The Opioid Crisis: Prevalence and Markets of Opioids

E A Gardner, et al. Forensic Science Review. Volume 34, Issue 1, January 2022.

Introduction

The Three Waves of the Opioid Crisis

Between 1999 and 2019, nearly half a million people died from opioid overdose, over half of all US deaths due to drug overdose. The opioid crisis came in three distinct waves: prescription opioids, heroin, and illicitly manufactured fentanyls (IMFs). The first phase of the opioid crisis resulted from the release and promotion of OxyContin (OxyER), an extended-release formulation of oxycodone. OxyER was patented by Purdue Pharma, owned by several members of the Sackler family. As shown in Figure 1, the overprescribing of opioids, primarily OxyContin, resulted in an increase in accidental deaths by drug overdose that exceeded that of automobile deaths in 2009. OxyER was responsible for over 186,000 deaths between 1999 and 2019.

A patented abuse-resistant formulation of OxyContin, OxyAR, was released in 2009. The efforts were successful; overdoses of OxyContin decreased by more than 40% by 2014. However, the mitigation effort led to the second wave of the opioid crisis, heroin. Heroin was being offered at an unusually high purity and low cost. Naive users, accustomed to prescription formulations, as well as experienced users unaccustomed to the high purity, were overdosing with their first dose. The introduction of the abuse-resistant formulation for OxyContin in 2010, combined with the increased availability of inexpensive, relatively pure heroin, had the dire consequence of causing a spike in deaths from heroin overdose starting in 2010.

As heroin abuse rose between 2010 and 2017, deaths due to heroin overdose exceeded those of OxyContin in 2016. However, there were major differences between the opioid crises of the past and the current one: the online market for drugs of abuse and the rapid introduction of novel psychoactive substances (NPS), analogs of known drugs of abuse.

The third and deadliest wave of the crisis began in 2013 when drug traffickers began mixing fentanyl with street heroin. Fentanyl came to the US from China, either directly or through Canada and Mexico. It could be ordered online from China and shipped through the regular mail service. From Mexico, it was smuggled into the country already mixed with heroin or other drugs. A kilogram of fentanyl cost a few thousand dollars and was worth millions on the street. The increased potency and favorable economics resulted in an even sharper increase in drug overdose deaths. In 2016, accidental deaths from opioids alone exceeded that of traffic accidents.

Fentanyl is an easily manufactured synthetic opioid with many potential sites for adding heteroatoms or functional groups to create analogs. The appearance of fentanyl was quickly followed by illicitly manufactured fentanyl analogs (IMF) that were advertised as legal to sell and purchase.

When heroin overdose deaths started to rise, deaths due to natural and semisynthetic opioids (a) held relatively steady. The death rate from opioids did not begin to decline until 2018-2019. In fact, it may be more accurate to call the three waves of the opioid crisis “the three concurrent crises of prescription opioids, heroin, and IMFs”.

The overdose death rate from IMFs, combined with heroin and prescription opioids, contributed to the decrease in US life expectancy from 78.8 (2014) to 78.5 years (2017), the first three-year decrease since World War I and the 1918 flu epidemic. The greatest decrease occurred for white non-Hispanics aged 45-54, the age group most affected in all three waves of the opioid crisis.

The current opioid crisis has not been confined to the US alone. While the US led the world in the prescribing and consumption of opioids, Canada and many European countries were not far behind. Table 1 lists the 10 countries with the highest rate of opioid prescriptions. Much of Europe prohibits the advertising of prescription drugs and has avoided high rates of prescription opioid abuse. Abuse has also remained low in Asia. There was concern that Latin America, South Africa, and India could soon be facing a similar epidemic. Despite the widespread abuse of prescription opioids, much of the world suffers a lack of access to effective analgesics. In 2013, over 70% of the world’s population had limited or no access to prescription opioids for necessary medical treatment.

While the prescription opioid crisis was primarily focused in North America, heroin and fentanyl have not been concentrated in any one area. Between 2012 and 2017, an increase in IMFs has been reported for Canada, Australia, Estonia, Denmark, Norway, France, Sweden, Finland, Germany, Belgium, and Russia. There was concern that prescription opioids, heroin, and IMFs were becoming a global crisis.

Opioids, Pharmacology, and Effects

The primary focus of this review is on the prevalence and markets of opioids; a brief overview on opioid pharmacology and effects are provided below, helpful to readers from nontoxicology disciplines.

The analgesia afforded by opioids occurs through binding to the [delta]-, [kappa]-, and [micro]- opioid receptors, alternatively designated as the DOP, KOP, and MOP receptors. Natural, semisynthetic, and synthetic opioids act as agonists (heroin), antagonists (naloxone), or mixed agonist-antagonists (buprenorphine) at the different opioid receptors. The interaction is structure dependent and results in analgesia and a variety of side effects. The primary analgesic effect from opioids prescribed for pain occurs through activation of the MOP receptor, which can be accompanied by interaction with the DOP and KOP receptors. In addition to analgesia, the side effects that lead to abuse include euphoria and a reduction in consciousness. Opioids affect brainstem neurons that control breathing, leading to respiratory depression and even death in cases of overdose. Other side effects that may occur include hypogonadism and endocrine effects, chronic obstructive pulmonary disease, increased pain sensitivity, vomiting, urinary retention, dysphoria, muscular rigidity, miosis, pruritus, chronic constipation, serious fecal impaction, sexual dysfunction, and chronic dry mouth that can lead to tooth decay.

Opioids are administered via oral or intravenous routes, although subcutaneous, transdermal, sublingual, intramuscular, epidural, intrathecal, and intraarticular routes are also used. There are significant first-pass effects in oral administration and 40-60% of the morphine may not reach the brain. Morphine is the baseline to which other opioids are evaluated. The strength of an opioid is listed in morphine milligram equivalents (MME). Oxycodone has an MME of1.5, so 80 mg of oxycodone is equivalent to 120 mg of morphine. The onset through oral administration of morphine is 15-60 min and the half-life is 3-6 h. Fentanyl is more lipophilic, resulting in a much faster onset and a duration of up to 72 h. Remifentanil has an even faster onset than fentanyl but is metabolized by enzymes in the blood, making it useful for an anesthesia when fast clearance is desirable. Naloxone and naltrexone are antagonists that bind to all three of the opioid receptors, making them valuable in the reversal of an overdose.

Nonmedical use or misuse is use without a prescription or for a purpose other than prescribed. Opioid use can affect the development of a young person’s brain, resulting in delays in neurological development and changes in behavioral development. The risk of fatal overdose from prescription drugs is high and nonfatal overdose can result in aspiration, brain damage, nerve damage, and injuries from trauma.

Prescription Opioids

Prevalence

1) 1890-1996 (Debate on the Use of Opioids for Treating Chronic Noncancer Pain)

The first US opioid crisis was primarily due to iatrogenic addiction and the widespread availability of morphine. In the late 1800s, doctors had few alternatives for treating pain. Morphine and the introduction of the hypodermic syringe enabled physicians to provide immediate pain relief. Morphine was used to treat asthma, bronchitis, cholera, chlorosis, colic, diarrhea, nausea, dysentery, toothaches, hemorrhoids, intermittent fever, leukorrhea, “female troubles”, and pain. Once a patient became addicted, morphine was freely available and poorly controlled outside the doctor’s office. While many socioeconomic groups were affected by the first morphine epidemic, typical morphine addicts were white women, who dosed themselves and their families with tinctures and patent medicines.

In the early 1900s, the crisis began to ebb. New classes of analgesics were discovered. Advances in bacteriology provided alternate treatments for conditions such as diarrhea, previously treated with opioids. The Harrison Narcotic Control Act of 1914 was enacted to control the manufacture, sale, and distribution of narcotic drugs. The act also required physicians in private practice to register and be licensed by the state to prescribe, administer, or dispense narcotics. This was generally the function of a state medical board. Pharmaceutical opioids were restricted to postoperative pain and terminally ill cancer patients for whom addiction was not an issue. The standard was set; opioids were considered unsafe and ineffective for treating chronic noncancer pain (CNCP). Other concerns included iatrogenic addiction, fear of the legal consequences of prescribing opioids, tolerance, concern that high doses could lead to addiction, and patients exaggerating their level of pain.

The current opioid crisis was again the result of iatrogenic morphine addiction. The introduction of OxyContin, a high-dose, extended-release, schedule II opioid, did not occur in a vacuum. Attitudes toward the use of opioids to treat CNCP were changing, and there was a push to change policies for treating CNCP with opioids. Purdue Pharma’s unprecedented promotion of a schedule II drug pushed the limits to the breaking point.

