Opioids

By George F. Koob, Michael A. Arends, Mandy L McCracken and Michel Le Moal

A current survey and synthesis of the most important findings in our understanding of the neurobiological mechanisms of addiction is detailed in our Neurobiology of Addiction series, each volume addressing a specific area of addiction. Opioids, Volume 4 in the series, explores the molecular, cellular and systems in the brain responsible for opioid addiction using the heuristic three-stage cycle framework of binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation.

• Highlights recent advances in opioid addiction
• Includes Neurocircuitry, Cellular and Molecular neurobiological mechanisms of opioid addiction
• Defines opioid abuse and addiction potential, including biological tolerance

• Language: English
• Publisher: Academic Press
• Release date: May 31, 2023
• ISBN: 9780128169896

George F. Koob

George F. Koob, Ph.D., received his Bachelor of Science degree from Pennsylvania State University and his Ph.D. in Behavioral Physiology from The Johns Hopkins University. He was recently appointed (in 2014) as Director of the National Institute on Alcohol Abuse and Alcoholism (currently on a leave of absence as Professor at The Scripps Research Institute, Adjunct Professor in the Departments of Psychology and Psychiatry at the University of California San Diego, and Adjunct Professor in the Skaggs School of Pharmacy and Pharmaceutical Sciences at the University of California San Diego). As an authority on drug addiction and stress, he has contributed to our understanding of the neurocircuitry associated with the acute reinforcing effects of drugs of abuse and the neuroadaptations of the reward and stress circuits associated with the transition to dependence. Dr. Koob has published over 780 scientific papers. In collaboration with Dr. Michel Le Moal, he wrote the renowned book Neurobiology of Addiction (Elsevier, 2006). He was previously Director of the NIAAA Alcohol Research Center at The Scripps Research Institute, Consortium Coordinator for NIAAA's multi-center Integrative Neuroscience Initiative on Alcoholism, and Co-Director of the Pearson Center for Alcoholism and Addiction Research. He has trained 75 postdoctoral fellows and 11 predoctoral fellows. He is currently Editor-in-Chief of the journal Pharmacology Biochemistry and Behavior and Senior Editor for Journal of Addiction Medicine. Dr. Koob taught for 35 years in the Psychology Department at the University of California San Diego, including courses such as Drugs Addiction and Mental Disorders and Impulse Control Disorders, courses that regularly matriculated 400-500 students each. He also taught Contemporary Topics in Central Nervous System Pharmacology at the Skaggs School of Pharmacy and Pharmaceutical Sciences at UCSD for 9 years. Dr. Koob's research interests have been directed at the neurobiology of emotion, with a focus on the theoretical constructs of reward and stress. He has made contributions to our understanding of the anatomical connections of the emotional systems and the neurochemistry of emotional function. Dr. Koob has identified afferent and efferent connections of the basal forebrain (extended amygdala) in the region of the nucleus accumbens, bed nucleus of the stria terminalis, and central nucleus of the amygdala in motor activation, reinforcement mechanisms, behavioral responses to stress, drug self-administration, and the neuroadaptation associated with drug dependence. Dr. Koob also is one of the world's authorities on the neurobiology of drug addiction. He has contributed to our understanding of the neurocircuitry associated with the acute reinforcing effects of drugs of abuse and more recently on the neuroadaptations of these reward circuits associated with the transition to dependence. He has validated key animal models for dependence associated with drugs of abuse and has begun to explore a key role of anti-reward systems in the development of dependence. Dr. Koob's work with the neurobiology of stress includes the characterization of behavioral functions in the central nervous system for catecholamines, opioid peptides, and corticotropin-releasing factor. Corticotropin-releasing factor, in addition to its classical hormonal functions in the hypothalamic-pituitary-adrenal axis, is also located in extrahypothalamic brain structures and may have an important role in brain emotional function. Recent use of specific corticotropin-releasing factor antagonists suggests that endogenous brain corticotropin-releasing factor may be involved in specific behavioral responses to stress, the psychopathology of anxiety and affective disorders, and drug addiction.

Book preview

Opioids

George F. Koob

National Institute on Alcohol Abuse and Alcoholism and National Institute on Drug Abuse, National Institutes of Health, Bethesda, MD, USA

Michael A. Arends

The Scripps Research Institute, La Jolla, CA, USA

Mandy Mccracken

Waggoner Center for Alcohol and Addiction Research, The University of Texas, Austin, TX, USA

Michel Le Moal

University of Bordeaux and Neurocentre Magendie, Inserm, Bordeaux, France

Table of Contents

Cover image

Title page

Opioids

Copyright

Preface

Acknowledgments

VOLUME FOUR. Opioids

1. Definitions

2. History of opioid use, misuse, and addiction

3. Medical use and behavioral effects

4. Pharmacokinetics

5. Addiction potential

6. Behavioral mechanism of action

7. Neurobiological effects

Index

Opioids

Volume 4 of Neurobiology of Addiction series:

Volume 1: Introduction to Addiction

Volume 2: Psychostimulants

Volume 3: Alcohol

Volume 4: Opioids

Volume 5: Nicotine and Marijuana

Copyright

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Preface

The present series of volumes of Neurobiology of Addiction are a direct extension of our original book from 2006, Neurobiology of Addiction (Koob and Le Moal, 2006, Elsevier). As we embarked on updating the original book years ago, we quickly realized that a prodigious amount of new work had been done on the neurobiology of addiction during the ensuing years. From 2006 until 2022, the number of PubMed citations for opioid addiction alone had nearly doubled. This extraordinary research progress in the field of the neurobiology of addiction required a different theoretical and practical approach to writing our second book.

From a theoretical perspective, we chose to use a heuristically identified domain model that originated in our seminal Science paper on addiction: Drug abuse: hedonic homeostatic dysregulation (Koob and Le Moal, 1997). Here, based on the social psychology of self-regulation theory, experimental psychology, and psychiatry, we originally defined addiction as a cycle that consists of three stages: binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. Eventually, three corresponding domains and neurocircuits coalesced around these three stages: binge/intoxication (incentive salience/pathological habits domain, basal ganglia neurocircuits), withdrawal/negative affect (negative affect domain, extended amygdala neurocircuits), and preoccupation/anticipation (executive function, prefrontal cortex neurocircuits). Several human clinical, behavioral, and self-report studies have confirmed these three neurofunctional domains, at least for alcohol use disorder (Kwako et al., 2019; Votaw et al., 2020; Witkiewitz et al., 2022). Thus, the new revised volumes of the Neurobiology of Addiction series are a current survey and synthesis of the most important findings in our understanding of the neurobiological mechanisms of addiction, now organized along the three stage/three domain construct while retaining synthesis at the circuit, cellular, and molecular levels of analysis.

OPIOIDS, Volume 4 in the series, explores the molecular, cellular, and neurocircuitry systems in the brain that are responsible for opioid addiction using the heuristic three-stage cycle framework of binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. It outlines the history and behavioral mechanism of action of alcohol relevant to the neurobiology of opioid addiction, including neurocircuitry, cellular, and molecular neurobiological mechanisms of opioid addiction in each stage of the addiction cycle. We explore evolving areas of research that are associated with many aspects of the opioid addiction cycle, including neurobiological studies of hyperalgesia, hyperkatifeia, craving, sex differences in the response to opioids, and epigenetic/genetic interactions with opioids.

From a practical perspective, organization of the original book in different volumes was necessitated by the prodigious increase in research and publications from 2006 to present. We had prided ourselves in finding virtually all published work in 2006 and citing as much of it as possible. Most of the early cited literature has been retained in the present series, but such an approach of citing every study from 2006 to present was not humanly possible for the present series. As a result, for many of the topics, we rely on key seminal papers and review articles. For each seminal advance, where possible, we included summary figures. We did extensive searches using keywords relevant to the most prevalent dependent measures to study neurobiological mechanisms in each stage of the addiction cycle.

We hope readers will see how the field has substantially evolved at the level of refined techniques and consolidated theoretical approaches and apologize in advance to researchers who may have a key seminal paper that we missed.

We are very excited and encouraged about the tremendous advances that have been made in unveiling the neurobiology of addiction, both clinically and preclinically. We look forward to further insights that tomorrow's research will provide.

George F. Koob

Michael A. Arends

Mandy McCracken

Michel Le Moal

References

1. Koob G.F, Le Moal M. Drug abuse: hedonic homeostatic dysregulation. Science. 1997;278:52–58.

2. Kwako L.E, Schwandt M.L, Ramchandani V.A, Diazgranados N, Koob G.F, Volkow N.D, Blanco C, Goldman D.Neurofunctional domains derived from deep behavioral phenotyping in alcohol use disorder. Am J Psychiatry. 2019;176:744–753.

3. Votaw V.R, Pearson M.R, Stein E, Witkiewitz K. The Addictions Neuroclinical Assessment negative emotionality domain among treatment-seekers with alcohol use disorder: construct validity and measurement invariance. Alcohol Clin Exp Res. 2020;44:679–688.

4. Witkiewitz K, Stein E.R, Votaw V.R, Hallgren K.A, Gibson B.C, Boness C.L, Pearson M.R, Maisto S.A.Constructs derived from the addiction cycle predict alcohol use disorder treatment outcomes and recovery 3 years following treatment. Psychol Addict Behav. 2022 doi: 10.1037/adb0000871.

Acknowledgments

The authors owe debts of gratitude to Aaron White for his invaluable help with the epidemiological data, Brigitte Kieffer for her comments on a late draft of the manuscript, and Janet Hightower for redrawing all figures that appear in the Neurobiology of Addiction series.

VOLUME FOUR: Opioids

Abstract

A current survey and synthesis of the most important findings in our understanding of the neurobiological mechanisms of addiction is detailed in our Neurobiology of Addiction series, each volume addressing a specific area of addiction. Opioids, Volume 4 in the series, explores the molecular, cellular, and neurocircuitry systems in the brain responsible for opioid addiction using the heuristic three-stage cycle framework of binge/intoxication, withdrawal/negative affect, and preoccupation/anticipation. This volume outlines the history of opioids, including evolution of the current opioid overdose epidemic and behavioral mechanism of action of opioids, both of which have relevance to the neurobiology of opioid addiction. It includes neurocircuitry, cellular, and molecular neurobiological mechanisms of opioid addiction in each stage of the addiction cycle and explores evolving areas of research associated with many aspects of stages of the opioid addiction cycle, including neurobiological studies of hyperalgesia, hyperkatifeia, craving, sex differences in the response to opioids, and epigenetic/genetic interactions with opioids.

Keywords

Addiction; Analgesia; Cellular; Craving; Hyperalgesia; Hyperkatifeia; Molecular; Neurobiology; Neurocircuitry; Opiates; Opioid use disorder; Opioids; Protracted withdrawal; Withdrawal

1. Definitions

2. History of opioid use, misuse, and addiction

2.1 Early history of opioid use/misuse

2.2 Current opioid misuse

2.3 Opioid crisis

3. Medical use and behavioral effects

3.1 Medical use

3.2 Peripheral physiological actions

4. Pharmacokinetics

5. Addiction potential

5.1 Opioid intoxication

5.2 Opioid withdrawal

5.2.1 Classic opioid withdrawal syndrome

5.2.2 Opioid-induced hyperalgesia

5.2.3 Negative emotional symptoms of withdrawal: hyperkatifeia

5.2.4 Acute withdrawal

5.2.5 Conditioned withdrawal and conditioned negative reinforcement

5.2.6 Neonatal opioid withdrawal syndrome

5.3 Opioid tolerance

5.3.1 Pharmacodynamic tolerance

5.3.2 Theoretical basis of tolerance

5.3.3 Acute tolerance

5.3.4 Conditioned tolerance

5.4 Historical misuse of opioids: chipping and compulsive use

5.5 High-potency opioid addiction

5.6 Addiction cycle, opponent process, and negative reinforcement

5.7 Allostasis and addiction

6. Behavioral mechanism of action

6.1 Endogenous opioids

6.1.1 Discovery of endogenous opioid peptides

6.1.2 Localization of endogenous opioid peptides

6.2 Opioid peptides in analgesia, activation, reward, and incentive salience

6.3 Opioid peptides in aversion, pain, and negative affect

7. Neurobiological effects

7.1 Binge/intoxication stage: acute reinforcing and analgesic effects

7.1.1 Neurobiological mechanisms: neurocircuitry bases for acute reinforcing effects of opioids

7.1.2 Neurobiological mechanisms: neurochemical bases for acute reinforcing effects of opioids

7.1.3 Conditioned reinforcement, incentive salience, and habits: opioids

7.1.4 Neurobiological mechanism: brain imaging of the binge/intoxication stage

7.1.5 Neurobiological mechanism: cellular bases for acute reinforcing effects of opioids

7.1.6 Neurobiological mechanism: molecular bases for acute reinforcing effects of opioids

7.1.7 Sex differences in response to opioids: binge/intoxication stage

7.1.8 Summary: binge/intoxication stage

7.2 Withdrawal/negative affect stage: tolerance, withdrawal, and dependence

7.2.1 Neurobiological mechanisms in the withdrawal/negative affect stage: neurocircuitry

7.2.2 Neurocircuitry of the withdrawal/negative affect stage: brain imaging

7.2.3 Neurobiological mechanisms in the withdrawal/negative affect stage: cellular

7.2.4 Neurogenesis in opioid withdrawal

7.2.5 Neurobiological mechanisms in the withdrawal/negative affect stage: molecular

7.2.6 Genetics of opioid withdrawal

7.2.7 Epigenetics of opioid withdrawal

7.2.8 Sex differences: withdrawal/negative affect stage

7.2.9 Summary: withdrawal/negative affect stage

7.3 Preoccupation/anticipation stage: protracted withdrawal, craving, and relapse

7.3.1 Neurobiology of protracted withdrawal

7.3.2 Opioid-primed reinstatement of opioid seeking

7.3.3 Cue- and context-induced reinstatement of opioid seeking

7.3.4 Reconsolidation/reconditioning with drug-related cues

7.3.5 Stress-induced reinstatement of opioid seeking

7.3.6 Incubation-potentiated reinstatement of opioid seeking

7.3.7 Human imaging studies of craving in the preoccupation/anticipation stage

7.3.8 Cellular mechanisms of protracted withdrawal, craving, and relapse in the preoccupation/anticipation stage

7.3.9 Molecular mechanisms of protracted withdrawal, craving, and relapse in the preoccupation/anticipation stage

7.3.10 Genetics in the preoccupation/anticipation stage

7.3.11 Epigenetics in the preoccupation/anticipation stage

7.3.12 Sex differences in the preoccupation/anticipation stage

7.3.13 Summary of preoccupation/anticipation stage

References

1. Definitions

Opiates were originally derived from extracts of the juice of the opium poppy (Papaver somniferum) and defined as any preparation or semisynthetic derivative of opium. Because of the development of synthetic drugs with morphine-like action, the term opioid came into use and can be defined as all drugs, natural and synthetic, with morphine-like actions. Thus, in this book, we refer to these drugs simply as opioids. Opioids also include endogenous morphine-like substances that bind to the same brain sites (receptors) as opioids and antagonists of opioid drugs (Jaffe and Martin, 1990; Martin, 1967). Opioids are drugs with major medical uses that have been used for thousands of years to relieve much human suffering. The two major uses have historically been for the treatment of diarrhea and pain.

2. History of opioid use, misuse, and addiction

2.1. Early history of opioid use/misuse

One of the first references to the medical use of opium was by the Greek Theophrastus who, at the beginning of the 3rd century BCE, spoke of meconium (Macht, 1915), which was composed of extracts of stems, leaves, and fruit of Papaver somniferum. Parcelus (1490–1540 AD), a famous physician of the middle ages, used opium often, and his followers were equally enthusiastic (Macht, 1915). Thomas Sydenham, one of the great physicians of the 17th century, wrote to describe the treatment of a series of dysentery epidemics in 1669–72:

And here I cannot but break out in praise of the great God, the giver of all good things, who hath granted to the human race, as a comfort in their affliction, no medicine of the value of opium, either in regard to the number of diseases it can control, or its efficiency in extirpating them.

Latham (1848).

However, equally early along with the description of beneficial opioid medical actions, withdrawal from opioids was also described. An early description of opioid withdrawal in 1700 AD was written by Dr. John Jones, who detailed withdrawal that is associated with the cessation of chronic opium use. In Chapter 23 of Mysteries of Opium Revealed (Jones, 1700), he wrote:

A return of all diseases, pains and disasters, must happen generally, because the opium takes them off by a bare diversion of the sense thereof by pleasure.

Such a description presaged the ultimate dilemma with opioids (e.g., their beneficial medical effects are accompanied by significant side effects, the most devastating of which is opioid addiction with chronic uncontrolled use).

The history of opioid misuse in the Western world began with the spread from the Middle East of opium to Europe and China. Europeans traded opium for tea from China through the British East India Company. More specifically, British merchants smuggled opium into China to balance their purchases of tea for export to Britain. The Chinese ultimately realized the addictive properties of opium and attempted to stop the trade, resulting in the Opium Wars of the 1840s. The result of the British victories was the opening of ports for British trade, the ceding of Hong Kong to the British, and ultimately the legalization of opium importation to China (Fay, 1975; Wakeman, 1978). Subsequently, opium use spread to the United States with the immigration of Chinese laborers. Unlimited opium use in the United States helped contribute to the Harrison Act of 1914 and, paradoxically, the social marginalization of opioid use and development of heroin addiction (Acker, 2002).

2.2. Current opioid misuse

Opioid use disorder is a major medical problem in the United States, affecting roughly 2 million people annually according to the National Survey on Drug Use and Health (Substance Abuse and Mental Health Services Administration, 2021). The rate of heroin abuse and addiction over the past 40 years has fluctuated. There were a total of 2.3 million people who had ever used heroin in 1979, dropping to 1.5 million in 1990, then rising again to 2.4 million in 1996, and then reaching 5.7 million in 2019. In 2019, there were an estimated 431,000 current heroin users, defined as having used heroin in the past month. This is roughly double the total number of past-month users in 1996, which was 216,000 (Substance Abuse and Mental Health Services Administration, 2020; https://www.samhsa.gov/data/report/2019-nsduh-detailed-tables; accessed June 16, 2022).

The percentage of young adults aged 18–25 years who had ever used heroin in the late 1960s was ∼0.2%, which then rose to a peak of 2.3% in 1977 and then declined steadily into the mid-1990s. The rate then rose from 0.7% in 1996 to 1.8% in 2002 before dropping to 1.2% in 2019 (Substance Abuse and Mental Health Services Administration, 2020; https://www.samhsa.gov/data/report/2019-nsduh-detailed-tables; accessed June 16, 2022). The rate for 12- to 17-year olds hovered between 0.1% and 0.2% up through 1995. From 1996 to 2002, the rate rose from 0.2% to 0.4% before dropping to 0.1% in 2019 (Substance Abuse and Mental Health Services Administration, 1996, 2002, 2003).

In the European Union, approximately 83.4 million or 29% of adults aged 15–64 years are estimated to have ever used an illicit drug. Approximately 1 million Europeans used heroin or another illicit opioid in the past year. Roughly 514,000 people received medications to treat opioid problems in 2020. Problems with opioids accounted for 28% of cases of treatment for substances (European Monitoring Centre for Drugs and Drug Addiction, 2022).

2.3. Opioid crisis

Starting at the point of the original publication of the Neurobiology of Addiction (Koob and Le Moal, 2006), opioid misuse has evolved into a major public health epidemic in the United States that continues unabated at the time of this writing. The nationwide public health crisis continues to escalate. Three waves of the opioid crisis have unfolded over the past few decades. The misuse of prescription opioids began to rise in the late 1990s as a result of overprescription by physicians. Purdue Pharma introduced OxyContin, a long-acting form of oxycodone, in 1996. Sales grew from $48 million in 1996 to nearly $1.1 billion in 2000 (Van Zee, 2009). Overdoses of oxycontin and other prescription opioids increased rapidly until plateauing around 2010 when such deaths plateaued and deaths from heroin began to rise. A few years later, around 2013, deaths from overdoses of synthetic opioids, such as fentanyl, began to climb and continue to rise. In 2021, there were 80,816 overdoses that involved opioids compared with 8407 in 1999 when the epidemic was just beginning (Centers for Disease Control and Prevention, 2022b). An estimated 645,338 people died from opioid overdoses in the intervening years. Between 2005 and 2019 in the United States, opioid-related deaths increased 234% (from 14,918 to 49,860) (https://nida.nih.gov/research-topics/trends-statistics/overdose-death-rates; accessed September 19, 2022).

Three distinct waves of the opioid overdose epidemic are now evident, including a first wave of an increase in opioid prescriptions, followed by increases in heroin overdoses and then by increases in synthetic opioid overdoses. The first wave of opioid overdose deaths began with the increase in the prescription of opioids in 1999, triggered by the widespread increase in the use of opioids for pain management, particularly with the availability of the highly potent oxycodone (Centers for Disease Control and Prevention, 2011; Fig. 1).

Figure 1  Three waves of opioid overdose deaths. From 1999 to 2019, nearly 500,000 people died from an overdose that involved any opioid, including prescription and illicit opioids. This rise in opioid overdose deaths can be outlined in three distinct waves. The first wave began with an increase in the prescription of opioids in the 1990s, with overdose deaths that involved prescription opioids (both natural and semisynthetic opioids and methadone) increasing since at least 1999. The second wave began in 2010, with rapid increases in overdose deaths that involved heroin. The third wave began in 2013, with significant increases in overdose deaths that involved synthetic opioids, particularly involving illicitly manufactured fentanyl. The market for illicitly manufactured fentanyl continues to change. Fentanyl can be found in combination with heroin, counterfeit pills, and cocaine. From Centers for Disease Control and Prevention, National Center for Injury Prevention and Control. Understanding the epidemic. Atlanta: Centers for Disease Control and Prevention; 2022a. https://www.cdc.gov/drugoverdose/epidemic/index.html (Accessed June 17, 2022).

The second wave of overdose deaths began in 2010 with increases in overdoses of heroin (Rudd et al., 2014). The death rate from heroin overdose for the 28 states surveyed increased from 1.0 to 2.1 per 100,000, whereas the death rate from prescription opioid overdose declined from 6.0 per 100,000 in 2010 to 5.6 per 100,000 in 2012. Heroin overdose death rates increased significantly for both sexes, all age groups, all census regions, and all racial/ethnic groups other than American Indians and Alaska Natives (Rudd et al., 2014).

