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Waves of the Opioid Epidemic
The Centers for Disease Control and Prevention describe the U.S. opioid epidemic as having arrived in three waves. \\\ Although research more recently states that since 2016, the United States has been experiencing the fourth wave of the opioid epidemic. The epidemic began with the over prescription and abuse of prescription drugs. However, as prescription drugs began to become less accessible in 2016 in response to CDC opioid prescribing guidelines, there was an increase in accessibility to cheaper, illicit alternatives to opioids such as heroin and fentanyl.

First Wave
The first wave, which marked the start of the epidemic, began in the 1990s due to the push towards using opioid medications for chronic pain management and the increased promotion by pharmaceutical companies for medical professionals to use their opioid medications. During this time, around 100 million people in the United States were estimated to be affected by chronic pain; however, opioids were only reserved for acute pain experienced secondary to cancer or terminal illnesses. Physicians avoided prescribing opioids for other medical conditions because of the lack of evidence supporting their use, the concern of opioids having addictive properties, and the fear of being investigated or disciplined for liberal opioid practices. However, in 1980, a letter to the editor featured in the New England Journal of Medicine (NEJM) challenged these notions. The letter advocated for more liberal use of opioids in pain management, which the World Health Organization eventually supported. In addition, medical organizations began to push for more attentive physician responses to pain, referring to pain as the "fifth vital sign." This was coupled with the promotion of opioids by pharmaceutical companies who insisted that patients could not become addicted. Opioids became an acceptable treatment for a wide variety of conditions, leading to a consistent increase in opioid prescriptions. From 1990 to 1999, the total number of opioid prescriptions grew from 76 million to approximately 116 million, which led to them becoming the most prescribed class of medications in the United States.

Mirroring the positive trend in the volume of opioid pain relievers prescribed is an increase in the admissions for substance use disorder treatments and an increase in opioid-related deaths. This illustrates how legitimate clinical prescriptions of pain relievers are being diverted through an illegitimate market, leading to misuse, addiction, and death. With the increase in volume, the potency of opioids also increased. By 2002, one in six drug users was prescribed drugs more powerful than morphine; by 2012, the ratio had doubled to one in three. The most commonly prescribed opioids have been oxycodone and hydrocodone.

Second Wave
The second wave of the opioid epidemic started around 2010 and is characterized by the rise in heroin use and overdose deaths. Between 2005 and 2012, the number of people who used heroin almost doubled from 380,000 to 670,000. In 2010, there were 2,789 fatal heroin overdoses, almost a 50% increase from the years prior. This spike reflects the increase in heroin supplies in the United States and the decrease in prices, which encouraged a large proportion of individuals with an established dependency and tolerance on opioids to transition towards a more concentrated and cheaper alternative. During this same period, there was also a reformulation of OxyContin that made it more difficult to crush and use it; however, the effect of this formulation on the rise in heroin use is still unclear.

Third Wave
According to the CDC, / /the third wave of the opioid epidemic began in 2013, and the third wave ended in 2016. (Jenkins, Ciccarone, Manchikanti)This wave coincides with the steep rise in overdose deaths that involved synthetic opioids, particularly illegally produced fentanyl. \\\ During this time, prescription opioid deaths increased marginally, while heroin deaths remained stable. The affected population was younger, less frequently male, and more likely to be white and rural compared to previous waves. However, the third wave also saw increases in opioid-related overdoses among Black and Hispanic PWUD in urban areas. The rise in fentanyl deaths is attributed to the fact that it is 50 to 100 times more potent than morphine, and fentanyl is often mixed into heroin or cocaine to increase the potency at a low cost. Considering that compared to white populations, Black Americans tend to consume cocaine more often than heroin or other prescription opioids, this increase in deaths is linked to the increased prevalence of fentanyl laced cocaine

Fourth Wave
The fourth wave, which is reported to have begun in 2016, is characterized by polysubstance use and increased use of stimulants like methamphetamines and cocaine. The availability and use of illicit fentanyl continue to be the leading cause of fatalities, but the recent rise of polysubstance use, which is the practice of using multiple drugs at once or in succession, and stimulants is linked to the increased fatality rate with the ongoing opioid epidemic. Between 2012 and 2018, there was a threefold increase in mortality related to cocaine use and a fivefold increase in mortality related to psychostimulants like methamphetamine. This increase has primarily been observed in male populations from non-Hispanic American Indian, non-Hispanic Black, and non-Hispanic White populations. Researchers attribute the increase in illicit drug use to the CDC's recommendations to reduce opioid use through measures like tapering opioid prescribing. \\\

Causes
The epidemic has been described as a "uniquely American problem." The structure of the U.S. healthcare system, in which people not qualifying for government programs are required to obtain private insurance, favors prescribing drugs over more expensive therapies. According to Professor Judith Feinberg, "Most insurance, especially for poor people, won't pay for anything but a pill." Prescription rates for opioids in the United States are 40 percent higher than the rate in other developed countries such as Germany or Canada. While the rates of opioid prescriptions increased between 2001 and 2010, the prescription of non-opioid pain relievers (aspirin, ibuprofen, etc.) decreased from 38% to 29% of ambulatory visits in the same period, and there has been no change in the amount of pain reported in the United States. This has led to differing medical opinions, with some noting that there is little evidence that opioids are effective for chronic pain not caused by cancer.

The annual opioid prescribing rates have been slowly decreasing since 2012, but the number is still high. There were about 58 opioid prescriptions per 100 Americans in 2017. Characteristics of jurisdictions with a greater number of opioid prescriptions per resident include small cities or large towns, cities with more dentists and primary care doctors per capita, cities with a higher percentage of white residents, cities with a higher uninsured/unemployment rate, and cities with more residents who have diabetes, arthritis, or a disability.[2].

Several studies have been conducted to find out how opioids were primarily acquired, with varying findings. A 2013 national survey indicated that 74% of people who recreationally use opioids acquired their opioids directly from a single doctor, friend, or relative who received their opioids from a clinician. Among pharmacies, the most prolific distributor was Walgreens, which bought 13 billion oxycodone and hydrocodone pills from 2006 through 2012 (about twenty percent of all such pills in US pharmacies). Though aggressive opioid prescription practices played the biggest role in creating the epidemic, the popularity of illegal substances such as potent heroin and illicit fentanyl has become an increasingly large factor. It has been suggested that decreased supply of prescription opioids caused by opioid prescribing reforms directed people who were already addicted to opioids to illegal substances.

In 2015, approximately 50% of drug overdoses were not the result of an opioid product from a prescription, though most recreational users' first exposure had still been by lawful prescription. By 2018, another study suggested that 75% of people who use opioids recreationally started their opioid use by taking drugs obtained in a way other than by legitimate prescription.

History
Opiates such as morphine have been used for pain relief in the United States since the 1800s, and were used during the American Civil War. Opiates soon became known as a wonder drug and were prescribed for a wide array of ailments, even for relatively minor treatments such as cough relief. Bayer began marketing heroin commercially in 1898. Beginning around 1920, however, the addictiveness was recognized, and doctors became reluctant to prescribe opiates. Heroin was made an illegal drug with the Anti-Heroin Act of 1924, in which the US Congress banned the sale, importation, or manufacture of heroin.

In the 1950s heroin addiction was still fairly uncommon among average Americans, many of whom saw it as a frightening condition. The fear extended into the 1960s and 1970s, although it became common to hear or read about drugs such as cannabis and psychedelics, which were widely used at rock concerts like Woodstock.

Heroin addiction began to make the news around 1970 when rock star Janis Joplin died from an overdose. During and after the Vietnam War, addicted soldiers returned from Vietnam, where heroin was easily bought. Heroin addiction grew within low-income housing projects during the same time period. In 1971, congressmen released an explosive report on the growing heroin epidemic among US servicemen in Vietnam, finding that ten to fifteen percent were addicted to heroin. "The Nixon White House panicked," wrote political editor Christopher Caldwell, and declared drug abuse "public enemy number one". By 1973, there were 1.5 overdose deaths per 100,000 people.