In the mid-1980s, physicians were indeed beginning to question the prohibitions against prescribing opioids for the management of CNCP. Supporters claimed that when opioids were taken for pain, the patient did not become addicted, tolerance did not lead to higher doses, and pain was tragically undertreated. There was a growing perception that opioids were only addictive when used recreationally, supported by overinterpretation of patient studies in a hospital setting. Two reports were often cited in support of these conclusions. Porter and Jick, cited 1,352 times according to Google Scholar, was actually a 100-word correspondence that simply stated that a review of the records for 11,882 hospitalized patients who received at least one dose of an opioid found only four documented cases of addiction “in patients who had no history of addiction”. Another study of 38 patients treated for <2 to >10 years with opioids for nonmalignant pain was cited 1,032 times, according to Google Scholar. Two-thirds of the patients in this study received less than 20 MME/day and only 4 of the 38 patients were prescribed greater than 40 mg/day of an opioid. Of the 38 patients, only 2 (5.2%) developed opioid abuse issues. While the conclusion of this study was that long-term use of opioids for chronic pain does not lead to addiction, the lifetime susceptibility to drug use disorders is 2-3%, half that of the patients in the study. Perry and Heidrich have been cited 440 times for finding that of 10,000 patients treated with opioids at burn centers, none became dependent on opioids. However, the report was actually the analysis of a survey given to staff members at burn units about the dose of pain reliever given relative to the level of pain perceived by the medical personnel. Of the 179 respondents, from clinics with a sum of 10,000 patients who were treated with a variety of pain regimens during debridement, 12% (n = 22) knew of a patient who abused opioids as a result of their treatment. All but one was attributed to a history of abuse. The one incident of addiction not attributed to prior abuse was a 3-year-old child. Ironically, in 1984, Perry later identified the need by both medical staff and the patients to maintain a low level of pain. When self-dosing with morphine post-surgery, patients do not try to eliminate all pain, rather attain a level of tolerable pain.

Criticisms of studies cited during this time included a lack of controls or no comparison of the effectiveness of opioids treatment with that of nonopioid analgesics. Most studies focused on hospital patients and not those in outpatient care. Any resulting addiction was attributed to the patient, either due to previous drug abuse or being genetically hard-wired for addiction. In 2013, Kissin performed an extensive search of the literature and was unable to find a single randomized controlled trial of long-term opioid treatment for pain that went beyond three months.

In the 1990s, doctors and psychiatrists began to question whether patients being treated for pain were susceptible to addiction during long-term opioid therapy, and the ethics of withholding opioids from patients in pain who were also diagnosed with drug use disorder (DUD). The claim was made that physical dependence or tolerance were not indications of addiction in a patient being treated for a diagnosed physical ailment. Patients were allegedly being harmed by physicians’ reluctance to prescribe opioids. Withholding opioids from patients with chronic pain was equated with patient mistreatment. In order to relieve physicians’ fears relating to prescribing opioids, several states passed intractable pain legislation that protected them from prosecution by state and federal regulators and from sanction by their state medical boards. By 2000, Texas, California, Oregon, and Washington had passed intractable pain laws.

2) 1996-2020 (Introduction and Promotion of Prescription Opioids Formulations)

In 1996, the American Academy of Pain Medicine and the American Pain Society produced a joint statement promoting the use of opioids to treat CNCP, claiming that addiction did not occur in patients being treated for pain; that respiratory depression from opioids is negated by pain; that there should not be an upper limit for dosage; and that diversion could be easily avoided. Purdue Pharma, owned by the Sackler family, announced the release of OxyContin ER (OxyER), a high-dose, extended-release formulation of oxycodone, in the same year. Because the oxycodone was released at a controlled rate, dosing was only required every 12 h. It would allow patients to adhere to their dosage regimen, sleep through the night, and allow doctors to increase their dose as needed. The Food and Drug Administration (FDA) allowed the label to contain statements that addiction was very rare while under a doctor’s care and that the extended release of OxyContin reduced the risks of taking an opioid. According to the FDA, there was no known upper limit to the amount of OxyER that could be prescribed for pain. Consequently, OxyER was approved for pills containing 10-160 mg. The 160-mg dose was discontinued after one year. Most immediate-release oxycodone (OxyIR) contained a 2.5- to 30-mg dose, often in combination with acetaminophen, ibuprofen, or aspirin. The low dose of opioid, relative to the nonnarcotic pain reliever, minimized abuse since the nonnarcotic would reach toxic levels before euphoric levels of the opioid could be attained. The OxyIR had to be taken every 4 h, opposed to 12 h for OxyER.

Purdue Pharma had previously released an extended-release opioid, MS Contin, in 1987. It was available in doses of 15-600 mg of morphine, taken every 8-12 h. MS Contin attained high value as a street drug due to the high dose that could be rapidly released into the system by chewing the pill or extracting the morphine and injecting it. One 1997 survey of users and drug dealers in Vancouver, Canada, indicated the high dose was reflected in a higher street price for the pills. However, MS Contin was marketed for the treatment of pain due to cancer. The plan for OxyER was to promote it for CNCP according to a three-pronged campaign:

• To reach patients suffering from noncancer pain by replacing the combination opioid pain medications, e.g., acetaminophen and a weak opioid, with OxyER;
• Aggressively market OxyER by minimizing its addictive potential and maximizing its purported effectiveness; and
• Educate physician groups, patient groups, and advocacy organizations through financial relationships.

Between 1996 and 2002, Purdue Pharma used all-expense-paid symposia to recruit and train more than 5,000 physicians, pharmacists, and nurses for the Purdue Pharma national speaker’s bureau. These participants then promoted OxyER through paid presentations and articles. More than 20,000 educational programs on the treatment of pain were funded through grants and sponsorships with the goal of promoting the long-term use of opioids for CNCP. The number of salespersons employed for pharmaceutical sales was increased from 318 to 671, and Purdue Pharma more than doubled the number of physicians on its contact list. Physicians were rated by their willingness to prescribe opioids. Promotions offered by the sales representatives included coupons for a free prescription of a 7- to 30-day supply of OxyER. In 2001, over 30,000 coupons had been redeemed. Fishing hats, stuffed plush toys, and music compact discs were used to promote the sale of a schedule II drug and the sales representatives averaged bonuses of $71,500 in 2001. As sales increased exponentially, Purdue Pharma portrayed addiction as insignificant and promoted an extended length of time on opioids with no ceiling dose. Opioids were promoted over combinations, claiming nonsteroidal anti-inflammatory drugs (NSAIDs) and Tylenol have “life-threatening” side effects. In 1998, Purdue Pharma sent 15,000 copies of a video, “I Got My Life Back” promoting opioids for CNCP to physicians.

The market for CNCP was much larger than for non-cancer-related pain. Over the next five years, 1997-2002, sales of OxyContin for CNCP increased nearly 10-fold from 670,000 to 6.2 million. Prescriptions for cancer-related pain underwent a four-fold increase over the same time period.

The abuse and diversion of OxyContin began to gain attention as early as 1999, starting in rural Maine, the Northeast, and Appalachia. The pills were being crushed for ingestion or inhalation. The oxycodone in the powder could be extracted in water and injected. Instructions for abusing OxyContin were basically included in the FDA-approved package insert included with the pills.

In 2001, Purdue Pharma spent $200 million promoting OxyER and released a second version of the “I Got My Life Back” video. The OxyER labeling was changed to reflect that it had not been established that patients would not become addicted when adhering to the prescription guidelines and that the extended-release formulation did not reduce the abuse liability of the drug.

By 2002, OxyER accounted for 68% of all oxycodone sales. The lifetime nonmedical use increased to 1.9 million and by 2004, it was 3.1 million people. Overdose deaths from prescription opioids exceeded those of heroin and cocaine. In response to widespread reports of OxyER abuse, Purdue Pharma sponsored the Researched Abuse, Diversion and Addiction-Related Surveillance (RADARS[R]) program to monitor prescription drug abuse, misuse, and diversion.

By 2005, results from the SAMHSA 2005 National Survey on Drug Use and Health showed that 2.1 million people had initiated drug abuse with OxyER. Franklin et al. analyzed the Washington State workers’ compensation system and found the shift to more liberal guidelines for prescribing opioids had resulted in an increase in prescriptions of Schedule II opioids in addition to OxyER and there was a 50% increase in daily dose when extended-release opioids were prescribed. The increase in opioid prescriptions was concurrent with an increase in worker deaths.

In 2006, there were seven states with more opioid prescriptions than people. The states with more than 100 prescriptions per 100 residents and the states with fewer than 50 prescriptions per 100 residents are listed in Table 2. Some of the hardest hit were the Appalachian states —Alabama, Kentucky, Mississippi, Ohio, Tennessee, and West Virginia. In 2006, five of the seven states with the highest prescription rates were Appalachian states. Comprising 25% of the US states, they represented 50% of states with high prescription rates in 2012 and 2011. In 2019, Alabama was the only state where the prescription rate for opioids exceeded the number of residents. New York, also an Appalachian state, was among the lowest. Nationwide, in 2006, there were 72 opioid prescriptions for every 100 people. By 2019, the number had decreased to 47. There were actually far fewer people with prescriptions than the number of prescriptions dispensed. Many prescriptions were only written for a 90-day or less supply. Despite the recommendation for restricting the dosage to every 12 h, prescriptions were written for up to six doses per day.

In 2007 Purdue Pharma executives pleaded guilty and were fined $634.5 million for the deceptive marketing of OxyContin as less addictive and having less potential for abuse than other drugs.

By 2008, annual prescription opioid deaths exceeded 9,000. Jones et al. analyzed data from the National Survey on Drug Use and Health (NSDUH) from 2008-2011 and determined the source of prescription opioids fueling the increase in opioid deaths was not drug dealers, it was family and friends. People with less than 30 days of nonmedical use of prescription opioids obtained the drug for free from family and friends (62%). Long-term users, >200 days, obtained the prescription opioid from multiple sources, including for free from family and friends (26%), prescriptions from multiple doctors (27%), and purchased from family and friends (23%). Other sources included stolen from family and friends, drug dealers, and other. Prescriptions were the major source of opioids, risking diversion, misuse, and death.

The prescription opioid crisis affected a different demographic than previous drug crises. Opioid overprescribing was associated with small cities or large towns with a predominantly white population, more dentists and primary care physicians, a greater number of uninsured and unemployed, and a greater population with disabilities. In the previously mentioned NSDUH report 55.5% were male, 73.5% white non-Hispanic, and a greater number had an annual income above $75,000 (25.6%) than below $20,000 (23.7%). From 2009-11, the greatest increase in opioid overdose deaths was in non-Hispanic white males between the ages of 45 and 54 years of age. Indicators for opioid prescription were poor physical health, poor mental health, young, obese, uninsured, smoking, white, and female. Fifteen percent of older adults were also misusing benzodiazepines. Concurrent opioid and benzodiazepine use increases chance of overdose. Overlapping opioid and benzodiazepine prescriptions may have occurred through lack of coordination of care, possibly over multiple prescribers.

In 2009, Purdue Pharma patented an abuse-deterrent formulation of OxyContin (OxyAR), the first drug to be designated as abuse deterrent by the FDA. OxyAR was released in August 2010. Distribution of OxyER was discontinued at the same time. Purdue Pharma also successfully argued that extended-release oxycodone without the abuse-resistant features presented a high risk for addiction, preventing other pharmaceutical companies from receiving FDA approval for generic extended-release oxycodone.

The abuse-deterrent pills could not be crushed into a powder for oral ingestion, although it was still possible to abuse the drug by taking more pills than prescribed. Attempts to dissolve the pill to extract the oxycodone resulted in a gel that could not be injected. Users quickly developed methods to overcome the physiochemical barriers to extract oxycodone from OxyAR, including heating, freezing, grinding, and microwaving.

The efforts were successful in reducing the number of prescriptions of OxyContin. OxyContin still ranked 15th in all prescription drugs, with more than $3 billion in sales during 2010. Past month abuse use of OxyContin decreased in established abusers by 45% (from 45.1% to 26.0% of respondents in drug treatment for drug abuse) over the next three years and remained constant through June 2014 when the study ended. Of the 88 respondents, 43% were using non-oral routes of administration, 34% had defeated the ADF features, 20% were using only oral ingestion and 3% stopped abusing drugs. The data were acquired from the Survey of Key Informants’ Patients (SKIP) program and Researchers and Participants Interacting Directly (RAPID) Program surveys by the Purdue Pharma-funded RADARS system. The RADARS system was transferred to the Denver Health and Hospital Authority’s Rocky Mountain Poison and Drug Center in 2006.

However, in this same year (2014), heroin overdose deaths had tripled to 10,574 and there were 12,159 deaths due to prescription opioids, 1,216 more than 2010. Alpert et al. found that up to 80% of the increase in heroin deaths could be attributed to the reformulation of OxyContin. They concluded that OxyContin, not the nonmedical use of pain killers, was predictive of growth in heroin mortality. At the same time, deaths attributed to prescription opioids did not decrease. The reformulation has also been blamed for increases in the number of Hepatitis A, B, and C as well as HIV cases.

OxyContin misuse decreased more in states that had higher initial misuse; however, a 1% decrease in OxyContin misuse due to reformulation led to 3.1 heroin deaths/100,000 in 2013. The increase in deaths was greatest for working-age white males, the demographic most affected by the opioid crisis in general. Consumers turning to heroin or synthetic opioids negated any reduction in OxyContin misuse.

In theory, a reduced supply of a drug should lead to increased cost, thus lowering demand. Factors that undermine supply-reduction efforts include new suppliers attracted by the increase in price and substitution with an alternative product. In the case of OxyAR, many users transitioned to other prescription opioids. In 2015, there were more than 90 deaths per day from opioid overdose. From 2010 to 2017, annual prescription opioid deaths increased by 3,552 a year.

In 2011, at the peak of opioid prescriptions, President Barack Obama declared that prescription drug abuse was America’s fastest-growing problem. The number of prescriptions and the prescriptions per 100 people for the US is shown in Figure 3. Opioid prescriptions continued to increase through 2012 before finally beginning to decline from 255 million in 2012, decreasing to 192 million in 2017. This was still more than three times higher than the 62.5 million prescribed in 1996 and nearly four times higher than Europe in 2015. Relating the number of prescriptions to the number of users, there were 11.4 million Americans, 12 years or older, who misused opioids in 2017. Over 11 million used prescription opioids, 886,000 used heroin, and 562,000 used both. Over 79% of opioid abusers had an opioid prescription prior to being diagnosed with opioid use disorder (OUD). Half of the remaining diagnosed abusers had a relative or friend with a prescription. Adults under 50 misusing prescription opioids bought them or obtained them for free from friends or relatives. Those over 50 obtained them through prescriptions from one or more doctors. Nearly 62 million Americans were prescribed opioids in 2016. In 2017, prescription opioids were still a primary driver of overdose deaths. By 2019, there was a 40% decrease in the number of opioid prescriptions. The average opioid dose was also decreasing from 58 to 48 MME per day from 2006 to 2015, but that was still three times higher than in 1999.

In 2016, between 9 and 11 million Americans were using prescription opioids for long-term treatment of CNCP. Studies reported that 10%-40% of CNCP patients would develop OUD. Twenty-one million people were diagnosed with substance abuse disorder, similar to the number of people with diabetes and 150% higher than all cancers. Opioid overdose accounted for 20% of all deaths for adults aged 24-35. From 2016 to 2017, overdoses treated in emergency departments in the Midwest and large cities increased by 70% and 54%, respectively. Efforts to curtail opioid abuse included Prescription Drug Monitoring Programs (PDMPs), Medicaid Lock-In Programs, pain clinic laws, diversion control, black box warnings, and abuse-deterrent drug formulations.

Questions as to the efficacy of opioids for CNCP and whether other treatments would be more effective were being raised before the introduction of OxyER and continued as the opioid crisis progressed. Sites et al. found despite a 6% increase in opioid treatment for pain, there was no improvement in health or disability. In 2015, Chou et al. did a thorough review of the literature and found no evidence for the effectiveness of longterm opioid therapy for improving either pain or function; rather, there was evidence of a dose-dependent potential for harm. Finally, in 2019 the CDC reported there was no benefit in pain relief or function when an opioid dose was increased versus a maintenance dose and that doses above 20 MME increase the potential for overdose and death.

Market

1) Promotion Strategy

At the peak of the prescription opioid crisis, the depressed economy and persistent poverty in the Ohio Valley, Appalachia, Maine, and Alabama proved fertile ground for prescription opioid abuse. With addiction rates 6-7 times the national average, addiction decimated communities.

This would not be the first time the Sackler family made a fortune through the promotion of an addictive prescription drug. In the 1960s, Arthur Sackler’s advertising agency, William Douglas McAdams Inc. was hired by Roche to promote the tranquillizer Valium. The promotion included advertising campaigns aimed at physicians, recruiting physicians to endorse Valium, and promoting scientific studies funded by pharmaceutical companies. Advertisements promoted the drug for a wide variety of conditions, even for people with no psychiatric symptoms at all. Valium became the first $100 million drug, and then the first $1 billion drug. Then it became the most prescribed drug in the country.

Promoting Opioids Formulation for Pain Treatment. Arthur Sackler died in 1987, well before OxyContin was patented, but Purdue Pharma used many of the same marketing strategies Sackler developed for promoting Valium. A national speaker’s bureau was established to provide a pool of speakers who promoted OxyContin at all-expense-paid educational conferences for physicians, pharmacists, and nurses. The Purdue Pharma sales force made sales visits to primary care physicians every 3-4 weeks and promoted more liberal use of time-release opioids. They designed a “Partners against Pain” website where consumers could search for a local physician who treated pain. By 2003, nearly 50% of opioid prescriptions were written by primary care physicians, and in 2009 they were writing 42% of the prescriptions for immediate-release opioids and 44% for the extended-release formulations. Pain management physicians, including anesthesiology and physical medication and rehabilitation, wrote less than 24%.

Purdue Pharma also provided financial support to researchers, universities, the American Pain Society, the Joint Commission, the American Pain Foundations, the Federation of State Medical Boards, and the American Academy of Pain Medicine. All of these became advocates for the use of opioids, creating a climate that encouraged the liberal use of drugs with a high abuse potential. Many of them have been listed in court cases involving Purdue Pharma.

Pain as the fifth vital sign was introduced at the annual meeting of the American Pain Society in 1995. In 1999, it was adopted by the Department of Veterans Affairs and incorporated into a VHA National Pain Management Strategy and published as the “Pain as the 5th Vital Sign Toolkit” in 2000. In the same year, the Joint Commission on Accreditation of Healthcare Organizations (JCAHO), now The Joint Commission (TJC), designated pain as the fifth vital sign, stressing patient’s right to pain management and incorporating pain management into the evaluation of medical organizations. This led to the evaluation of pain management being linked to hospital funding with the unintended consequence of increasing opioid prescriptions as institutions attempted to attain high evaluations for pain management. Concerns that establishing pain treatment as a patient’s right could lead to the overprescription of opioids were criticized as opioiphobia.

The mission of the American Pain Foundation was to eliminate the undertreatment of pain. As late as 2007, their guide for the treatment of pain promoted opioids over NSAIDs and acetaminophen due to their ceiling dose, while claiming there was no maximum dose for opioids recommended for treating pain.

Limiting Physician Liability for Prescribing Opioids for Chronic Pain. By 2004, 13 states had enacted intractable pain acts or other acts limiting physician liability for prescribing opioids for chronic pain. Many experts in pain treatment did not believe the acts had gone far enough. Despite the acknowledged surge in opioid overdose deaths and publishing a new model policy for prescribing opioids intended to reduce the number of opioid prescriptions, the Federation of State Medical Boards of the United States, Inc. (FSMB) was concerned that pain was still being undertreated and recommended physicians should not be held liable for prescribing opioids, fear disciplinary action, nor fear investigation from federal, state, and local regulatory agencies. The Federation requested and received $100,000 from Purdue Pharma for printing and distribution of the model. The policy was incorporated by many state boards. Application of the model resulted in increasing the number of opioid prescriptions and in practice gave physicians free rein in the context of prescribing opioids.

Between 2002 and 2004 there were 41 lawsuits filed against doctors who negligently prescribed OxyContin, with 29 of them against one doctor. Most of the lawsuits took place in Louisiana, Ohio, and Pennsylvania. Some of the cases against the doctors were dismissed because they were improperly joined with Purdue Pharma, while other defendants were granted remand (Seeber v. Cleggett-Lucas

United States District Court for the Eastern District of Louisiana August 16, 2002, Decided; August 19, 2002, Filed, Entered; August 20, 2002, Entered CIVIL ACTION NO. 02-1666 SECTION “F”; Anderson v. Cleggett-Lucas United States District Court for the Eastern District of Louisiana March 11, 2003, Decided; March 12, 2003, Filed, Entered CIVIL ACTION NO. 02-2194 SECTION: I/2). The lawsuits against doctors abruptly ended in 2004, coinciding with the changes in state medical board policies.

The policy supported by the FSMB that limited the liability of physicians who prescribed opioids also led to the establishment of “pill mills”, a name given to pain clinics that prescribed opioids inappropriately and in large volumes. The pill mills proliferated in Ohio, Florida, Texas, and the Rust Belt (c); the highest concentration was believed to be in Texas and Florida. In 2009, 90 of 100 top oxycodone-dispensing doctors were in Florida. Some characteristics of a pill mill included allowing patients to choose specific drugs, drugs dispensed on site, transactions in cash only, no physical exam is required, there are large crowds in and around the clinic, and there are guards in place.

Pain clinic laws and PDMPs were put in place to control the pill mills. While some states had established PDMPs prior to the opioid epidemic, in 2020 all states except Missouri had PDMPs in place. The most effective require physicians to participate. Where participation was mandatory, doctor shopping decreased by 8-16%, filling of one prescription multiple times decreased by 5-6% in Medicare part D recipients, and there was a 5% reduction in crime. Together, the pain clinic laws and the PDMPs decreased prescription opioid overdose deaths by 12% and did not cause an increase in heroin abuse.

Encouraging Physician Prescription of Opioids for Pain Treatment. In addition to the physician spokespersons, Purdue Pharma provided grants to universities and funded researchers to promote opioids. Joranson reported that while medical use of fentanyl, hydromor-phone, morphine, and oxycodone increased, abuse actually decreased, supporting the theory that patients taking opioids for pain did not become addicted. However, the data was from 1990-1996, when the primary use of opioids was for postoperative pain and terminal cancer patients. By the time of publication in 2000, four years of promotion of OxyContin had resulted in increases in medical use of oxycodone from 2,000 kg to 15,304 kg and hydromorphone from 141 kg in 1996 and to 14,116 kg in 2000. Opioid prescriptions had increased by 45.4 million. In a report examining OxyER abuse, the authors acknowledged OxyER was the most highly abused prescription opioid. However, the abuse was credited to street and recreational users; it was critical that the treatment of pain be maintained. This study used data from a RADAR survey; the research was supported by grants from Purdue Pharma to the home universities of the three authors, who were also paid consultants for Purdue Pharma. Another study led to recommendations to rely on long-acting opioids for chronic pain and restricting short-acting opioids for acute pain.

The 2010 Patient Protection and Affordable Care Act also served to minimize the effect of OxyAR. The act tied the Hospital Consumer of Healthcare Providers and Systems Survey results to hospital reimbursements under the Inpatient Prospective Payment System. Previously, funding had only been tied to submitting the surveys. Thirty percent of the total performance score was based on the patient experience, even though multiple studies concluded that patient experience does not relate to quality of care. Three of the 25 questions addressed pain:

• Did the patient need medication for pain;
• Was the patient’s pain well controlled; and
• How often did the staff do everything they could to help with the patient’s pain.

Denials of requests, including laboratory tests, referrals, pain medication, new medications, etc., were associated with worse satisfactions ratings. In some cases, physicians felt pressure to prescribe opioids for pain to improve patient satisfaction. The result was an increase in prescribing opioids for acute pain from minor procedures as well chronic pain. In 2018, the three questions on pain were changed to pain management and in 2019, any mention of pain was removed from the questionnaire.

The World Health Organization (WHO) introduced the “analgesic ladder” in 1986. While the focus was on the lack of pain relief for terminal cancer patients in underdeveloped countries, WHO determined that even in developed countries, pain was undertreated due to scarcity, fear of addiction, or incorrect administering of drugs. The WHO guidelines stated pain treatment should be given “by the clock, by the mouth, and by the ladder. The ladder outlined an effective inexpensive palliative therapy for end-of-life pain that is still in use. The first step is non-opioid analgesics such as aspirin and paracetamol. The second step added mild opioids in addition to the non-opioid. The final step was strong opioids. At each step, adjuvant drugs could be added to treat non-pain-related symptoms. In 1986, the focus was on the treatment of cancer and later on AIDS patients.

Purdue Pharma’s reach extended to the WHO. In 2011, WHO released a new set of guidelines for the treatment of pain in adults, followed in 2012 with guidelines for the treatment of pain in children. The guidelines repeated the trademark Purdue Pharma claims that opioids were known to be safe, less than 1% of patients became addicted to opioids, and there was no danger of addiction or accidental death when properly prescribed. The guide for children stated that there was no upper limit to opioid dosage. A year later, an application was successfully submitted, adding oxycodone to the list of essential medications for children. Any reluctance to prescribe opioids was opioiphobia on the part of poorly educated physicians. The primary change in the guidelines for treatment of pain in children was the elimination of the second step in the ladder of pain. Instead of transitioning to mild opioids with a nonopioid pain reliever, the new guidelines recommended going from treatment with a nonopioid straight to strong opioids. After WHO Director Margaret Chan did not respond to a letter sent by 12 members of the US House of Representatives, Reps. Katherine Clark and Hal Rogers sent a 43-page report outlining how Purdue Pharma had influenced these policy changes. The letter warned that the opioid crisis in the US could be spreading around the globe. WHO reinstated the three-step ladder of pain in 2018 and the guidelines for children were undergoing review.

In May 2012, Purdue Pharma, Endo Pharmaceuticals, Johnson & Johnson, the American Pain Foundation, the American Academy of Pain Medicine, the American Pain Society, Wisconsin Pain & Policy Studies Group, and the Center for Practical Bioethics, The Federation of State Medical Boards, and The Joint Commission were all part of US Senate Finance Committee investigation into drug companies and the opioid crisis. The American Pain Foundation’s board has since voted to dissolve the organization.

2) Legal Action Against Purdue Pharma and the Sacklers

Beginning in 2004 and continuing through 2020, states, counties, cities, Native American Nations, and other jurisdictions began filing civil cases against Purdue Pharma. These jurisdictions were suing based on deceptive marketing practices and the deception about the potency of the 12-h time-release OxyContin, along with defrauding state governments. Numerous states, including New Hampshire, Rhode Island, Vermont, California, New York, Montana, and Ohio have brought civil lawsuits against Purdue Pharma. Cities that have brought civil suits against Purdue Pharma include Boston, Chicago, Alexandria, Jacksonville, Portland, Las Vegas, Reno, and Santa Fe. Numerous civil lawsuits have also been filed against the company from many counties across the country. Purdue Pharma was also a defendant in cases in which Native American tribes were the plaintiffs (e.g., the Blackfeet Tribe of Ohio and the Riverband Tribe of Wisconsin). In all, over 60% (n = 36) of all the states had some jurisdiction filing to sue Purdue Pharma in civil court, as no part of the country was untouched by the opioid epidemic. There were also several cases filed by states, cities, counties, hospitals, Native American tribes, and other municipalities that were never even brought to court. In two of the previously mentioned cases, Purdue Pharma settled out of court for millions of dollars ($10 million in West Virginia and $24 million on Kentucky). The city of Everett, WA, filed a civil suit against Purdue Pharma in January 2017. Part of the suit claims that Purdue Pharma did not follow the order to track black-market use or suspicious excessive ordering of OxyContin, which was part of the settlement of the case filed in Kentucky in 2007. The city claimed that fake patients were purchasing the opioid and selling it on the street to the citizens of Everett. This case was then transferred to the national Multidistrict Litigation.

Due to the increase in lawsuits brought against Purdue Pharma, the Judicial Panel on Multidistrict Litigation transferred all of the opioid-related litigations that were pending to federal court. Litigation brought by municipalities, individuals, hospitals, and other third parties were transferred to the national court. By 2019, there were more than 2,400 cases filed by local governments pertaining to the opioid crisis. Most of the cases were seeking reimbursement from the company for all of the money the jurisdictions have spent and continue to spend on addressing the opioid addiction crisis.

By 2019, Purdue Pharma had reached several settlements with states including a $270 million settlement with the state of Oklahoma. Purdue Pharma and the Sackler family eventually settled over 2,000 suits for a payment as much as $12 billion with the Sackler Family paying an additional $3 billion. The settlement included the filing of Chapter 11 bankruptcy by the company as well as the family relinquishing ownership of the company. All of the new profits for the company would be used for the public to treat addiction and the family would not be charged criminally. It was not until 2020 that the company would be held criminally liable. Although Purdue Pharma had settled many of the civil cases for billions of dollars in 2019, there was another large civil settlement in 2020 that included another $2.8 billion. In January 2021, a new civil lawsuit was filed by the County and City of San Francisco. This case sought a jury trial against the defendant Purdue Pharma L.P. for setting up illegal opioid marketing and creating an illegal supply chain.

Ironically, with all the lawsuits filed against Purdue Pharma for its role in the opioid addiction crisis, in May 2020, a lawsuit was filed against the United States by an individual because this individual could not obtain the needed OxyContin for their medical issue.

While most of the focus has been on Purdue Pharma and OxyContin, other pharmaceutical companies have been implicated in the overpromotion of opioids. Criminal cases at the federal level have been brought against Endo International (settled, $8.75 million),AmerisourceBergen Corporation (ongoing), McKinsey & Co. (settled, $600 million), Cardinal Health (settled, $44 million), McKesson (settled, $150 million), Costco (settled, $17.5 million), Mallinckrodt (settled, $35 million), Indivior Inc. (guilty plea, $600 million), Luken (ongoing).

By March 21, 2021, every state except Nebraska had a civil case against an opioid pharmaceutical company, distributor, or pharmacy. On July 22, 2021, a $26 billion global settlement was proposed to resolve opioid lawsuits against the four companies: Amerisource Bergen ($6.4 billion), Cardinal Health ($6.4 billion), McKesson ($7.9 billion), and Johnson & Johnson ($5 billion). In total, this was the second largest cash settlement, after the tobacco settlement in 1998. Additionally, a settlement with the state of New York and Johnson and Johnson was released on June 26, 2021. The $230 million settlement also included a commitment from Johnson & Johnson to stop the manufacture and sale ofall opioids and opioid products in the US. This was in addition to a $572 million settlement with the state of Oklahoma related to the overpromotion of their Duragesic fentanyl patch.

Global Perspective

In 2015, 28 million years of healthy life were lost to drug use. Seventy percent of years lost were due to opioids. High-income countries are home to 12% of the global population and account for 90% of prescription opioid consumption. Of the estimated 1.3 million opioid users in the European Union, 77% were centered in Germany, France, Spain, Italy, and the United Kingdom. About 16% of the opioid abusers in the European Union, Croatia, and Turkey (EU+2) used the prescription opioids: tramadol, buprenorphine, methadone, morphine, codeine, and methadone. Dihydrocodeine and oxycodone seizures were relatively low. Opioids were a factor in 82% of the 8,300 overdose deaths reported to the European Monitoring Centre for Drugs and Drug Addiction (EMCDDA).

The rate of opioid prescribing doubled in France between 2004 and 2017. Oxycodone prescriptions increased by almost 2,000%, from a very low initial rate. In 2018, the amount seized nearly doubled, due mainly to large seizures in Turkey. In 2019, etizolam was linked to an increase in opioid overdose deaths.

Canada had the second highest rate of opioid prescriptions, increasing by a factor of 3 between 2001 and 2013. The countries with the lowest number of prescription opioids were Rwanda, Nigeria, Malia, Chadb, Cameroona, Myanmar, Sudan, Comorosb, Burundia, Burkina Faso, and Afghanistan.

The prescription opioid, tramadol, was the cause of an opioid crisis in West, Central, and North Africa. The number of tramadol seizures decreased significantly in 2018, from 125 to 32 tons, which may be attributable to new laws regulating tramadol in India. It was also a drug of abuse in Egypt. Like fentanyl, tramadol is easy to synthesize, the precursors are inexpensive, and tramadol is not internationally regulated. At high doses, tramadol acts as a stimulant. Illicit tramadol was primarily synthesized in India and China.

As legal actions mounted against Purdue Pharma in the US and additional extended release opioids were approved in the US, the Sackler-owned Mundipharma Corporation began a global effort to promote OxyContin, using the same methods that were so successful in the US. In China, Mundipharma again promoted pain as the fifth vital sign and launched a Good Pain Management campaign with the Ministry of Health and the Chinese Society of Clinical Oncology. Italy and Australia were also targeted. In 2019, over 100 academics, doctors, and bureaucrats were accused of participating with Mundipharma to increase the prescribing of OxyContin, including the author of the law removing restrictions against opioid use. In Australia, Mundipharma was fined $209,000 by the Therapeutic Goods Administration for promoting misleading information about Targin, an oxycodone naloxone combination. In 2019, the sale of Mundipharma was included with the Purdue Pharma settlement.

Heroin

Prevalence (1980-2020)

The introduction of OxyAR occurred in an environment ripe for the second wave of the opioid crisis, heroin overdose. Heroin has always been a small percentage of US drug use. The number of heroin overdose deaths had been slowly rising, but was well under the number for cocaine. In 2010, the past-year drug use by 22.6 million respondents was 77% marijuana, 32% psychotherapeutics, 7% cocaine, 1.5% methamphetamine, and 0.88% heroin. However, heroin was a much more dangerous drug, accounting for 8% of all drug-overdose deaths.

In 2010, the year OxyER was discontinued, the price of a heroin balloon containing 0.1 g of black tar heroin had dropped to $15-20, one-third to one-half the cost of prescription opioids. The number of heroin users doubled from 2008 to 2014 and heroin overdoses increased by 300% from 2010 to 2015. The rise in heroin deaths was greatest among young, unmarried, white males, with lower education and living in poverty. Past users of opioids for nonmedical use were 19 times more likely to initiate heroin use. The longer the prescription opioid abuse, the greater the likelihood of transitioning to heroin. In 2015, CDC data indicated that 45% of people who used heroin were also addicted to prescription opioids and people who use prescription opioids were 40% more likely to become addicted to heroin. In 2011, heroin overdose deaths surpassed those of cocaine. Deaths due to heroin overdose overtook those of OxyContin in 2016.

Fentanyl first appeared in the Northeast as a contaminant in heroin, presumably because it was easier to mix with the white powder heroin sold by the Sinaloa Cartel than the black tar heroin in the West and Midwest. The DEA Heroin Signature Program (HSP) was established over 40 years ago to profile the chemical composition of heroin seized by law enforcement in the US. In 2014, fentanyl was only found in 0.5% of several hundred seizures analyzed by the HSP. This increased to 0.6% in 2015, 14% in 2017, and 24% in 2018.

Again, the exponential increase in fentanyl deaths did not quench heroin or prescription opioid abuse. While nearly 800,000 people used heroin in 2018, 12.5 times as many people abused prescription opioids. Heroin users often continued to misuse prescription opioids even after ceasing heroin use.

Market

Until the 1980s, close to 70% of heroin smuggled into the US came from the Golden Triangle (Southeast Asia) and the Golden Crescent (Southwest Asia). The remaining 30% came across the southwest border from Mexico. Heroin from Asia was generally a brown powder and Mexico was producing black tar heroin. In the 1990s, white powder heroin from Colombia began infiltrating the American market, pushing out the Asian competitors. By the early 2000s, Colombian heroin was mainly distributed in the Eastern US and Mexican heroin in the West. Asian heroin had decreased to only 2%. Since 2015 over 90% of the heroin samples analyzed by the DEA HSP were from Mexico or potentially from Mexico, using South American processing. Poppy production had decreased in South America and Mexican drug trafficking organizations (DTOs) were producing heroin internally.

Black tar was a relatively unprocessed heroin produced along the western coast of Mexico. It was smuggled into the US by plane or driven over the southwestern border to Los Angeles. From there, it was shipped to Denver, Honolulu, Las Vegas, Portland, Salt Lake City, San Francisco, Seattle, and St. Louis. Black tar heroin was seldom seen east of the Mississippi.

A heroin crisis had been quietly growing even as prescription opioid use was spiking. Beginning in the early 1980s, a new “customer based” Mexican drug ring infiltrated California and Midwest America, resulting in a gradual change in the distribution of black tar heroin. Starting in Reno, it spread to medium-sized cities like Boise, Indianapolis, Nashville, and Myrtle Beach, into the Midwest, across the Mississippi into Appalachia. Heroin in these states was now black tar, predominantly delivered by the Xalisco Boys—young men, mostly sugarcane and farm workers, from the small Mexican municipality of Xalisco in the Pacific Coast state of Nayarit. The syndicate targeted middle- and working-class white neighborhoods with younger populations and high levels of prescription opioids. By 2000, they had spread to at least 17 states.

The Xalisco Boys did not use violence or threats to keep their dealers and customers in line. Instead, drug trafficking became a business comparable to a pizza-delivery service. Cells were established in moderate-sized cities, with a boss and several drivers, who generally stayed in the US for six months and then went home. The drivers were set up in a rented apartment and provided with older model cars. A cell phone number was distributed to local addicts who used it to order their heroin. A driver would go to the delivery address: a corner, parking lot, and later, even private residences. The bosses would call customers to make sure they were satisfied with the product. Established customers received free product in exchange for referring new customers. The drivers carried the heroin in their mouths, in small balloons packed with 0.1 g of black tar heroin. If caught, the drivers had only a small amount of heroin and would be deported rather than charged with a crime.