The third wave of synthetic opioid misuse began in 2013, with significant increases in overdose deaths that involved synthetic opioids, particularly those that involved illicitly manufactured fentanyl (O'Donnell et al., 2017). Fentanyl and other highly potent synthetic opioids from China and Mexico are sold as counterfeit prescription pills. Fentanyl appears to be increasingly sold to users both alone and as an adulterant, leading to rising fentanyl-involved deaths. As of 2022, illicitly manufactured fentanyl is now found in combination with other drugs, such as heroin and cocaine, and in counterfeit pills (Gladden et al., 2019). Recent evidence suggests that such deaths now involve younger individuals, including teenagers, who suffer overdoses in context of the accidental use of adulterants with synthetic opioids (Muller and Ceron, 2022; Ahmad et al., 2021).

The first wave of the opioid crisis involved three factors that converged to produce widespread liberal prescription practices: (1) changes in perception of the need to treat pain, (2) false claims of the safety of extended-release opioids with regard to addiction, and (3) misconceptions about the mechanisms of addiction that continue to persist today. In the domain of perception of the need to treat pain, pain specialists and patient advocacy groups made a major effort in the 1980s to argue that the inadequate treatment of noncancer pain and underutilization of pharmaceutical opioids led to unnecessary suffering (Morgan, 1985). Indeed, pain evolved to become the fifth vital sign (i.e., one of a group of the four to six most crucial medical signs that indicate the status of the body's vital functions; Morone and Weiner, 2013; Tompkins et al., 2017). Influential regulatory agencies such as the Joint Commission on the Accreditation of Healthcare Organizations mandated pain assessment at every patient encounter and the treatment of all patients in accredited healthcare settings by 2001 to receive federal healthcare dollars (Haugh, 2005; Ahmedani et al., 2014).

The second factor that contributed to the first wave of the opioid crisis centered around the misconception and misrepresentation that chronic opioid administration in a long-acting preparation did not have addiction potential or had minimal addiction potential (Van Zee, 2009). In the early 1980s, a key and highly cited letter showed that only 4 of 11,882 hospitalized patients with no history of addiction showed signs of addiction with the use of opioids (Porter and Jick, 1980). This observation was then used to argue that the development of addiction was very rare with opioid use for medical conditions. However, as of 2015, there were no well-controlled long-term studies that indicated that opioid treatment for pain beyond 12 weeks effectively relieved pain or improved function (Chou et al., 2015).

There appears to be no clear consensus about whether chronic opioid therapy can actually lessen pain levels or pain-related disability or improve quality of life (Chou et al., 2015). Indeed, a review of long-term therapy for chronic pain versus no opioid therapy or nonopioid therapy evaluated >1 year outcomes with regard to pain, function, and quality of life, and a dose-dependent risk of serious harms was found (Chou et al., 2015). For example, compared with no opioid use, opioid therapy for chronic pain was associated with a higher risk for opioid overdose (Dunn et al., 2010), opioid abuse and dependence (now referred to as opioid use disorder; Edlund et al., 2014), and various other illnesses, from fractures (Saunders et al., 2010) to myocardial infarction (Li et al., 2013b). A study examined whether exposure to prescription opioids is a risk factor for incident opioid use disorder among individuals with a new episode of chronic noncancer pain, based on data from HealthCore Integrated Research Database (representing the west, midwest, and southeast regions). Among individuals with a new chronic noncancer pain episode, prescription opioid exposure was a strong risk factor for incident opioid use disorder, and the duration of opioid therapy was more important than daily dose in determining opioid use disorder risk (Edlund et al., 2014). For example, 0.12% of individuals with low-dose/acute-opioid use had a postindex opioid use disorder diagnosis, whereas 6.1% of individuals with high-dose chronic use had a postindex opioid use disorder (Edlund et al., 2014).

The third factor that contributed to the first phase of the opioid crisis is the general misconception, which persists today, that opioids somehow produce addiction with a minimal emphasis on tolerance and withdrawal and much more emphasis on craving that contributes to compulsive drug seeking (Lyden and Binswanger, 2019). That craving does contribute to compulsive drug seeking is accurate but misses the point of what drives such intense cravings and what drives the problematic pattern of behavior. Indeed, a prominent alternative hypothesis is that patients often escalate their dose because of tolerance and enter the classic addiction cycle via the hyperkatifeia of the withdrawal/negative affect stage of the addiction cycle (Koob and Le Moal, 2001; Kosten and George, 2002; Evans and Cahill, 2016; Koob, 2020; see Section 5.2.3 Negative emotional symptoms of withdrawal: hyperkatifeia).

Opioids produce addiction by producing hyperkatifeia, hyperalgesia, and misery (Koob, 2020). Hyperalgesia and hyperkatifeia that are produced by opioid withdrawal are elaborated in depth in the Behavioral Mechanism Action section. Opioids produce physical or somatic withdrawal signs but also profound negative emotional signs and symptoms that drive drug seeking and craving. Such negative emotional signs and symptoms can arise with chronic opioid use, driving the individual into the addiction cycle via the withdrawal/negative affect stage, independent of recreational use. Indeed, in chronic pain patients, the treated pain returns and is exacerbated by hyperalgesia and hyperkatifeia with profound tolerance. For example, with opioids, hyperalgesia is a common response to chronic use in animal models and humans (Ballantyne and Koob, 2021; Cahill and Taylor, 2017; Celerier et al., 2001; Chu et al., 2008). Acute opioid use can relieve pain and be lifesaving in acute situations, but chronic opioid administration can actually cause pain, both physical and emotional. Such pain and the misery of hyperalgesia and hyperkatifeia drive the dose requirement upward during chronic pain treatment, thereby completing an allostatic cycle in which the treatment is ultimately causing the problem (Ballantyne and Koob, 2021).

Additionally, the continuing increase in overdoses of opioids speaks to greater problems that are associated with social determinants of health, all of which have been exacerbated by the coronavirus disease 2019 (COVID-19) pandemic (Koob et al., 2020). Social determinants of health are conditions in the environments where people are born, live, learn, work, play, worship, and age that affect a wide range of health, function, and quality-of-life outcomes and risks (Office of Disease Prevention and Health Promotion, 2022). They include the social environment, the physical environment, and health services and include five domains: economic stability, education access and stability, healthcare access and quality, neighborhood and built environment, and social and community context. These social determinants of health may contribute to the general dystopia that has seemingly enveloped the United States and reflect the notable increases in deaths of despair (Case and Deaton, 2015, 2017). Despair can be hypothesized to be a critically important mediator in a complex causal field that links economic troubles with diverse forms of morbidity and mortality (Shanahan et al., 2019; Fig. 2).

More specifically, life expectancy in the United States began to decline around 2014 after increasing for decades. Prominent elements of deaths of despair include deaths from drug and alcohol overdoses, liver disease, and suicide (Case and Deaton, 2015, 2017). Deaths of despair were linked to a declining quality of life, including decreases in emotional and physical well-being, increases in financial difficulties, and increases in serious mental illness (Shanahan et al., 2019). Deaths of despair were originally described as beginning in the late 1990s among non-Hispanic white men and women in midlife (Case and Deaton, 2015). However, such deaths have now been shown to have increased among people in midlife across racial and ethnic groups (Gaydosh et al., 2019; Woolf and Schoomaker, 2019).

Figure 2  Hypothesized developmental progression from economic stagnation to deaths of despair. Taken with permission from Shanahan L, Hill SN, Gaydosh LM, Steinhoff A, Costello EJ, Dodge KA, Harris KM, Copeland WE. Does despair really kill? A roadmap for an evidence-based answer. Am J Publ Health 2019;109(6):854–8.

3. Medical use and behavioral effects

3.1. Medical use

Opium contains not only 10% morphine but also thebaine and codeine. Morphine was first isolated from opium by Serturner in 1804 (Macht, 1915). It was named after Morpheus (the God of Dreams) or Morphina (the God of Sleep). Codeine was first isolated from opium in 1832 by Robiquet (Macht, 1915) and was used in the United States as a tonic for a wide variety of problems and ailments. It is still the most widely prescribed legal opioid (Foley, 1993). Heroin (3-6-diacetylmorphine) was developed by the Bayer company in 1898 as a cough suppressant with an alleged stimulant action on the respiratory system (the latter was later proven false; Sneader, 1998; Fig. 3).

Opioids are the most powerful and effective drugs for the acute relief of pain. Pain relief from morphine at a standard intramuscular or subcutaneous dose of 10 mg lasts up to 3–4 h. Opioid analgesia has been described as the selective suppression of pain without effects on other sensations at reasonable analgesic doses (Gutstein and Akil, 2001). However, opioid analgesia also distinguishes between different types of pain. Opioids have minimal effects on first pain, the initial sharp sensation that is produced by a noxious stimulus, but are very effective against what has been called second pain, the dull continuous ache that continues after a noxious stimulus (e.g., the reaction to the specific sensation; Cooper et al., 1986). Presumably, this distinction has survival value, in which the selective suppression of second pain by endogenous opioids allows relief from the pain of a previous injury but does not eliminate awareness of the immediate danger of a new injury. Opioids are less effective in reducing neuropathic pain, requiring higher doses (McQuay, 1988). Perhaps more importantly for the neurobiology of addiction, opioids are also effective acutely in reducing emotional pain (Stewart, 1987).

Opioids at higher doses, however, can produce local anesthetic effects, and these effects have been hypothesized to be mediated by an action on the dorsal root entry zone in the spinal cord (Jaffe and Rowe, 1996). Such effects may be the basis for the potent and effective use of opioids epidurally and intrathecally. Opioids also produce analgesia when administered in the periphery or at local sites, and opioid receptors are present on peripheral nerves (Fields et al., 1980).

Opioids are administered epidurally for the management of obstetric pain. Such use is based on the concept of selective sites of analgesic action at a specific segmental level of the spinal cord. Both epidural and intrathecal administrations have been used for chronic pain states, such as lower back pain, neuralgia, and limb pain (Arner et al., 1988). In the case of epidural administration, opioids can bind to opioid receptors in the spinal cord and produce analgesia without motor or sensory dysfunction (Yaksh, 1981). Drugs with high selectivity for the μ-opioid receptor and high lipid solubility, such as fentanyl, are taken up rapidly into the spinal cord and show a fast onset of action (Littrell, 1991).

Opioids are often used to relieve pain during general anesthesia. However, they also have been a component of balanced anesthesia, in which a balance of agents is used to produce different components of anesthesia (e.g., analgesia, amnesia, muscle relaxation, and the abolition of autonomic reflexes with the maintenance of homeostasis; Woodbridge, 1957). The inclusion of an opioid can reduce preoperative pain and anxiety, decrease adverse responses to manipulations of the airways, lower requirements for inhaled anesthetics, and provide immediate postoperative analgesia. Other medical uses of opioids include the treatment of diarrhea and cough.

Patient-controlled analgesia is a method of opioid administration whereby the patient can titrate the rate of opioid administration to meet individual pain relief needs (Hill et al., 1991). Although this can be achieved with oral dosing, there are specifically designed infusion pumps that can deliver a continuous infusion with bolus doses by the intravenous, subcutaneous, or epidural routes. Pumps are programmed to the needs of the patient, with limits set to prevent overdose. Evidence suggests that patient-controlled analgesia is as safe and effective as other methods and may be more effective under certain conditions. Patient-controlled analgesia provides a more consistent level of analgesia and is associated with greater patient compliance (Macintyre, 2001).

Table 1 provides the equivalent doses of commonly prescribed opioids that are required to produce analgesia that is equivalent to a standard dose of morphine (10 mg; Gutstein and Akil, 2001). There are numerous natural and synthetic opioids for mild to moderate pain relief, many of which have a high oral-to-parenteral ratio (Foley, 1993). Codeine, a natural component of opium, is the most commonly used opioid analgesic for the management of mild to moderate pain, which is often combined with aspirin or acetaminophen. It is significantly less potent than morphine. Oxycodone is a long-acting synthetic derivative of morphine that was used for the management of mild to moderate pain and is nearly equipotent with morphine. It is 20–30 times more potent than morphine via the parenteral route. It has a relatively short half-life (2–3 h) and is excreted mainly via the kidney.

Table 1

a  For morphine, hydromorphone, and oxymorphone, rectal administration is an alternate route for patients unable to take oral medications, but equianalgesic doses may differ from oral and parenteral doses because of pharmacokinetic differences.

b   Caution: Codeine doses above 65 mg often are not appropriate due to diminishing incremental analgesia with increasing doses but continually increasing constipation and other side effects.

c  Oxycontin is an extended-release preparation containing up to 160 mg of oxycodone per tablet and is recommended for use every 12 h.

d  Doses for moderate pain are not necessarily equivalent to 30 mg oral or 10 mg parenteral morphine.

e  Risk of seizures; parenteral formulation is not available in the United States.

Taken with permission from Gutstein HB, Akil H. Opioid analgesics. In: Hardman JG, Limbird LE, Goodman-Gilman A, editors. Goodman and Gilman's the pharmacological basis of therapeutics. 10th ed. New York: McGraw-Hill; 2001. pp. 569–619.

3.2. Peripheral physiological actions

In nontolerant adults, morphine can produce coma, constricted (pinpoint) pupils, and respiratory depression at toxic doses (Ellenhorn and Barceloux, 1988). At analgesic doses, morphine decreases body temperature, decreases pituitary function (reflected by decreases in luteinizing hormone, follicle-stimulating hormone, and adrenocorticotropic hormone [ACTH] levels), decreases respiration, suppresses the cough reflex, and elicits nausea (Gutstein and Akil, 2001). Opioids at therapeutic doses have little or no effects on blood pressure or heart rate but can cause orthostatic hypotension, particularly in the elderly (Hugues et al., 1992; Medical Economics Company, 2004). Opioids decrease gastrointestinal secretions and decrease gastrointestinal motility (Manara and Bianchetti, 1985). Opioids relieve diarrhea through an action on the intestine that slows gastrointestinal motility and delays the transit of intraluminal contents (Galligan and Burks, 1982) and through a specific transport antisecretory action (Sandhu et al., 1983; Schiller, 1995). Opioids produce pruritis when administered either systemically or intraspinally (Ballantyne et al., 1988) and suppress the immune system (Gutstein and Akil, 2001).

4. Pharmacokinetics

Intravenously injected heroin rapidly enters the blood. After smoking, blood levels peak in 1–5 min. Heroin levels then decrease rapidly, reaching the limits of detection in 30 min. After systemic administration, heroin (3-6-diacetylmorphine) is rapidly converted to 6-monoacetylmorphine and then to morphine by removal of the 3-acetyl group and then the 6-acetyl group (Inturrisi et al., 1984; Pichini et al., 1999; Fig. 4). Intravenous heroin has a half-life of only 3 min and is rapidly converted to 6-monoacetylmorphine and then more slowly to morphine (Inturrisi et al., 1984). The elimination half-life by the smoked route has been shown to be 3.3 min for heroin, 5.4 min for 6-acetylmorphine, and 18.8 min for morphine (Jenkins et al., 1994). Morphine is then largely metabolized to morphine 3-β-glucuronide and morphine 6-β-glucuronide (Osborne et al., 1990).

Systemic 6-monoacetylmorphine is 3–10 times more potent than morphine (depending on the nociceptive test; Umans and Inturrisi, 1981). Evidence from opioid-binding studies shows that heroin acts through its metabolites because it does not bind to opioid receptors in brain homogenates (Inturrisi et al., 1983). Both 6-monoacetylmorphine and morphine bind to opioid-binding sites with near equal affinity. Thus, heroin is basically a prodrug that acts via its conversion to 6-monoacetylmorphine and then to morphine. The conversion to 6-monoacetylmorphine is very rapid, occurring via esterase enzymes in the brain and blood and virtually every tissue, including the liver. Thus, 6-monoacetylmorphine conversion accounts for the rapid onset and greater potency of heroin than morphine. 6-Monacetylmorphine is eventually converted to morphine, so morphine also contributes to the duration of heroin's effect.

Figure 3  Advertisements from the Bayer Company and Martin M. Smith & Co. Ltd. for the use of heroin for the treatment of cough, circa early 1900s.

Figure 4  Biotransformation pathway for heroin in humans. Taken with permission from Pichini S, Altieri I, Pellegrini M, Zuccaro P, Pacifici R. The role of liquid chromatography-mass spectrometry in the determination of heroin and related opioids in biological fluids. Mass Spectrom Rev 1999;18:119–30.

Morphine 6-β-glucuronide is produced following morphine administration in humans (Osborne et al., 1988). It is a pharmacologically active metabolite, but its potency is so poor that it unlikely contributes to analgesic effects of morphine (Skarke et al., 2003). Analgesic effects of morphine and morphine 6-β-glucuronide were tested in a transcutaneous electrical pain model in healthy volunteers. Morphine 6-β-glucuronide did not significantly contribute to the effects of heroin. Morphine 3-β-glucuronide has poor affinity for all opioid receptor subtypes (Pasternak et al., 1987) but has some excitatory effects when injected in the brain, consistent with convulsant effects of some opioids in rodents. In a controlled clinical trial, morphine 3-β-glucuronide was shown to be devoid of activity and also had no antimorphine effects (Penson et al., 2000).

5. Addiction potential

5.1. Opioid intoxication

Intoxication for an individual after an intravenous self-injection or smoking has been described as four components that can overlap in time (Agar, 1973, p. 55). First, there is a profound euphoria, termed the rush, which has been described as occurring ∼10 s after the injection begins and includes a wave of euphoric feelings, frequently characterized in sexual terms (Dole, 1980):

So I snort again and holy f___ing s__t! I felt like I died and went to heaven. My whole body was like one giant f___ing incredible orgasm.

Inciardi (1986, p. 61).

After a while she asks me if I want to try the needle and I say no, but then I decide to go halfway and skin-pop [injecting into the muscle just beneath the skin]. Well, man, it was wonderful. Popping was just like snorting, only stronger, finer, better, and faster.

Inciardi (1986, p. 62).

Travelin’ along the mainline was like a grand slam home run f___, like getting a blow job from Miss America. The rush hits you instantly, and all of a sudden you’re up there on Mount Olympus talking to Zeus.

Inciardi (1986, p. 62).

In this first state, there also are visceral sensations, a facial flush, and deepening of the voice. While other effects show tolerance with chronic use, the rush is resistant to tolerance. Second, the high follows and is a general feeling of well-being that can extend several hours beyond the rush and shows tolerance. Third, the nod is a state of escape from reality that can range from sleepiness to virtual unconsciousness. Individuals with opioid addiction are described as calm, detached, and very uninterested in external events (Dole, 1980). Fourth, being straight is the state where the user no longer experiences the rush, nod, or high but also is not experiencing withdrawal. This state can last up to 8 h following a heroin injection or smoking.

The route of administration and infusion rate with that route profoundly influence subjective and physiological effects of opioids (Marsch et al., 2001). Healthy volunteers received intravenous injections of two doses of morphine at three different infusion rates. Faster infusions produced greater positive subjective effects than slower infusions on measures of good drug effect, drug liking, and high. Faster infusions also resulted in greater opioid agonist effects (Marsch et al., 2001; Fig. 5). In experimental studies of heroin addiction, detoxified individuals with opioid addiction were allowed to intravenously self-administer heroin with self-regulated access to increasing doses over a 10-day period in a residential laboratory setting in a locked unit of a large psychiatric hospital. The early phase of the acquisition of heroin self-administration was accompanied by an increase in mood elation and a decrease in somatic concern. Later stages of acquisition were characterized by a profound shift toward greater dysphoria, a notable rise in somatic concern, anxiety, depression, social isolation, and motor retardation (Mirin et al., 1976; Babor et al., 1976). Initially, the reinforcing properties of heroin stemmed primarily from its ability to relieve tension and produce euphoria. However, as the frequency of drug self-administration increased, tolerance quickly developed to the euphorigenic effects, although single injections remained capable of producing brief periods (30–60 min) of positive mood (Mirin et al., 1976). However, this tolerance was accompanied by a distinct shift in the direction of increasing psychopathology and dysphoria. Symptoms included sleep disturbances, social isolation, belligerence, irritability, less motivation for sexual activity, and motor retardation (Mirin et al., 1976; Babor et al., 1976; Haertzen and Hooks, 1969).

5.2. Opioid withdrawal

The characteristic withdrawal syndrome that is associated with withholding derivatives of opium from chronic users was described well early on by C.K. Himmelsbach, Director of Research, U.S. Public Health Service Hospital in Lexington, Kentucky (Himmelsbach, 1943). The symptoms included yawning, lacrimation, rhinorrhea, perspiration, gooseflesh, tremor, dilated pupils, anorexia, nausea, emesis, diarrhea, restlessness, insomnia, weight loss, dehydration, hyperglycemia, elevations of temperature and blood pressure, and alterations of pulse rate. Although many of these symptoms were recognized at that time as manifestations of disturbances in function of the autonomic nervous system (Himmelsbach, 1943), it also was recognized at this time that a negative affective state could accompany these physical signs of opioid withdrawal. A negative affective state is defined as a dysphoric state that is accompanied by depressive-like and anxiety-like symptoms that do not fully meet the criteria of a major mental disorder, such as a major depressive episode or generalized anxiety disorder. Individuals with opioid addiction were described as attempting to obtain sufficient drug to prevent the dysphoria associated with the [opioid] withdrawal syndrome (Reichard, 1943).

Figure 5  Mean peak change scores for drug effect, drug liking, bad, and high effects on the Visual Analog Scale (VAS); the adjective agonist measure on the Adjective Rating Scale (ARS); and the Lysergic Acid Diethylamide (LSD) scale of the Addiction Research Center Inventory (ARCI) for each infusion rate and dosing conditions. VAS: On this measure (Preston et al., 1988), subjects rated the extent to which they experienced six effects (drug effect, drug liking, good drug effects, bad drug effects, drug-induced high, and sick). The analog scales consisted of a line approximately 100 mm in length, anchored at each end by not at all and severe. Subjects were instructed to move a cursor along the line to reflect the degree to