Modern prescription opiates such as Vicodin and Percocet entered the market in the 1970s, but acceptance took several years and doctors were apprehensive about prescribing them. Until the 1980s, physicians had been taught to avoid prescribing opioids because of their addictive nature. A brief letter published in the New England Journal of Medicine (NEJM) in January 1980, titled "Addiction Rare in Patients Treated with Narcotics", generated much attention and changed this thinking. A group of researchers in Canada claim that the letter may have originated and contributed to the opioid crisis. The NEJM published its rebuttal to the 1980 letter in June 2017, pointing out among other things that the conclusions were based on hospitalized patients only, and not on patients taking the drugs after they were sent home. The original author, Dr. Hershel Jick, has said that he never intended for the article to justify widespread opioid use.

In the mid-to-late 1980s, the crack epidemic followed widespread cocaine use in American cities. The death rate was worse, reaching almost 2 per 100,000. In 1982, Vice President George H. W. Bush and his aides began pushing for the involvement of the CIA and the US military in drug interdiction efforts, the so-called War on Drugs. The initial promotion and marketing of OxyContin was an organized effort throughout 1996–2001, to dismiss the risk of opioid addiction. Purdue Pharmaceuticals, which heavily promoted oxycodone, increasing their earning to US$35 billion by 2017.

8-hour 2015 deposition of Richard Sackler about his family's role in the opioid crisis in the United States.

Purdue Pharma hosted over forty promotional conferences at three select locations in the southwest and southeast of the United States. Coupling a convincing "Partners Against Pain" campaign with an incentivized bonus system, Purdue trained its salesforce to convey the message that the risk of addiction was under one percent, ultimately influencing the prescribing habits of the medical professionals that attended these conferences. Consulting firm McKinsey & Company reached a nearly $600 million settlement with 49 of 50 U.S. states in 2021 over the firm's role in driving opioid sales for Purdue Pharma and other pharmaceutical companies. In 2016, the opioid epidemic was killing on average 10.3 people per 100,000, with the highest rates including over 30 per 100,000 in New Hampshire and over 40 per 100,000 in West Virginia.

According to the Substance Abuse and Mental Health Services Administration's National Survey on Drug Use and Health, in 2016 more than 11 million Americans misused prescription opioids, nearly 1 million used heroin, and 2.1 million had an addiction to prescription opioids or heroin.

While rates of overdose of legal prescription opiates have leveled off in the past decade, overdoses of illicit opiates have surged since 2010, nearly tripling.

In a 2015 report, the US Drug Enforcement Administration stated that "overdose deaths, particularly from prescription drugs and heroin, have reached epidemic levels." Nearly half of all opioid overdose deaths in 2016 involved prescription opioids. From 1999 to 2008, overdose death rates, sales, and substance use disorder treatment admissions related to opioid pain relievers all increased substantially. By 2015, there were more than 50,000 annual deaths from drug overdose, causing more deaths than either car accidents or guns.

In 2016, around 64,000 Americans died from overdoses, 21 percent more than the approximately 53,000 in 2015. By comparison, the figure was 16,000 in 2010, and 4,000 in 1999. While death rates varied by state, in 2017 public health experts estimated that nationwide over 500,000 people could die from the epidemic over the next 10 years. In Canada, half of the overdoses were accidental, while a third were intentional. The remainder were unknown. Many of the deaths are from an extremely potent opioid, fentanyl, which is trafficked from Mexico. The epidemic cost the United States an estimated $504 billion in 2015.

In 2017, around 70,200 Americans died from drug overdose. 28,466 deaths were associated with synthetic opioids such as fentanyl and fentanyl analogs, 15,482 were associated with heroin use, 17,029 with prescription opioids (including methadone), 13,942 with cocaine use, and 10,333 with psychostimulants (including methamphetamine).

In 2021, there was an increase in overdose deaths; more than 106,000 drug-related overdoses occurred, including deaths caused by both illegal and prescribed opioids. Of this, 70,601 deaths were caused by synthetic opioids primarily fentanyl. Additionally, 32,537 overdose deaths involved stimulants like cocaine or psychostimulants with abuse potential (primarily methamphetamine).

Between 2017 and 2019, rappers Lil Peep, Mac Miller, and Juice Wrld died of drug overdoses related to opioids. William D. Bodner of the Drug Enforcement Administration's Los Angeles field division and special agent in charge of the investigation into Miller's death said in a statement, “The tragic death of Mac Miller is a high-profile example of the tragedy that is occurring on the streets of America every day.”

Heroin
Between 4–6% of people who misuse prescription opioids turn to heroin, and 80% of heroin addicts began abusing prescription opioids. Many people addicted to opioids switch from taking prescription opioids to heroin because heroin is less expensive and more easily acquired on the black market.

Women are at a higher risk of overdosing on heroin than men. Overall, opioids are among the biggest killers of every race.

Heroin use has been increasing over the years. An estimated 374,000 Americans used heroin in 2002–2005, and this estimate grew to nearly double where 607,000 of Americans had used heroin in 2009–2011. \\\ During the first two waves of the opioid epidemic, heroin use increased among non-Hispanic Whites but decreased among non-White groups; additionally during this time, the vulnerability for overdose shifted to younger age groups. \\\ In 2014, it was estimated that more than half a million Americans had an addiction to heroin.

Demographics
In 2016, opioid overdoses took the lives of approximately 91 Americans each day. Roughly half of these deaths were caused by prescribed opioids. Given the complexity of the topic and the difficulty of controlling factors while researching, there is much speculation the differences between demographics

In 2015, Anne Case and Angus Deaton's theory of the deaths of despair identified the root causes of the increase in opioid deaths as high levels of poverty, income inequality, and unemployment due to deteriorating labor markets, a lack of access to social capital, a lack of access to healthcare, and high social isolation. They reported that opioid overdose deaths were disproportionately affecting white, middle-aged, and less-educated Americans, particularly those living in rural areas. ///

Race In the US, addiction and overdoses affect mostly non-Hispanic Whites from the working class. The prevalence of opioid overdose deaths per 100, 000 within the USA was highest for non-Hispanic White, followed by Black, Hispanic, and Asian/Pacific Islander individuals. During the first and second wave of the opioid epidemic, non-Hispanic White and non-Hispanic Native Americans were most affected by opioid overdose. While all groups were affected in the third and fourth wave of the epidemic, non-Hispanic Native Americans and non-Hispanic Black individuals saw the greatest rise in deaths.

Native Americans and Alaska Natives experienced a five-fold increase in opioid-overdose deaths between 1999 and 2015, with Native Americans having the highest increase of any demographic group. \\\ With the belief that there would be a low risk of addiction, Indian Health Service physicians, like doctors nationwide, readily prescribed opioids. In addition, structural health care deficiencies from the provider and cultural beliefs against receiving care from the patient, as well as inadequate community support structures for substance misuse, contributed to high mortality rates. In 2015, American Indians/Alaska Natives had the greatest drug overdose mortality rates of any U.S. population, comparable to White Americans. \\\ In 2018, the opioid crisis continued to disproportionately affect non-Hispanic Whites and Native Americans with the National Institutes of Health (NIH) reporting a rise in opioid morbidity and opioid related fatalities.

\\\ During 2019-2020, non-Hispanic American Indian/Alaska Native and non-Hispanic Black individuals experienced the greatest increases in drug overdose mortality rates. Additionally, when accounting for the age-adjusted death rate, non-Hispanic American Indian/Alaska Native and non-Hispanic Black individuals in 2020 and 2021. The percentage of individuals with documentation of prior treatment for substance use disorders was low, especially among Black individuals, at 8.3%. Hispanic, non-Hispanic Native Hawaiians, and non-Hispanic Asians experienced the lowest rate of overdose deaths. \\\