Up to 10 pounds of heroin, about $600,000 on the street, could be brought into a cell every week. Black tar heroin was generally considered crude and low in purity. Now, black tar heroin was being offered at an unusually high purity and low cost. Unlike many drug epidemics, rural areas were harder hit than urban areas. Unnoticed by much of law enforcement, a pure, cheap heroin supply had infiltrated the same states hit hardest by the prescription opioid crisis.

Global Perspective

Afghanistan was responsible for 85% of global opium production. Over 96% of all opium was produced in three places: Afghanistan, Mexico, and Myanmar. Worldwide, 62 million people reported past year nonmedical use of opioids in 2019. Half of that number was past use of heroin or opium. The highest prevalence of past-year use was in North America, the Near and Middle East/Southwest Asia, and Oceania. Heroin production had been decreasing since 2017, but it was still at the highest level in recent times. While the US had the greatest percentage of opioid overdose deaths, opioid abuse was increasing in Europe as well. In the EU opioid use was rare, but was associated with the most harm and was the major contributor to overdose deaths. The Golden Triangle was the primary source of heroin in Canada and Australia. Heroin was the main opioid in Western and Central Asia.

In Ireland, the data suggest that drug use had become more common among the general adult population aged 15 to 64 years in the years up to 2019. Cannabis remained the most commonly abused drug. However, users of heroin were most likely to attempt rehabilitation programs and heroin was the main drug reported by first-time entrants.

Afghanistan was the predominant source for heroin in Europe and Ireland. Most of the drugs trafficked into the country were controlled by large criminal gangs. Heroin used in Ireland was trafficked through the Balkans. As Ireland is an island, smuggling drugs into the country is dependent on sea or air travel. The main mode of trafficking drugs was by freight through Rosslare Europort (County Wexford, Ireland) and Dublin port, or through Dublin and Shannon airport. Only a very small amount of purchases at the retail level were made on Darknet markets.

Asian heroin was primarily a brown powder in the free-base form imported from Afghanistan or Pakistan. White powder heroin in the salt form comes from Southeast Asia and was less common. While heroin was the primary cause of drug treatment admissions in the EU+2, there was only a slight upward trend in heroin abuse, as measured by the number of first-time treatment admissions from 2000-2009. There was a slight decrease in availability for 2010-11, and both price and purity have decreased. The number and amount of seizures through 2017 remained stable. Global poppy production increased in 2017 and 2018, after decreasing from the 2000 peak.

Fentanyl, Fentanyl Analogs, and Novel Opioids

Prevalence

Fentanyl was first synthesized (by Janssen in 1960) as part of an effort to develop a faster-acting, potent analgesic with a therapeutic index greater than morphine. It is up to 1,000 times more potent than morphine and is faster acting. The therapeutic index for fentanyl is 400, versus 80 for morphine. As an anesthetic, fentanyl was a significant improvement. However, the therapeutic dose for fentanyl is 50-100 [micro]g, while the fatal dose is 2 mg, so as a drug of abuse, fentanyl is far more dangerous then heroin. Janssen followed fentanyl with the analogs carfentanil, sufentanil, and alfentanil. Carfentanil is 10,000 times more powerful than morphine and is only approved for veterinary use. The toxic dose, 20 [micro]g, is barely visible to the naked eye. Jansen also synthesized [alpha]-methylacetylfentanyl, 3-methylfentanyl, [beta]-hydroxyfentanyl, but these were not adopted as pharmaceuticals due to a narrow therapeutic index. Fentanyl and related prescription synthetic opioids are all US Schedule II narcotics. Nonprescription fentanyls are Schedule I, as there is no accepted medical use.

Until the 1990s, IMF overdose deaths were rare. Between 1979 and 1991, Henderson analyzed samples from over 3,000 suspected fatal fentanyl overdoses, of which 112 deaths were confirmed to be fentanyl or a fentanyl analog. The 2010 spike in demand for heroin caused dealers to look for ways to maintain supply and potency. Fentanyl, rapidly followed by fentanyl analogs, filled the need and then some.

1) 1990-2013

Just as the changes in heroin trafficking introduced by the Xalisco Boys laid the foundation for the second wave of the opioid crisis, the proliferation of novel psychoactive substances (NPS) provided the infrastructure for IMFs, the third wave of the opioid crisis.

Spice and Bath Salts were the new drugs of concern at the turn of the century. Clandestine chemists had discovered the literature on cannabinoid agonists developed in research labs. The synthesis was easy and the agonists produced a much more profound high than marijuana. The psychoactive substances in Spice escaped detection for several years as the agonists were unknown to law enforcement and the forensic crime laboratories. Bath Salts were cathinone analogs developed to replace cathinone after it was controlled in Israel. Both Spice and Bath Salts were being synthesized by Chinese chemical companies, sold online and shipped to customers in the US through standard mail services. As the individual Spice and Bath Salts were controlled, the manufacturers quickly transitioned to new analogs. In 2017, the US Justice Department brought the first charges of manufacturing fentanyl and fentanyl analogs against the Chinese nationals, Xiaobing Yan and Jian Zhang. The Yan indictment listed the fentanyl analogs, acetyl fentanyl, valeryl fentanyl, furanyl fentanyl, fluoroisobutyrylfentanyl as well as the Bath Salts, methylone, [alpha]-PVP, [alpha]-PBP, TH-PVP, 4-MEC, pentedrone, 2C-I, UR144, and XLR-11. The NPS manufacturers had quickly adapted to take advantage of the fentanyl market.

Fentanyl overdose deaths had been steadily increasing since the turn of the century. The rate of increase was steeper than that of heroin during the same time period. By 2010, the number of heroin and fentanyl overdose deaths had nearly merged. Heroin overdose deaths only exceeded fentanyl deaths by 29. The groundwork had been laid. The same techniques used to stay ahead of scheduling laws for NPS would make the third wave of the opioid crisis the most deadly yet.

2) 2013-2020

Fentanyls are the drugs associated with the most overdose deaths. Fentanyl’s potency is 50 times greater than heroin and the analogs can be hundreds times more potent. Contamination of heroin, other drugs of abuse, and counterfeit prescription drugs with IMFs eclipsed both prescription opioids and heroin. Not being aware of the fentanyl contamination, both naive users and experienced users were at risk for overdose and death. Appalachia, New England, and the Midwest were hardest hit. Through 2015, fentanyl overdose deaths were higher east of the Mississippi, possibly because it was easier to mix into the Colombian white powder. In 2016, the increase in IMF deaths accounted for almost all of increases in drug overdose deaths for that year and exceeded those of prescription opioids in the US.

The fentanyls were even more deadly than heroin. The correlation between emergency room visits and overdose deaths was 1:1 for fentanyl deaths, while heroin was 10:1, although the fentanyl emergency room visits may have been underreported. New fentanyl analogs were being created at a faster rate than controls could be put in place or forensic or clinical laboratories could develop validated testing methods.

Between 2010 and 2013, only the prescription fentanyls, sufentanil, remifentanil, and alfentanil were submitted to the National Forensic Laboratory Information System (NFLIS). The only IMF submitted at that time was [alpha]-methylfentanyl. From 2013 to 2019, 73 different IMFs had been seized by US law enforcement. The International Narcotics Control Board (INCB) had identified 129 fentanyl analogs and 15 potential precursor chemicals.

The market created by the large number of prescription opioid users affected by the introduction of OxyAR was easily filled by fentanyl. One kilogram of fentanyl, purchased for around $3,800, could be shipped into the US in a standard shipping envelope and divided into over 1,000,000 doses or pressed into pills. One kilogram could bring in $10-30 million, retail, at a time when a kilo of heroin generated about $200,000.

Fentanyls are sold on the street as a powder, on blotter paper, mixed with or substituted for other street drugs, or as counterfeit prescription drugs. They can be smoked, insufflated, or injected. Several IMFs have been found in cocaine, vape liquids, and methamphetamine.

Users report that fentanyl produces different effects than heroin. The hit is much faster and produces tingling in the extremities. Some report that fentanyl has a different vinegary smell, a different color, or has a different look when prepared for injection, but that it is impossible to be sure. Tactics employed by users to avoid fentanyl-contaminated heroin included: only buying from a trusted dealer; learning the physical characteristics of fentanyl; taking small test hits; having another user observe; reverting to prescription opioid abuse; snorting rather than injecting; and seeking medical assisted treatment (MAT).

Market

The IMFs and fentanyl precursors were synthesized in China and shipped to the US, either directly or through Canada and Mexico. About 97% of Fentanyl seized from international mail in 2016 and 2017 originated in China. In Mexico, precursors from China were synthesized into fentanyl through crude methods by cartels and brought into the US already mixed with heroin or other drugs.

Illicitly manufactured fentanyl is easily synthesized from inexpensive precursor chemicals without sophisticated laboratory techniques. The clandestine laboratories are mobile and are not dependent on agricultural products for raw materials. Some are up to US pharmacy standards, but others have low standards for quality control. Initially, fentanyl was being synthesized by the “Siegfried” method using the precursor chemicals, 4-anilino-N-phenethylpiperidine

(ANPP) and N-phenethyl-4-piperidone (NPP). Both precursors were inexpensive and not controlled or tracked. In 2017, the United Nations’ Commission on Narcotic Drugs (CND) 1988 UN Convention placed both precursors under international control. The control seems to have limited the availability of these chemicals through illicit channels. Forensic profiling of fentanyl seized in the US since 2018 indicates the Janssen method, that does not require NPP or ANPP, was the synthetic route.

The majority of NPS, including fentanyls, produced in China, were for export. Opioid abuse was not prevalent and the laws relating to drug abuse were very stringent. Between 2005 and 2009, there were only 14 cases of fentanyl abuse reported in Beijing. Still, according to the United Nations Office on Drugs and Crime, China had become the source of new psychoactive substances sold to the United States, Russia, the United Kingdom, Australia, New Zealand, and other countries. Acknowledging that the increasing abuse of new psychoactive substances was causing serious public health and public safety problems worldwide, China began initiating controls on the manufacture and distribution of fentanyls in 2013. In 2015, China enacted the Measures for the Listing of Non-pharmaceutical Narcotic Drugs and Psychotropic Substances that included a control mechanism for new NPS, listing 116 new psychoactive substances. Additional fentanyls were added in 2017, making a total of 23. Regulations regarding drugs are taken very seriously in China. Within a few months of being controlled, an IMF would be taken off the market. However, it was quickly replaced with new “legal” synthetic opioids.

From 2016 through 2017, China assisted other countries investigating NPS mailed and smuggled abroad, resulting in the arrest of dozens of suspects, the investigation and destruction of eight illegal manufacturing sites, and the seizure of thousands of kilograms of new psychoactive substances. The Chinese government provided information to 58 countries and regions related to IMFs being produced in China.

In an effort to better deal with the proliferation of NPS being developed by clandestine labs, China continued to add fentanyl analogs to the lists of controlled substances, adding 32 in 2018. Finally, in 2019, the government made major changes to Article 7, paragraph 2, of the “Listing Measures” with recommendations for determining whether nonpharmaceutical narcotic drugs or psychotropic substances should be listed:

• Addictiveness or addictive potential;
• The health hazards to the human heart;
• Illegal manufacturing, trafficking or smuggling activities;
• Abuse or proliferation; and
• Causing domestic, international, or other social harm.

Specific measures were added to control fentanyl analogs without requiring them to be individually controlled, including fentanyl analogs with one or more of the substitutions:

• Substitution of the N-propionyl group by another acyl group;
• Substitution of the N-phenyl group with any aromatic monocycle whether or not the aromatic monocycle was further substituted;
• Substitution on the piperidine ring with alkyl, alkenyl, alkoxyl, ester, ether, hydroxyl, halo, haloalkyl, amino, or nitro groups; and/or
• Replacement of the phenethyl group with another group, except with H.

A total of 431 NPS and the entire class of fentanyl analogs were also added to the Supplementary List of Controlled Species of Non-Pharmaceutical Narcotic Drugs and Psychotropic Substances with Non-medical Use.

In the latter half of 2019, The Chinese government began pushing back against US pressure. In August 2019, the US Treasury imposed sanctions on three Chinese businessmen. Fujing Zheng, his father Guanghua Zheng, and Xiaobing Yan were indicted for trafficking fentanyl in the US. The sanctions froze any property owned by the men and bans US citizens from doing business with them. The Chinese reaction was blunt. China had permanently scheduled all fentanyl analogs; the DEA had only temporarily scheduled a limited number of fentanyls for a time period of two years. In the quarter after control measures were implemented in China, only four cases of fentanyl analogs smuggled from China had been detected by the Customs and Border Patrol (CBP), while the US government’s ineffective crackdown on a chain of drug companies vigorously peddling and physicians indiscriminately prescribing opioids combined with the negative effect of marijuana legalization was the root of the fentanyl crises. This was repeated by the Chinese Foreign Ministry spokesman Geng Shuang a few days later.

The statement that only four cases of fentanyl analogs had been smuggled from China was likely technically true as the trafficking routes were no longer directly into the US. Fentanyls were being shipped to intermediary countries and then to the US.

By 2020, the controls put in effect by the Chinese government reduced the amount of IMFs shipped directly into the US. China was still the main producer of IMFs, although there had been a shift in production to India and Mexico. China was also a source for precursors and production equipment. Mexican DTOs had transitioned to manufacturing analogs as well as fentanyl. The Sinaloa Cartel and Cartel de Jalisco Nueva Generation were producing low-quality and low-purity fentanyl and analogs, using precursors smuggled in from China and India. Online sales predominated on both public websites and the darknet using social media and password-protected marketplaces. As of 2021, China’s postal service, China Post, has been providing the United States Postal Service (USPS) with advanced electronic data (AED) on parcels mailed to the US.

Global Perspective

Synthetic opioids were becoming a greater percentage of the NPS identified each year. In 2014, they accounted for 2% of the new NPS and in 2018, synthetic opioids were 9% of the NPS identified for the first time. Fentanyl overdoses were increasing in Canada (327%), the UK (64%), and Australia (61%). There were over 500 fentanyl deaths in Canada in 2014. A study was conducted on drug paraphernalia collected from a needle exchange center in Tijuana, Baja California, Mexico. Fentanyl was found in 93% (n = 55) of white powders containing heroin and all 9 powders containing methamphetamine were contaminated with fentanyl. Fentanyl overdoses in Australia were due to misuse of prescription drugs, not IMFs. Australia, Canada, Italy, the UK, Northern Ireland, and Ukraine have approved the opioid overdose medication Naloxone as an over-the-counter (OTC) drug for harm reduction.

While opioids were not an issue, China was also facing the spread of new psychoactive substances. The popularity of the No. 0 capsule (dimethyltryptamine 5-MeO-Dipt), Rush (nitrite inhalants), GHB, and the demand for “smart drugs” (methylphenidate and amphetamine) by parents of students before exams all indicate that the control of new psychoactive substances in China was very serious.

The main drugs of abuse in China were methamphetamine, heroin, and ketamine. The number of drug abusers had declined over the past two years, due to the six-pronged drug governance system targeting full coverage of drug prevention education, full management of drug users, full chain of combating drug crimes, full supervision of drug products, full monitoring of any drug situation, and full implementation of anti-drug work responsibilities at all levels. Drug use was becoming increasingly covert and difficult to detect. The number of new types of drugs had increased, making it difficult to identify and investigate drug trafficking. Forty-one new psychoactive substances were detected in 2020, of which five were newly discovered. Users had also increased their awareness of counter-surveillance and were leasing short-term room rentals when using drugs and using foreign instant messengers or game platforms other than QQ and WeChat for communication.

Over half the drugs seized in China in 2019 were illegally imported from: (a) the Golden Triangle (opium), at the borders of Thailand, Laos, and Myanmar where the Ruak and Mekong rivers converge; (b) the Golden Crescent (opium), which includes eastern Turkey, Iran, Afghanistan and Pakistan; and (c) the Silver Triangle (cocaine), includes the Latin American countries of Colombia, Peru, Bolivia, and Brazil. A smaller problem was marijuana smuggled in by Americans, Europeans, and through online purchases. Online drug trafficking activities increased due to the convenience, security of the network connection, and the simplicity and speed of online payment. Network drug trafficking using virtual identity to connect and trade drugs online, mobile banking, WeChat, Alipay transfer, and other network payment methods to pay; also, delivering drugs through delivery channels had become the norm. Domestic drug production was characterized by small scale, scattered distribution, simplicity of process, family owned, small trucks, mobile drug production. However, the trend was to move production abroad.

The production of nonlisted precursor chemicals increased, influenced by the demand for raw materials for drug manufacturing inside and outside China, illegal drug manufacturing and smuggling activities, and order-based R&D. Some unscrupulous elements use fraudulent business qualifications and license filing certificates to register as “shell corporation” in order to illegally trade, transport, store, import and export chemicals through illegal channels.

Manufacturing and smuggling of NPS were gradually spreading from the “Yangtze River Delta” region to other regions. The NPS manufacturers and sellers have changed methods for drug transactions, production, transportation, and money laundering. Some organizations were using overseas servers as a springboard to take advantage of the blind zone for domestic and foreign monitoring. Establishing a case involved the collaboration of many parties with different interests and protocols; there was a lag before NPS were listed, or a lack of basis for criminal charges, making it difficult to obtain a conviction. Finally, the suspects themselves often did not know the production volume, the use of new psychoactive substances, and the shipping destination.

COVID-19

In 2018, there was some indication that the US opioid crisis was declining. Drug overdose deaths decreased in 2018 by 4.1%, and there was a 2% decrease in opioid deaths. This was mainly due to the decrease in prescription opioid (13.5%) and heroin deaths (4.1%), as deaths due to synthetic opioids increased by 10%. In late 2019, fentanyl production around Wuhan was disrupted by the COVID-19 virus. An increase in price and decrease in availability led people to enter treatment. Social distancing requirements brought on by the COVID-19 pandemic resulted in narcotic addicts dying alone at home.

