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Fentanyl and Fatal Overdoses: From Chemical Production in China to Users in Pennsylvania.

Due to the devastating effects of opioid addiction in the US, resulting in more than 42,000 deaths in 2016 (CDC 2018), one of the Trump administration's policy aims is to halt or heavily restrict imports of illicit opioid compounds such as fentanyl from China (White House 2018). Fentanyl is legitimately used as an analgesic in the form of lozenges, patches, and parenterally to manage acute or chronic pain, usually in cancer patients. According to the Drug Enforcement Administration (DEA), "Licit fentanyl is diverted via theft, fraudulent prescriptions, and illicit distribution by patients, physicians, and pharmacists. Illicitly manufactured fentanyl is chiefly responsible for the current domestic crisis," having played a role in nearly half of opioid-related deaths (DEA 2008).

The major concern over fentanyl misuse is that it is up to 100 times more potent than morphine, and as little as 2 milligrams can be fatal in patients not previously exposed to it. Precise dosing is vital yet challenging given the drug's narrow therapeutic window. An excessive dose can easily result in respiratory depression and death.

The substance is lethal to not only users but also anyone intercepting products, such as customs and mail agents and even first responders. It can pose a threat to sniffer dogs as well, as US Customs and Border Protection (CBP) has indicated. Although exposure to the heavily diluted preparations sold on the street appears far less risky (Szalavitz 2018), the seized samples sent through the mail are extremely pure and potent (Owen 2018).

In addition to fentanyl, several fentanyl analogues exist. These are compounds that are chemically similar to fentanyl, such as carfentanil, a tranquilizer used to sedate large animals that is nearly 100 times the potency of fentanyl. Many other fentanyl analogues exist as "designer drugs" intended to undermine efforts to prohibit legal procession.

Beyond concerns surrounding the drug's extreme potency, fentanyl presents additional challenges for policymakers. It can be pressed into pills to mimic oxycodone or made to look like heroin. Because the drug is synthetic, it can be made in a lab using precursor chemicals and therefore does not need large fields and smuggling operations, as heroin requires. As one DEA agent put it, "For the cartels, why wait for a field of poppies to grow and harvest if you can get your hands on the precursor chemicals and cook a batch of fentanyl in a lab?" (McLaughlin 2017).

It is not just opioid pills that become laced with fentanyl. