Opioids and the Evolving Epidemic of Addiction in America

The current opioid crisis in the US is a social and public health nightmare. Both the inherent and new challenges are vexing, formidable, and overwhelming our social, health care, and legal systems. Questions surrounding legitimate opioid use, pain management, so called “recreational abuse,” and life-threatening opioid addiction is an ever-evolving and moving target. The unprecedented rise of mortality, trauma, disability, infectious disease (Klevens, Hu, Jiles, & Holmberg, 2012), and debilitating comorbid psychiatric conditions are expected sequala of addiction, while altering the life trajectories of millions of children and adolescents who are routinely exposed to addictive substances. Not surprisingly, the media frenzy and political hyperbole is squarely aimed at the usual low-hanging fruit: Big Pharma and overprescribing and medical mismanagement by alleged “bad doctors,” even those who prescribe opioids for their legitimate, long-suffering malignant pain patients (Gold & DuPont, 2018). Clearly, we need new pain treatment options, but physicians have to work with the medications and interventions that are currently available to help their patients.

But, do we just have an opioid epidemic? We do have a crisis in opioid overdoses, but even in these cases some are suicides and many are polydrug overdoses with opioids as one of several drugs.

It is shortsighted and tactically ineffective to narrow our gaze solely on opioids—particularly prescription opioids. The opioid crisis moved from prescription painkillers, with pharmaceutical quality control and known dosing, to cheap heroin, adulterated with potent illicitly manufactured fentanyl. Recently enacted federal policies limiting the production and availability of pharmaceutically produced opioid medications may be politically expedient, but expecting this action to reign in any illicit opioid use, addiction, or mortality is fanciful nonsense, as the evidence clearly shows. You cannot employ a static remedy to a rapidly evolving problem (Gold & Edwards, 2018).

Shutting Down the Pill Mills

Shortly after the turn of the century, a highly concerted collaboration between the Drug Enforcement Administration (DEA), local law enforcement, and public health officials were successful in shutting down overprescribing pill mills, which were de facto drug distributors. Innovative federal and statewide policy changes were enacted that now monitor and report the prescribing practice of every physician, on all patients who are prescribed any scheduled medication. This action effectively lifted the veil on the covert prescribing behavior of unscrupulous practitioners. This was an important effort but did not appear to curtail the opioid epidemic. A longer-lasting effect of this effort was to change the burden of opioid monitoring from resting solely on the shoulders of good, ethical, and overwhelmed physicians. These new policies successfully shifted some of the monitoring responsibility to the point of purchase at the local pharmacy. Moreover, pharmacists are legally liable for what they dispense (“America’s pill,” 2019; Christie et al., 2017).

As a result of these legislative and law enforcement interventions, the cost of doing business for the pill mills and high prescribers became prohibitive. However, opioid use and mortality continued to increase in record numbers. For instance, between 2015 and 2016, long after the heyday of the pill mills, annual mortality from opioid overdose climbed to an unprecedented sixty thousand deaths (Hedegaard, Warner, & Miniño, 2017). In addition, drug overdose has become the number one cause of death for Americans under the age of fifty. Data from the Florida Drug-Related Outcomes Surveillance and Tracking System reveal that more than 90 percent of opioid overdose deaths in 2016 showed other drugs of abuse present at the time of death. How many? The average was two to four, but as many as eleven were present during postmortem evaluation in many of the deceased (Pitt, Humphreys, & Brandeau, 2018).

Opioids, like other drugs of abuse, target the brain’s reinforcement centers to produce euphoria. Chronic use leads to dysphoria, anhedonia, and craving. Addiction to opioids often produces anxiety, insomnia, depression, and agitation, which addicts routinely self-treat with marijuana, sedative hypnotics drugs such as alcohol, benzodiazepines, or potent sleep preparations. The combination of opioids and sedative hypnotic drugs increases the risk for overdose mortality significantly, as both classes of drugs effect the autonomic nervous system located on the brainstem—the human autopilot that controls essential functions such as breathing and heart rate. In the majority of fatal overdoses, addicts use a sedative hypnotic drug to help them sleep—or more accurately “pass out”—and they become so sedated, that they simply stop breathing, which stops their heart within a few minutes . . . and they never wake up. Some overdoses are accidental, and others are the result of wishing you might die, or not caring if you die. Our clinical experience suggests that some of these drug combination overdose deaths are likely suicides due to intense shame and feelings of utter hopelessness (Hedegaard et al., 2017).

