By Fayçal Ibrahim.

To be able to understand the issue, we need to first explain what opioids are. According to the faculty of Medicine at Johns Hopkins University, Opioids are a class of drugs that work as pain killers, specially for surgery patients and a specific group of patients experiencing excruciating pain due to trauma, disease or cancer. Opioid drugs, therefore, span from prescription-based painkillers to many illegal drugs such as Heroin. Opioid drugs are very addictive, and such a situation is known as OUD (Opioid Use Disorder).

The Opioid crisis in the United States is a crisis that has been going on since the 1990s. Between 1999 and 2021, the Opioid crisis had already led to 645,000 deaths due to overdose [1]. 

It all began in the late 1990s, when doctors over-prescribed opioid painkillers like Oxycontin to their patients, even for less severe conditions, driven by Big Pharma to increase sales. This is known as the first wave. The second wave occurred when these patients became dependent on opioids but could not get a prescription to buy them, so they turned to cheaper, more accessible drugs on the illegal market, mainly heroin. It began in 2010 when the number of deaths due to heroin use rose rapidly. Just when everyone thought the crisis was subsiding, the third and deadliest wave occurred when a new synthetic opioid hit the market: Fentanyl, a drug 50 times more potent than heroin, is responsible for two-thirds of all opioid-related deaths – two milligrams of Fentanyl is enough to kill an average-sized person [2] [3].

There are actually two sides to Fentanyl, one that is legal and the other that is illegal.

The illegal side: Illicit fentanyl trafficking

We cannot discuss the illegal market of Fentanyl without discussing the role of Mexico, China, and India. In fact, the USA has openly accused China of being at the root of the current opioid problem, citing this East Asian country as the main source of Fentanyl and fentanyl-related narcotics detected in the USA. China is also accused of producing 70% of the world’s illicit Fentanyl [4].

Fentanyl arrived in the United States through the distribution of various illegal narcotics containing Fentanyl, including heroin, cocaine, and counterfeit drugs [5]. Most Fentanyl is shipped to the U.S. by Mexican transnational criminal organizations (TCOs) or other criminal organizations in Canada, who source their chemicals from Chinese producers [6]. More problematic, Fentanyl is easily ordered online from China and shipped to the U.S. via the U.S. postal system, with sellers dealing only in Bitcoin to ensure the opacity of payments [7].

Since 1996, the Chinese government has introduced restrictions and amended existing laws to regulate Fentanyl. However, these measures have always been deemed insufficient because producers have always found loopholes, producing precursor chemicals that can be used to manufacture Fentanyl – mainly N-Phenyl-4-piperidinone (NPP) and Anilino-N-phenylpiperidine (ANPP) – which are not covered by the regulations [4].

So, in the face of strong resistance and pressure from the USA, President Xi Jinping pledged in 2018 to tackle the problem at the G-20 summit. As a result, in 2019, China implemented new regulations that gave it complete control over all forms of Fentanyl and many fentanyl-related chemical productions in the country (including NPP and ANPP) [8]. These regulations include controlling websites advertising Fentanyl, enforcing stricter shipping rules, and creating special anti-drug teams to investigate fentanyl trafficking. These regulations have proved effective, thanks to their strengthening in recent years. It has led to 83,000 drug investigations, 90,000 drug-related detentions, the closure of 1,700 online sellers, the destruction of 173 production facilities, and the resolution of 290 cases of illegal drug trafficking [4].

The new regulations have restricted the supply of Fentanyl from China, prompting Mexican DTOs – who have increased their share of the global market for illegal fentanyl trafficking and the production of large quantities of fentanyl-related substances through clandestine laboratories, advanced refining processes, and processing techniques – to turn to Indian suppliers, who are becoming the world leaders in Fentanyl [8]. Several Chinese suppliers have relocated their production to India to escape China’s new restrictions on Fentanyl [4].

Moreover, India’s rapidly developing pharmaceutical sector is often neglected and under-regulated. The country’s industrial expertise in pharmaceuticals and chemicals gives it a key role in the global trafficking of illicit drugs, enabling it to benefit from China’s tightened control of Fentanyl [4]. 

With the United States recognizing India’s growing role in the global market for illegal Fentanyl, U.S. Customs and Border Protection has urged law enforcement agencies worldwide to pursue Indian drug traffickers [4].  

India’s Narcotic Drugs and Psychotropic Substances Act (NDPS) of 1985, amended to include Essential Narcotic Drugs like fentanyl in 2015, regulates narcotics for medicinal use [9]. Efforts to control illegal fentanyl production included restricting precursor exports in 2018 and taking over the supply chain in 2020. However, these measures have been partially effective as traffickers exploit loopholes by using alternative precursors not covered by regulations in India and China, keeping the future source of fentanyl uncertain [4].