The UNODC recounted interference with the cross-border trafficking of heroin from Mexico to the US due to the increased border controls. While Mexican production of black tar heroin was not affected by the restriction partly due to acetic anhydride manufacture in the country, border closures reduced trafficking operations to suppliers in the US. However, preliminary 2020 data showed an increase in fentanyl-related deaths. According to the Toxicology Investigators Consortium (ToxIC) Fentalog Study Group report, 64% of suspected opioid overdoses were positive for fentanyl in New York City, 86% in Bethlehem (PA), 100% in St. Louis (MO), and 25% in Portland (OR). Opioids combined with stimulants ranged from 50% (PA) to 81% (OR). Indications were that the Chinese distribution chain was quickly restored although there were some reports that the shipment of fentanyl precursors to Mexico had been disrupted. Increased controls at the border resulted in a decrease in shipments of heroin into the US. Recently, white powder heroin, made in Mexico using South American methods, started appearing in the east and Midwest.

Looking at Ireland as representative of Europe, the way people bought and used drugs changed significantly throughout the pandemic as a result of changes in supply, procurement, and personal usage patterns changing. People reported buying in larger quantities and less often, using home delivery and postal services to avoid excessive face-to—face interactions. Drug sales moved online. Other techniques were also employed to avoid face-to-face contact, such as dead drops. In this method, the buyer sends money to the seller via an online banking app or crypto currency, and the seller leaves the drugs hidden in a secret location for the buyer to retrieve. “Boredom” was the most usual answer given for increased drug use during COVID-19, along with “anxiety/to cope with the pandemic”.

Irish drug service providers were surveyed by the IGEES/Research Services and Policy Unit of the Department of Health and 56% of participants stated that they were aware of increases in the price of drugs. This trend generally continued throughout the EU, at both wholesale and consumer levels.

Drug usage habits have changed significantly due to the COVID-19 pandemic. The EMCDDA survey aimed at recreational drug users received 696 responses from Irish citizens. A shortage in heroin supply led to switching to synthetic opioids such as fentanyl, oxycodone, or other classes of illicit drugs such as crack cocaine. Overall, 24% of those surveyed reported not using illicit drugs since the beginning of the pandemic, with another 36% reporting a decrease in illicit drug use. The remaining 23% reported using more drugs since the pandemic started. Overall, 77% reported experiencing at least some difficulty in accessing drugs during the pandemic, some of whom purchased in larger quantities or from different dealers as a result.

During the COVID-19 pandemic there is a new potential overdose risk for those with opioid use disorders (OUDs) who were self-isolating, as typically there would be no one to monitor them and inject them with naloxone in emergencies.

Recreational and occasional users may not have other ways of finding new suppliers but in the case of people with substance use disorders and especially OUDs, users may resort to drug substitution. The risks introduced by supply disruption lie in the effect on drug purity or users substituting with synthetic opioids such as fentanyl. Sometimes users may not know that their drug contains fentanyl, believing that it is pure heroin and overdose at lower doses.

The pandemic may have had several effects on opium trafficking such as interruption to manufacturing by reduced manual workforce, shortages of imported chemical precursors, and difficulties by new users in accessing opiate vendors. There was also an increase in the price of acetic anhydride, a significant precursor of heroin. Some drug trafficking organizations transitioned to counterfeit COVID-19 medications and supplies. Some countries reported a stable supply of heroin, while others experienced local shortages.

Organized crime groups, who depend on global supply chains to produce, transport, and traffic illicit products, were obstructed by the pandemic. The worldwide restrictions enacted on air transport during the lockdown restrictions may have caused the drug supply in countries dependent on air transport to be completely disordered, although demand remained high. Interruptions to freight flows transporting commercial goods did not suffer the same restrictions; however, reductions were reported due to economic decline and supply chain disruption. Dietze and Peacock reported that 85% to 99% of Australian border seizures of heroin, cocaine, MDMA, and methamphetamine were imported by air travel, which had a significant impact on availability.

For illicit drugs trafficked by land, movement restrictions and border closures hinder access to drug distributors. Despite this, reports of illicit drug seizures from law enforcement agencies throughout Europe suggest that these restrictions did not had a significant impact on the distribution to supply markets. The National Crime Agency (NCA) confiscated 140 kg of cocaine from a UK port in April 2020 and 20 kg of heroin was confiscated from a commercial goods lorry traveling from Eastern Europe. The report further outlines how criminal organizations took a cunning approach to the restrictions implemented during the COVID-19 pandemic by concealing drugs in facemask consignments. Thus, the production and transport of certain illicit drugs remained at levels similar to prepandemic times.

The reports of increased seizures of heroin at sea suggested that organized crime groups altered their usual heroin land trafficking, possibly due to the perceived risk of detection. This was reinforced by seizures of opiates by law enforcement in the Islamic Republic of Iran attributed to land transportation as well as seizures of heroin reported from the Indian Ocean.

Drugs that have heavily relied on air travel were majorly disrupted with travel restrictions. This mainly applied to synthetic drugs in most countries and cocaine trafficking to Australia via commercial flights. Heroin is transported on both land and maritime routes co-mingled with legal cargo and so was not as drastically affected.

The pandemic caused alterations to opium poppy harvesting and heroin production. Afghanistan was the largest of the universal opium producers (84%) and is the primary supplier to Europe, South Asia, the Middle East, and Africa. The physical restrictions imposed on mobility and by the virus itself may have reduced the number of poppy lancers who harvested opium. Additionally, the effects of border closures with Iran and Pakistan reportedly reduced the workforces in nearby cultivating provinces as well as increasing the difficulty of illegal border crossings or increased prices for goods. Other heroin-producing locations appear to not have been affected by the COVID-19 pandemic. Myanmar harvested opium in early 2020 but sales of heroin to foreign consumers declined due to border closures with neighboring China. A decrease in the price of heroin in March indicated a decrease in demand contributed to the effect of counternarcotics operations.

Heroin and cannabis shortages were identified throughout the EU, leading to substitution of other drugs such as synthetic opioids. Confiscation of illicit drugs by police forces ramped up throughout the pandemic in certain locations of the world, including Ireland, though in other countries such as Italy they decreased.

Throughout the pandemic there was also been an emergence of new types of drugs. Catalani et al, identified 10 emerging NPS not previously reported by either the UNODC or EMCDDA through a web-based search. Included were opioids, cathinones, synthetic cannabinoid agonists, PCP-like molecules, and psychedelics. Nonfentanyl opioids such as isotonitazene sold online as a legal replacement to controlled opioids appeared to have been sold at the street level on the illicit opioid market.

Isotonitazene was formally identified as an NPS by the EMCDDA on behalf of Belgium on 26 August 2019. It is one of a series of benzylbenzimidazole compounds first synthesized mid-1950s, part of an attempt to develop better and safer opioid analgesics with fewer side effects. Although the 2-benzylbenzimidazole compounds have levels of analgesic potency several orders of magnitude higher than that of morphine, they are not fentanyl analogs. This group of structurally distinct opioid analgesics includes isotonitazene, etonitazene, and metonitazene. Isotonitazene has been available on the European drug market since at least April 2019. As of 28 March 2020, it had been identified in six Member States: Belgium, Estonia, Germany, Latvia, Sweden, and the UK. It was controlled in the US on June 18, 2020. As isotonitazene is an opioid analgesic, the social problems may have some similarities with those associated with controlled opioids such as heroin or fentanyl.

Conclusion

The overpromotion of prescription opioids resulted in addiction permeating every strata of American culture at a time when areas of the country were in a serious, long-term economic depression. At the height of the opioid crisis, drug dealers were no longer the source of illicit drugs. The US prescription manufacturing and supply system was far more effective than any drug trafficking route through Mexico or China. The world watched while a pharmaceutical company invested millions in promoting a drug and reaped billions. The fines paid by pharmaceutical companies were simply rolled in to the cost of doing business, as evidenced by their plans to claim them for federal tax purposes.

The second wave, heroin, was catalyzed by replacing an easily abused prescription opioid with an abuse-resistant formulation. The same areas hardest hit by the prescription opioid crisis had previously been infiltrated by a different form of Mexican DTO that used service-oriented heroin trafficking focused on small cities and rural areas with predominantly white populations. Would the heroin crisis have occurred in the absence of OxyContin or was it simply pushed forward a few years?

Within three years, the heroin crisis was overshadowed by the appearance of IMFs in heroin, counterfeit pills, and as pure powders. Fentanyl deaths had been rising steadily since 1999, but went unnoticed due to the scale of the previous two waves. As with many synthetic NPS, IMFs are easy to synthesize and can be far more potent than the plant-based alkaloids they are replacing.

The opioid crisis is not over. Prescription opioids and heroin overdose deaths are four and seven times higher than in 1999, respectively. While prescription opioid, heroin, and fentanyl overdose deaths did start to decline in 2017 and 2018, the COVID-19 pandemic has caused them to rise again. But however long the COVID-19 effect lasts, opioid abuse is not under control.

Can the opioid crisis be attributed to the unfortunate confluence of unrelated events or does it set a pattern for drug abuse crises in the future? Has the foundation already been laid for the next crisis? Fentanyls are currently the greatest cause of death by overdose, but deaths from stimulants and cocaine have been steadily rising. In 12 months prior to April 2021, cocaine and psychostimulants overdose deaths exceeded those of heroin. Cocaine overdose deaths are four times higher than in 1999. In the absence of the opioid crisis, would this increase be considered a crisis in its own right? Synthetic drugs are a continual threat. Novel opioids that are not analogs of fentanyl are appearing in online markets. Benzodiazepine prescriptions have been increasing in recent years and designer benzodiazepines have been appearing on Internet drug sites.