After the pill mills were effectively shut down, why did mortality from opioid overdose increase so dramatically? It is because addicts simply changed the drugs they took and when they got them. They switched to heroin or bought opioids on the street and the results were disastrous. Surveillance data revealed that the sevenfold increase in overdose mortality was directly attributed to the use of synthetic, illicitly manufactured opioids—namely fentanyl and its cousins (O’Donnell, Halpin, Mattson, Goldberger, & Gladden, 2017). The cheap, easy-access heroin was cut with Chinese and Indian fentanyl. Please note that these data exclude overdose deaths from the synthetic opioid called methadone (CDC, 2018).

Fentanyl

There is no analgesic or opioid more potent, faster acting, and more addictive than the fentanyl family of drugs. Fentanyl, a lipophilic substance was originally FDA-approved as a short-acting analgesic for use in surgery. Because it is lipid soluble (i.e., increasing is absorption and bioavailability) and approximately one hundred times more potent than morphine, simply touching it can be lethal. Its big brother, carfentanyl, is ten thousand times more potent that morphine. Other fentanyl cousins include acetyl-fentanyl and furanyl, all of which are being manufactured by amateur chemists in their garages or basements (NIDA, 2018). The best available evidence reveals that cheap, illicitly made fentanyl is responsible for the surging mortality prevalence observed in 2016 to 2017 (Jones, Einstein, & Compton, 2018). It is difficult for average citizens to fully comprehend the potency of this drug. Only one microgram of fentanyl is needed to produce analgesia in humans, and a microgram (μg) is one-millionth of a gram (gm). If an amateur chemist overshoots the calculation by an infinitesimal amount, death by overdose is a certainty (O’Donnell et al., 2017).

Why Are People Using Such a Dangerous Drug?

In short, people are using these drugs because they are cheap, widely available, and drug economics. The cost of manufacturing fentanyl is a mere fraction compared to the cost associated with producing and selling heroin. Consider the steps:

1. Farming poppy plants in Asia
2. Extracting and processing the thebaine and codeine
3. Converting the raw product into heroin
4. Smuggling the heroin out of Asia and into the US
5. Distributing the product to thousands of dealers in the US
6. Collecting the money
7. Laundering the money

When the pills shut down, the cost of illegally attained prescription opioids tripled (Cicero, Ellis, Surratt, & Kurtz, 2014). The addicts migrated to the easily accessible, low cost heroin, often cut with fentanyl. The same market forces are now driving addicts away from heroin to use illicitly manufactured fentanyl, as it is much cheaper than old-fashioned street heroin as well as the new street heroin laced with fentanyl. As we analyze the trend, it is going to get much worse (Pergliozzi, LeQuang, Taylor, & Raffa, 2018). Globally produced, synthetically manufactured opioid analogs are easy to make, easy to conceal, easy to distribute, cheaper to buy, and thus, will be used by more people, producing more addiction and more mortality. In these phases of the current opioid epidemic it is important to keep in mind that prescription opioids, from pills mills and script MDs, involved legal, FDA-approved medications—doses or purity of opioid pill was not a question. Once the epidemic morphed from prescriptions to illicit drugs, the dose and purity became major issues. Add fentanyl, other drugs of abuse and other impurities and the likelihood of death, disability, and disease increases.

The Bigger Picture

What has been largely ignored in the so-called “opioid crisis,” is the powerful undertow of early exposure to drugs of abuse as teens or young adults set the stage for future use, abuse, and dependence. Mothers increasingly expose their offspring to alcohol, tobacco, marijuana, and other drugs in utero and in early life. The brain changes in response to these exposures, making drug use and dependence more likely “recreational” drug use, binge drinking, and the unprecedented use of marijuana, made available via ballot-box initiatives rather than the FDA. Rather than proving safety and efficacy for a specific medical diagnosis via double-blind, placebo-controlled studies, like we are doing for ketamine as a treatment for depression, marijuana was simply voted to be “medicine” without the benefit of scientific scrutiny regarding its safety and potential efficacy. As a result of marijuana legalization, competitive free-market forces demanded production of highly potent marijuana products.

Why are these other drugs important to the opioid discussion? Most opioid overdose death autopsies reveal poly drug use. Alcohol, marijuana, and other drugs are found alongside heroin and fentanyl. Recent findings by the National Institute on Drug Abuse (NIDA) show that adolescent marijuana users are 2.6 times more likely than nonusers to use opioids (2017). With this association in mind, consider that in the US eight thousand people per day, mostly adolescents and children, will use their very first addictive substance (NIDA, 2017). Of these, seven thousand will use highly potent marijuana. The evidence shows that early initiation is associated with a twofold increase in the prevalence of addiction compared to those who delay initiation until age eighteen or above (Olfson, Wall, Liu, & Blanco, 2018). Specifically, 18 to 20 percent of early-initiated teens will become addicted via marijuana and/or alcohol, and of these most will quickly progress to stronger and faster-acting intoxicants as neuroadaptation and tolerance compels them (Compton et al., 2019) Consider the treatment implications of early initiation: for example, a twenty-four-year-old presents as using heroin or fentanyl daily, but he or she has used numerous drugs and been “addicted” for ten years. This is tantamount to treating patients who present to oncologists with stage-four cancer; the treatment options are very limited, and the survival rate is very low. A viable public health and prevention goal would be to delay the age of initiation to at least eighteen years old. According to current data, this would reduce the prevalence of addictive disease by 50 percent.

The opioid crisis is best thought of as part of the larger, continuously evolving drug epidemic in America. The foundation of which is societal sanctioning of teenage recreational pharmacology that has resulted in the aggressively marketed and widespread use of intoxicants that, by design, hyperactivate the brain’s reward biology, producing measurable neuroadaptations and acute changes in neuro-connectivity as well as the subjective experience of pleasure. Simply stated, all drugs of abuse (including alcohol) stimulate their own taking by producing an intense, short-lived, and highly pleasurable experience that exceeds what could be experienced naturally. Specifically, the human reward system is a complex, sequential interaction among specific neurotransmitters, neuropeptides, and hormones that mediate our emotional and mental state (Baler & Volkow, 2006).

However, exogenous synthetic opioids bind to opioid receptors mu (μ), kappa (κ), and delta (δ) and usurp neural signal transmission (Narita, Funada, Suzuki, 2001; Zhu, Rockhold & Ho, 1998). Opioid receptors are found in both the central and peripheral nervous system (Zhang, Kranzler, Yang, Luo, & Gelernter, 2008). Opioids are distributed throughout the brain in varying concentrations depending on their classification, however they are found to be highly abundant in the amygdala, the 0, and the caudate putamen (Filliol et al., 2000). These areas, as well as the ventral tegmental area, contain interneurons that compose the complex neural circuitry involved in opioid dependence. Opioid receptors differ in their affinity to bind with specific ligands to induce varying degrees of analgesia and anti-nociception, in addition to numerous physiological effects (Cowan, Zhu, Mosberg, Omnaas, & Porreca, 1988). Endogenous opioid peptides, including enkephalins, β-endorphins, endomorphins and dynorphins, are mediated by binding to opioid receptors and therefore play a role in modulating mood and regulating stress responses (Blum et al., 2014b).

The primary neurotransmitters involved in brain reward include: dopamine, endogenous opioids, gamma amino butyric acid (GABA), norepinephrine, and serotonin (NIDA, 2018). Although the etiology of addiction is not well elucidated, we have discovered phenotypical risks factors rooted in the accumulation of single nucleotide polymorphisms (SNPs), which are genetic variations found in our DNA (Blum et al., 2015) of which some increase the risk for reward deficiencies. These heritable deficiencies can be provoked and manifest as a result of social and environmental stressors or simply by experimentation with mood-altering substances (Blum et al., 2008). Reward deficiencies include addictive diseases, depression, anxiety, stress disorders, PTSD, hedonic overeating, and obesity. Numerous SNP’s have been identified and to a large extent sequenced and codified (Blum et al., 2014a). Through novel genetic testing they can be identified and used to determine relative risk for addiction and related concurrent conditions involving reward deficiency. As a result, users erroneously feel that they have done something of importance, because their brain misinterprets the drug-induced euphoria as evidence of accomplishment that should be repeated frequently. In other words, newly initiated drug abusers conclude, “If I feel this good, my life must be good.” This is how addiction reprioritizes the brain to become narrowly focused on reward via continued drug use. As a result, families, friends, health, jobs, and another important remnants of addicted people’s pasts are increasingly diminished and appear to move to the periphery of importance in their lives (Li et al., 2015). Treatment and recovery should be narrowly focused on reversing this.

It is also important to note that addiction is not to a single or specific drug, per se. Addiction is chronic, progressive, neurobiological disease that alters how humans experience pleasure, joy, and contentment by usurping the brain’s reward system America is the world’s number one market for drugs. During the past year, Americans spent $150 billion on marijuana, heroin, cocaine, and methamphetamine, and another $227 billion on alcohol. Drug preferences are most likely determined genetically, but when people’s drugs of choice are not available, others will be used. Polysubstance abuse is the now the norm and not the exception (Connor, Gullo, White, & Kelly, 2014).