To tackle the problem of illicit Fentanyl trafficking, the United States Federal government has laid out many plans and passed many laws.

Targeting “drug trafficking organizations, their financial infrastructure and distribution networks” is the priority of the U.S. Department of Justice (DOJ) to “disrupt and dismantle” them [10]. In addition, the DOJ will use intelligence-gathering and information-sharing techniques with other law enforcement agencies to obtain information to investigate and punish “traffickers who participate in significant transnational, national, and regional drug trafficking organizations.”

In its Unity Agenda, the Biden-Harris administration has prioritized the fight against the opioid crisis and declared a continued bilateral collaboration between Xi Jinping on counter-narcotics. In addition, the administration has taken several steps to tackle the problem. To continue its partnership with Mexico and Canada in the fight against illegal Fentanyl, the U.S. also created the Trilateral Committee on Fentanyl 2022. After the Biden administration realized that the fight against illicit synthetic drugs had to be a top priority of global policy, over a hundred nations and eleven multilateral organizations came together to form the Global Coalition to Address Synthetic Drug Threats [11].

Investing in border patrol agents and other law enforcement personnel who directly combat illicit fentanyl trafficking is one of many choices made to fortify border security and restrict the flow of Fentanyl into the United States. Additionally, the U.S. Customs and Border Protection received USD 535 million in financing for border technology as part of the budget proposal for 2024. Of this, USD 305 million was allocated for “Non-Intrusive Inspection Systems and Detection Technologies,” mostly used to detect Fentanyl [12]. These devices would be placed at various entry points that traffickers frequent. Extending the High Intensity Drug Trafficking Area (HIDTA) Program is another choice. In order to combat illicit traffickers in every state, this program provides USD 302 million to federal, state, local, and even tribal law enforcement fighting illegal traffickers in all states [12].

Additionally, President Biden slapped sanctions on many groups and individuals involved in the illicit fentanyl trafficking, upsetting the worldwide supply chain [11]. Not to add, U.S. law enforcement prioritized breaking up the TCOs to halt the trafficking, which resulted in several criminal indictments and charges against businesses, drug lords, and operatives of the biggest and most potent cartels. During these missions, law enforcement seized substances that involved Fentanyl, which together account for about 263 million lethal dosages of the drug [12].

In addition, the United Nations Commission on Narcotic Drugs agreed to restrict three particular compounds that drug traffickers use to synthesize Fentanyl at the U.S. government’s request illicitly [11].

This has also been reaffirmed concurrently with the Department of Homeland Security’s publication of the “Strategy for Combating Illicit Opioids.” [13]

However, Fentanyl and prescription opioids led to the addiction of about 75% of illicit fentanyl users. Therefore, we must concentrate on one of the underlying causes, which is the legal side of opioids like Fentanyl [14]. 

The legal side: Pharmaceutical companies

Overprescription

Fentanyl overprescription led to a quadruple increase in overdose deaths from 2000 to 2010. Despite a decrease after 2012, opioid prescriptions were still three times higher than in 2000, with enough in 16% of US counties for every resident. In 2016, prescription opioid overdoses accounted for 40% of all opioid deaths, over four times the rate in 2000 [15].

Insys Therapeutics was one of the primary pharmaceutical corporations behind this massive drive for overprescription. The company was found guilty of racketeering with schemes involving bribes, kickbacks, and even exotic dances to doctors who prescribed enormous amounts of Subsys, the company’s Fentanyl spray, to patients who did not need it [16]. 

Insys Therapeutics became the first maker of opioids to verge on bankruptcy when it agreed to pay a USD 225 million fine in 2019 to resolve bribery allegations stemming from criminal investigations [17]. In the course of this prosecution, four other executives were found guilty and the CEO and founder, John Kapoor, was sentenced to 66 months in jail [16]. Additionally, a physician named Edward Lubin was forced to pay USD 1.5 million for accepting bribes from Insys and writing excessive prescriptions for Fentanyl [18]. 

The state of Oklahoma also brought legal action against Johnson & Johnson for “engaging in false, deceptive and misleading marketing” by exaggerating the advantages while downplaying the risks of addiction, which contributed to the total of 6800 deaths that occurred in the state alone. It was revealed during the trial that J&J sales personnel visited doctors in Oklahoma more than 150,000 times, with a focus on high-volume prescribers. Additionally, J&J was a significant supplier of opioid materials—produced by a J&J subsidiary from opium poppy plants they cultivated and grew in Tasmania—to all other US pharmaceutical corporations. Consequently, the company was mandated to pay the state USD 572 million, which is equivalent to a year’s worth of services to address the situation [19].

