunction 642
33.3.5 CTAP Attenuates Heatstroke-Induced Activated Inflammation 644
33.3.6 CTAP Attenuates Heatstroke-Induced Overproduction of NOx and DHBA 644
33.4 Discussion, Conclusions, and Perspectives 646
33.4.1 Discussion 646
33.4.2 Conclusions 648
33.4.3 Perspectives 649
References 650
A Review of the Opioid System in Cancer Patients and Preliminary Results of Opioid Antagonists in the Treatment of Human Neoplasms 653
34.1 Introduction 654
34.2 Opioid Receptors 654
34.3 Opioid-Cannabinergic System Interactions 655
34.4 Opioid System-Pineal Interactions 656
34.5 Immunomodulatory Effects of Opioid Agonists and Antagonists 657
34.6 Oncostatic Properties of Opioid Agonists and Antagonists 658
34.7 Clinical Investigations of Opioid and Cannabinoid Systems 660
34.8 Clinical Investigation of the Opioid System in Cancer Patients 660
34.9 Clinical Studies with Opioid Antagonists in Human Neoplasms 661
34.10 Future Perspectives with Opioid Antagonists in Cancer Therapy 662
References 663
Nonclinical Pharmacology of VIVITROL®: A Monthly Injectable Naltrexone for the Treatment of Alcohol Dependence 666
35.1 Introduction 667
35.2 Extended-Release Formulation of Naltrexone 669
35.3 Medisorb Formulation of Extended-Release Naltrexone (XR-NTX) 669
35.3.1 Process for Formulating Medisorb Naltrexone Microspheres 670
35.3.2 Microsphere Release Mechanism 670
35.3.3 Selection of a Lead Formulation 670
35.3.3.1 In Vitro Release of Naltrexone from Microspheres 672
35.3.3.2 In Vivo Pharmacokinetic and Pharmacodynamic Evidence of Efficacy in Rats 672
Brain Mu-Opioid Receptor Changes 675
Suppression of Morphine Antinociception by XR-NTX: Extent of Opioid Receptor Blockade 676
Overriding the Blockade of Antinociceptive Actions of Opioids in Rats Treated with XR-NTX 679
35.3.3.3 Pharmacokinetic Profile of XR-NTX in Nonhuman Primates 681
35.3.4 Preclinical Summary 681
References 683
The Development of Sustained-Release Naltrexone and Clinical Use in Treating Opiate Dependence 686
36.1 Introduction 687
36.1.1 Opioid Dependence and Consequences 687
36.1.1.1 Epidemiology 687
36.1.1.2 Treatment for Heroin Use 687
36.1.2 Oral Naltrexone 688
36.1.2.1 Pharmacology of Naltrexone 688
36.1.2.2 Clinical Experience with Oral Naltrexone 688
36.1.2.3 Sustained-Release Naltrexone Preparations 689
36.1.2.4 Sustaining Therapeutic Levels 689
36.1.2.5 Biodegradability 690
36.1.2.6 Tissue Compatibility 690
36.1.2.7 Newer Formulations 691
36.2 Mode of Administration: Sustained-Release Preparation 692
36.3 Other Considerations 693
36.4 Merits of Depot Preparations 694
36.5 Polydrug Use 694
36.6 Accidental Opioid Overdose Following Treatment Cessation 695
36.7 Pain Management: Antagonism of Opiates 695
36.8 Concluding Comments 695
References 696
The Development of ProNeura Technology for the Treatment of Addictions 700
37.1 Introduction 700
37.2 Opioid Dependence 701
37.2.1 Overview of Opioid Dependence and Treatments 701
37.2.2 Overview of Buprenorphine and Use in Opioid Dependence 702
37.2.3 Limitations of Current Delivery and the Need for Long-Term Release Formulations 703
37.2.4 Probuphine: Continuous, Long-Term Delivery of Buprenorphine 704
37.2.5 Probuphine: Preclinical Studies 705
37.2.6 Probuphine: Clinical Studies 707
37.3 Alcoholism 709
37.3.1 Overview of Alcoholism and Treatments 709
37.3.2 Overview of Nalmefene and Use in Alcoholism 711
37.3.3 Limitations of Current Delivery and the Need for Long-Term Release Formulation 712
37.3.4 ProNeura Nalmefene Implants: Continuous, Long-Term Delivery of Nalmefene 713
37.4 Conclusions 715
References 715
Development of Opioid Transdermal Delivery Systems 720
38.1 Opioid Antagonists 721
38.2 Full and Partial Opioid Agonists 733
38.3 Conclusion 735
References 735
Intranasal Naloxone for Treatment of Opioid Overdose 740
39.1 Introduction 740
39.2 Pharmacological Basis for IN Use 742
39.3 The Evidence Regarding Use in Opioid Overdose Emergencies 742
39.3.1 Effectiveness 742
39.3.2 Adverse Events 744
39.3.3 Other Benefits 744
39.3.4 Gaps in the Evidence 745
39.4 Discussion 745
39.4.1 Current Place in Treatment 745
39.4.2 Potential Future Place in Treatment Systems 746
39.4.3 Unresolved Issues 747
References 748
Index 751