Sex

Since white women receive more prescription drugs than men, the number of overdose deaths is especially troubling. According to the NIH (2018), "The opioid epidemic is increasingly young, white, and female" with 1.2 million women being diagnosed with an opioid use disorder compared to 0.9 million men in 2015. \\From 1999 to 2014, 7% of women admitted to drug treatment in the US were pregnant, with maternal OUD at labor and delivery quadrupling; and neonatal abstinence syndrome increasing from 1.5 to 8.0 per 1,000 hospital births between 2004 to 2014. \\\

Age

In 2014, roughly 12 percent of young adults between the ages of 18 and 25 reported abusing prescribed opioids. Non-medical prescription drug use rates have been increasing in teenagers with access to parents' medicine cabinets, especially as 12- to 17-year-old girls were one-third of all new users of prescription drugs in 2006. Teens used prescription drugs more than any illicit drug except cannabis, more than cocaine, heroin, and methamphetamine combined. In 2014, roughly 6 percent of teenagers between the ages of 12 and 17 reported abusing prescribed opioids. Deaths from overdoseverdosesin affect younger people more than deaths from other opiates.

Geographic Location

In the United States, those living in rural areas of the country have been the hardest hit. According to Rita Noonan from the CDC, in rural areas, the overall death rate for accidental injuries is 50% higher than in urban areas. Differences in a multitude of factors, such as income, social supports, and accessibility to health care resources, have led to rural communities majorly exceeding urban areas when it comes to the rate of opioid-involved overdose deaths.

\\\ Between 1999 to 2017, Non-Hispanic Black populations in medium-small metropolitan regions saw a growth of opioid overdoses at 12.3%, while non-Hispanic whites in non-metropolitan areas had an increase of 13.6% annually. Urban Black Americans had the largest rise in overdose rates between 2013 and 2017, with younger (aged 55 years) and older adults seeing increases of 178% and 87%, respectively. However, Black individuals living in urban areas had the largest rise in fentanyl-related fatalities during the same time period. \\\

Prescription rates for opioids vary widely across states. In 2012, healthcare providers in the highest-prescribing state wrote almost three times as many opioid prescriptions per person as those in the lowest-prescribing state. Health issues that cause people pain do not vary much from place to place and do not explain this variability in prescribing. Researchers suspect that the variation results from a lack of consensus among elected officials in different states about how much pain medication to prescribe. A higher rate of prescription drug use does not lead to better health outcomes or patient satisfaction, according to studies.

In Palm Beach County, Florida, overdose deaths went from 149 in 2012 to 588 in 2016. In Middletown, Ohio, overdose deaths quadrupled in the 15 years since 2000. In British Columbia, 967 people died of an opiate overdose in 2016, and the Canadian Medical Association expected over 1,500 deaths in 2017. In Pennsylvania, the number of opioid deaths increased 44 percent from 2016 to 2017, with 5,200 deaths in 2017. Governor Tom Wolf declared a state of emergency in response to the crisis.

Economics\\\ Prescription opioids are considered a better financial choice for treating pain than surgery. This resulted in an increased use of prescription opioids by individuals living in communities that were underserved medically or did not have health insurance. Overdose death rates increased across most racial and ethnic groups due to county-level income inequality, particularly among Black and Hispanic individuals. In 2020, overdose rates were more than twice as high in counties with greater inequality compared to counties with lower inequality. \\\

Treatment and effects during COVID-19 pandemic
After slight decreases in opioid fatalities 2017–2018, overdose deaths in the US increased in 2019, due largely to an increase in non-medical use of fentanyl. The COVID-19 pandemic's interference of daily life through increased isolation, the social safety net, and the health care delivery system has intensified the opioid epidemic. US media, on national, state, and local levels, infer that overdose deaths are increasing.