Cephalon, which was forced to pay USD 425 million for selling three of its medications for purposes other than those approved by the FDA and thereby violating the False Claims Act, was another significant contributor to the crisis. Actiq, for example, was actually only authorized for use by cancer patients who were tolerant to opioids. However, Cephalon employed salespeople and medical experts between 2001 and 2006 to discuss with physicians the possible applications of their medications and to offer them for patients with migraines, sickle-cell pain episodes, physical trauma, and cancer patients who were not tolerant of them. In defiance of FDA regulations, the company also provided large payments to continuing medical education initiatives in order to support unauthorized uses of their medications [20].

With the most well-known opioid painkiller, Oxycontin, producing more than USD 35 billion in sales, Purdue Pharma was the most responsible for the US opioid crisis [21]. Although Purdue only accounted for 3% of the market overall – fourth largest – its medicine was the most popular among patients with addiction [22]. 

Based on the opioid chemical Oxycodone, Oxycontin was initially licenced by the FDA in 1995 and brought to the market by Purdue Pharma as a replacement for MS Contin, the company’s earlier morphine medication [23]. 

The company, first to patent their oxycodone medication, heavily marketed to doctors, increasing prescriptions from 316,000 in 1996 to 14 million by 2002. They invested $200 million in marketing and expanded their sales force to reach 94,000 doctors [24].

Purdue falsely advertised the medication as being less potent, less addictive, and therefore less potential for abuse than MS Contin. In fact, the company taught its salespeople to say that the chance of addiction was “less than one percent.” But in actuality, it was 50% more potent than morphine, which is what caused the initial wave of opioid-related deaths. Due to this deception, Purdue and three other corporation officials admitted to criminal charges and were ordered to pay USD 634 million in 2007 [24].

Since 2007, approximately 2,600 lawsuits demanding damages for the suffering and agony caused by Purdue and its owners, the Sackler family, have been filed. During this time, the Sacklers have taken out about $10 billion, making them one of the richest families in America [25].

As it would not be able to pay for everyone, Purdue filed for Chapter 11 bankruptcy protection in 2019 to deal with these cases. In 2023, the most recent bankruptcy deal with the Supreme Court stipulated that Purdue would have to pay $1.2 billion when it emerged from bankruptcy, with more payments anticipated in subsequent years. In exchange for shielding Sackler family members from civil claims, the Sacklers are expected to hand over up to $6 billion over 18 years, with roughly $4.5 billion in the first nine years.

A more intriguing explanation for the over-prescription of medications is that outside groups like the Joint Commission, the American Pain Society, and the Veterans Health Administration suggested in the 1990s that physicians consider patient-reported pain levels to be a “fifth vital sign.” Hospital administration implemented these guidelines to raise patient satisfaction levels. They started offering patient pain management surveys in 2006. Hospitals were able to compare themselves and have an impact on funding because of the public release of survey findings. Consequently, in an effort to increase patient satisfaction, physicians were occasionally advised to prescribe specific opioid-based medications at greater dosages. Furthermore, since opioids can only be obtained with a prescription, seeing a doctor frequently to fill these prescriptions would take up a significant amount of their time. As a result, it is more convenient for the doctor to write tremendous prescriptions at once [26].

Large supply of Opioid pills

One major issue is the abundance of opioids. A Purdue patent for OxyContin was invalidated in 2004 by several federal courts for deceiving authorities about the medication’s efficacy, and it paved the way for producers of generic drugs to join the market. 88% of the market was held by three generic manufacturers: Actavis, a division of Israel-based Teva Pharmaceutical Industries; Par Pharmaceutical, owned by Endo Pharmaceuticals, based in Ireland; and SpecGx, a subsidiary of Mallinckrodt, based in Ireland. Between 2006 and 2012, they supplied 76 billion opioid tablets. Because generic manufacturers don’t market their products and are therefore unknown to the public, they were rarely taken into consideration as a contributing factor to the issue [27]. 

Once authorities became aware of their important role in the market, they agreed to lower supply, enhance client sales monitoring, and stop distributors from selling to dubious pharmacies at the US authorities’ request. Mallinckrodt was fined USD 35 million for failing to comply [27].