Opioids and Pain Management

In spite of the aforementioned dangers associated with opioid abuse and addiction, there are millions of Americans who use them daily in order to manage chronic and/or intractable pain. The fact is, less than 10 percent of individuals receiving opioid treatment for chronic or intractable pain from a reputable, board-certified, pain-management physician will ever abuse them (Palmer et al., 2015), though most will become physically dependent upon them—not the same thing as addiction. Palmer et al. also found that preexisting risk factors are a determinant for OUD among chronic pain patients. The priorities and values of these individuals remain intact, and when their pain is adequately managed, they do not desire more opioids for purposes of brain reward. For these suffering individuals, opioids offer a vastly improved quality of life, as severe pain cannot be ignored and severely limits self-efficacy and quality of life (Sirohi & Tiwari, 2016).

What To Do

A renewed focus on basic research, prevention, and multimodal treatment within the framework of substance use disorder (SUD) is urgently needed. Addiction is a progressive disease whereby the reward system is usurped, hastening the onset of harm among vulnerable persons (Angres, DuPont, & Gold, 2015).
Due to the recent and unprecedented surge of mortality by opioid overdose, we strongly advocate for widespread dissemination of the mu-opioid-receptor antagonist naloxone, that is easily self-administered or can be administered to unconscious victims by family members or friends using a simple, disposable, injectable, pen-like device. This has already saved countless lives when administered by emergency medical personnel at hospitals and by mobile EMTs (Wermeling, 2015).

Until recently, naloxone was only available for intravenous use. In 2014, the FDA approved a subcutaneous/intramuscular autoinjector form that could be administered by any individual. In 2017, they approved a nasal spray form (i.e., NARCAN). Naloxone is similar to CPR or the EpiPen: it reverses the acute, life-threatening consequences of an illness, but does not address the illness itself. In response, The Surgeon General and the Director of the National Institute of Health (NIH) are calling for more public distribution and over-the-counter availability of this life-saving treatment (Strang et al., 2019). The early data a suggests that more citizens are taking the opioid crisis to heart and sense a responsibility to prepare themselves should the need to save a life arise (Walley et al., 2013).

In addition, under the Comprehensive Addiction and Recovery Act of 2016 (CARA), HHS was authorized to make grants to states to implement strategies for pharmacists to dispense naloxone pursuant to a standing order and to develop naloxone training materials for the public.

Overdose kits are increasingly common among providers and patients on long-term opioid therapy and others at risk for overdose. At a minimum, all kits should include:

• Nitrile gloves
• Naloxone/NARCAN Nasal Spray/Naloxone autoinjector
• Syringes
• Needles
• Optional supplies: alcohol pads, rescue breathing masks, and educational inserts

Investigators at Stanford University have reported that, given the current mortality associated with opioid overdose, naloxone is the single most important life-saving intervention known. In Pitt et al.’s analysis it is clear that no single intervention would “solve” the OUD epidemic (2018). But, without supporting education, prevention, MAT, and rehabs, they estimate that 500,000 will die in the next decade (Pitt et al., 2018). Of all of the interventions, naloxone availability and use would have the biggest impact. The researchers noted, and we wholeheartedly agree, that although naloxone, like CPR, can save lives, it does not treat the underlying disease or any pathophysiology. Hence, overdose prevalence continues to increase. We should view naloxone as analogous to EpiPens, CPR, or cardioversion in individuals suffering an acute cardiovascular event. When people are dying, saving their lives is what matters most (Pitt et al., 2018).

Multimodal Medication-Assisted Treatment

The importance of treatment adherence cannot be overstated; it remains a formidable and ongoing challenge, particularly with young opioid addicts. Dr. Mark Gold and Yale colleagues pioneered nonopioid detoxification by using alpha2-adrenergic agonists such as clonidine and, a few years later, similar acting agents including lofexidine as an alternative approach to detoxification and logical induction on to Naltrexone. By1978, the Yale group of researchers invented the use of clonidine as the first nonaddicting, nonopioid treatment for opioid withdrawal or detoxification. This discovery affirmed a considerable understanding of the mechanism of opioid withdrawal. Dr. Gold’s seminal work showed that that without naltrexone, detoxification was largely ineffective, and relapse was the rule. His team later studied health professionals with opioid use disorder, where clonidine detoxification and oral naltrexone was provided, and results improved (Kleber, Topazian, Gaspari, Riordan, & Kosten, 1987). Looking back, it also is a humbling reminder of the limitations of medically-assisted treatments (MATs) for opioid use disorder.