\\ Statistics reveal that during the COVID-19 epidemic, drug overdoses increased. According to statistics from the Centers for Disease Control and Prevention, there were 91,799 overdose fatalities in the United States in 2020, a more than 30% rise from 2019. Drug-related overdose fatalities increased to more over 106,000 in 2021, the greatest number of overdose deaths recorded in a 12-month period. Most of these deaths were caused by synthetic opioids other than methadone (mostly fentanyl or analogues) and methamphetamine. During this time, non-Hispanic Black and non-Hispanic American Indian populations had the highest rate of overdose deaths, and non-Hispanic American Indian and white populations had the greatest increase in overdose rates. Further, during the first year of the COVID-19 pandemic, overdose disparities widened between Black persons and White persons. For example, in 2020, overdose rates among Black men 65 years or older (52.6 per 100 000) were nearly 7 times those of White men of the same age (7.7 per 100 000).

During times of economic distress such as the COVID-19 pandemic or the 2008 recession, harmful rates of drug use has been seen to increase in populations experiencing joblessness and disadvantaged populations; moreover, Carpenter et al. found evidence that economic downturns lead to increases in the intensity of prescription pain reliever use as well as increases in clinically significant substance use disorders involving opioids.

In addition, the COVID-19 pandemic has marked the start of health care policies that, should they be adopted permanently, could not only lessen the effects of the pandemic on overdoses, but also make overall treatment of opioid use disorder more effective by eliminating obstacles to previously proven therapies for these disorders.

According to the US National Institute on Drug Abuse, the coronavirus disease 2019 (COVID-19) pandemic could hit certain populations, such as those suffering from substance use disorders and especially those with opioid use disorder, particularly hard. For opioid use disorder patients, COVID-19's effects on respiratory and pulmonary health is a significant threat. According to an April 2020 Health Affairs journal article "Once The Coronavirus Pandemic Subsides, The Opioid Epidemic Will Rage," recommended potential solutions include requiring doctors in large physician groups to get the federal waiver that would allow them to prescribe FDA-approved mediations to treat addiction. Under the Drug Addiction Treatment Act of 2000, physicians can obtain an "X-waiver" to prescribe buprenorphine. Other studies have looked at treatments for OUD during the COVID-19 pandemic. For example, one JAMA Internal Medicine research letter from December 2020 found that since the COVID-19 national emergency declaration, "the number of individuals filling buprenorphine prescriptions has plateaued but has not decreased; however, filled prescriptions for all medications collectively have decreased considerably."

Countermeasures
\\\ Increasing bystander intervention

There are currently two types of laws in place to reduce opioid overdoses through increased bystander intervention: Good Samaritan Laws (GSLs) and Naloxone Access Laws (NALs). GSLs allow a bystander to not face civil damages when acting in good faith to provide emergency care in the event of an overdose, and NALs increase the distribution and accessibility of Naloxone. Research suggests that increasing naloxone access will be the second most effective intervention for reducing overdoses. Most states have the following three or varying degrees of Naloxone access: third party distribution, pharmacist prescribing power, and standing orders. The standing order for naloxone allows for its distribution to a patient if they meet a certain criterion, which is most often the prescription of an opioid. The effectiveness of this legislation has been disputed since it's success depends on the change in behavior of people who are present during an overdose and the accessibility of naloxone.

In 2001, New Mexico was the first state to create a NAL, which granted third-party prescribing and criminal immunity to prescribers. By 2017, all states had a NAL in place. Connecticut first implemented a GSL in 2011, and it has been updated yearly since 2014. Some research suggests that Connecticut’s GSL has not affected overdose deaths but has resulted in positive behavioral changes with an increase ofin 9 calls; however, deaths may still continue to increase in spite of the increased awareness from GSLs.

From 2000 to 2014, McClellan et al. (2018) found that opioid overdose mortality decreased by 14% and 15% when laws increased the engagement of layperson intervention, respectively, through an increase in NALs or GSLs. NALs were related to greater reductions in mortality in Black populations, and GSLs were related to reductions of mortality in Black and Hispanic populations. Rees et al. (2019) found that NALs were associated with a statistically significant decrease in non-heroin opioid-related deaths. The adoption of a GSL resulted in a decrease of 12–19%; early adopters of NALs or those that passed NALs before 2011 experienced an 18–29% reduction in overdoses. However, it was also found that NALs were only effective on the Western coast, and the Eastern and Southern US experienced little impact due to fentanyl not fully reaching the West in 2014. \\\