Regulatory failures

Because many FDA officials have close ties to big pharma, it is crucial to begin any discussion of regulatory failures when a conflict of interest is involved. Indeed, 11 of the 16 FDA representatives who participated in the examination and clearance of 28 different medications now work for the firms they were previously in charge of regulating. Two of them contributed to the approval of OxyContin before taking positions at Purdue Pharma. This suggests a conflict of interest, which may help to explain a number of the subsequent failures.

It’s also crucial to note that pharmaceutical corporations funded 1.1 billion USD of the FDA’s $3 billion budget in 2022, which accounted for 75% of the funding allocated to the agency’s drug division [28].

The FDA attempted to regulate opioids and their prescribing by introducing the TIRF-REMS program in 2011. These are strict rules designed to ensure that doctors only prescribe opioids to the right cancer patients. However, instead of managing this program, the FDA handed it over to six different sponsors – pharmaceutical companies – to execute it, who in turn hired McKesson, one of the largest drug distributors, to administer it [29].

Additionally, the FDA had not successfully enforced marketing restrictions, which would have prevented corporations such as Purdue from adding deceptive claims and labeling to their products [30]. These statements were intended to persuade medical professionals that the drug is non-addictive and may be used for a variety of problems.

Response

Following such setbacks, there have been some readjustments. The TIRF-REMS programme was revised with FDA approval in 2020 “to ensure that the benefits of these drugs continue to outweigh the risks.” [31] With this modification, opioid medicine shall only be administered to eligible patients who demonstrate opioid tolerance. 

The US DOJ will give priority to combatting the diversion of restricted prescription medicines to unlawful users in order to combat the opioid epidemic. Physicians and businesses, including C-level executives, engaged in illegal opioid prescription, diversion, or distribution will face legal prosecution. The department will employ cutting-edge data analysis technologies to investigate questionable billing and prescribing practices. Furthermore, an evaluation will be conducted to ascertain drug prescription quotas and look into fraud and kickback schemes within the substance misuse treatment sector [10].

States and municipal governments have filed lawsuits against Johnson & Johnson and McKesson, Cardinal Health, and AmerisourceBergen—three of the nation’s biggest prescription distributors, holding over 90% of the market—for their respective roles in the opioid crisis. They have consequently decided to reach a settlement that is “the second largest settlement of civil litigation in U.S. history,” for a total of USD 26 billion [32]. Any state or municipal government that signs the agreement will receive a percentage of the proceeds in return for dropping civil claims against the companies. Services for the prevention and treatment of addiction will receive at least 85% of the funds [32]. In addition, a settlement of USD 13.8 billion has been agreed with pharmacy chains, with most of the funds going towards the same purposes [33].

Using the knowledge of its various agencies—the Substance Abuse and Mental Health Services Administration (SAMHSA), the Centers for Disease Control and Prevention (CDC), the National Institutes of Health (NIH), and the Food and Drug Administration (FDA)—the US Department of Health and Human Services (HHS) implemented a framework in 2017 to combat the opioid crisis [34]. The Biden Administration will be providing significant funding for this effort. Based on a five-point strategy, they will coordinate their efforts to improve access to services for opioid addiction prevention, treatment, and recovery; provide naloxone-based medications that can reverse an overdose; enhance public health data collection and reporting; encourage groundbreaking study that advances our understanding of pain and addiction; and advance pain management techniques to find alternatives to opioids for treating pain [35].

Furthermore, in 2022, the FDA unveiled the Overdose Prevention Framework, a comprehensive strategy aimed at preventing drug overdoses, decreasing the death rate from opioid overdoses, and addressing the significant effects of addiction on the American populace [36].

Additionally, the Biden administration implemented the American Rescue Plan, allocating USD 5 billion for the prevention and treatment of opioid addiction as well as expanding access to mental health services [33].

Today, bars and restaurants in the US offer free fentanyl tests and Narcan, a naloxone based drug that reverses an opioid overdose [2].

Conclusion

The opioid crisis in the U.S. remains a persistent and complex issue, leading to an alarming rate of overdose deaths and widespread addiction. Initially triggered by the overprescription of strong opioids like fentanyl, driven by aggressive marketing and insufficient regulatory control, efforts to curb the illegal production and distribution of fentanyl have seen partial success due to regulatory changes in China and India. However, traffickers still find loopholes. The emergence of synthetic opioids and changes in the global production and distribution landscape compounds the challenge. In response, the U.S. has adopted a comprehensive approach that includes tighter regulations, international collaborations, and significant investments in law enforcement and public health measures. Despite these actions, the problem continues to evolve, highlighting the need for ongoing vigilance, adaptable policies, and thorough strategies that address both the supply and demand for these perilous substances.

Edited by Justine Peries.

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[Cover Image] AI generated with ChatGPT.