Best treatment practices offer comprehensive multimodal treatment, including MAT; individualized, patient-centered care of adequate intensity and duration; and continuous support and participation in Twelve Step recovery programs. This the template for evidence-based treatment.

The most successful programs evaluate and treat all co-morbidities, whether cardiovascular, infectious, or psychiatric. They work to improved adherence to the treatment plan. The longer patients are in treatment the better. Providing group and individual therapy such as motivational interviewing (MI) and conjoint family therapy, psychosocial and addiction education, and adoption of a chronic disease, continuous care model with strict monitoring. This model has been used with unprecedented success with licensed professionals (e.g., doctors, nurses), pilots, business leaders, and those referred through their organization’s employee assistance programs (EAPs; DuPont, McLellan, White, Merlo, & Gold, 2009). Most of the top organizations recognize that helping valued contributors to the organizations makes good business sense. The EAP’s role is to assess and direct employees in need treatment for SUDs to the best available programs. The added benefit of the EAP model is accountability for full participation in the recommended course of treatment and follow-up care. As always, the employees have a choice: complete the recommended course of treatment or be terminated. This dilemma forces suffering addicts to make value judgements regarding their priorities. Although the five-year outcomes following EAP referrals are not as robust as those observed among doctors in the physician recovery network (PRN), they are substantially higher than non-EAP referrals.

Effective treatment is patient-centered, multimodal, and multidimensional in that it provides a level of care that reflects all patients’ disease severity, motivation to change, and level of emotional and social support. When treatment is so aligned, outcomes improve and relapse becomes the exception and not the rule. As it now stands, relapse, overdose, transmission of infectious disease decrease, and mortality are common. The chronic disease, continuing care model of recovery mitigates associated criminal activity and is cost effective on multiple levels. While the goal of all treatment is for all patients to become drug free and attain a high quality of life, some individuals with severe addictions or unique circumstances need MAT indefinitely. However, these patients are neither sober, as some critics have asserted, nor is it problematic for most of them as long as they adhere to all treatment recommendations and remain involved in continuous monitoring, and all recommended recovery-enhancement programs (McLellan, Lewis, O’Brien, & Kleber, 2000).

What is Recovery?

Recovery can be defined as a voluntarily maintained lifestyle characterized by sobriety, personal health, and good citizenship. To make recovery (and not relapse) the expected outcome of the treatment, there are three essential elements that must be consistently emphasized:

1. Adoption of a chronic disease medical model that incorporates a five-year continuous recovery plan, with the explicitly stated objective and expectation of sustained sobriety
2. Provision for ongoing posttreatment monitoring (i.e., drug testing) and adherence with all recommended professional- and peer-support activities
3. Insistence by continuing care managers or therapists that sustained abstinence is expected and ongoing support and education regarding relapse prevention and contingency planning for high-risk situations is encouraged and expected behavior

Each of these elements is central to the clinical practice guidelines of all highly successful treatment organizations. Unless we move forward from the current acute care, episodic, revolving-door approach and toward a chronic disease management model with long-term monitoring, individualized support, and immediate access to reintervention when needed, we will see more lives ruined and increased mortality (DuPont, Seppala, & White, 2016). We can do better.

References

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Mark S. Gold, MD

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Mark S. Gold, MD, is a teacher of the year, translational researcher, author, mentor, and inventor best known for his work on the brain systems underlying the effects of opiate drugs, cocaine, and food. He has worked as an advisor to many White House Drug Czars, White Houses, and NIDA and NIMH directors over his over-forty-year career. He is an author and inventor who has published over one thousand peer-reviewed scientific articles, texts, and practice guidelines. Dr. Gold has been a professor, eminent scholar, distinguished professor, distinguished alumni professor, chairman, and emeritus eminent scholar during his twenty-five years at the University of Florida. He is currently a professor at Washington University in St. Louis.

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Drew Edwards, EdD, MS

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Drew Edwards, EdD, MS, is the clinical consultant and medical educator for Lakeview Health in Jacksonville, Florida. Formerly an assistant professor and the director of psychiatry and health behavior at the Medical College of Georgia, Dr. Edwards was also the associate director of psychiatry at the University of Florida. Additionally, Dr. Edwards has conducted and published original research on depression and chronic illness and has published over 250 peer-reviewed and popular articles, curricula, CMEs, and training manuals on addictive disease, behavioral medicine, parenting, and youth culture as well books for parents on childhood depression and instilling self-esteem in children.

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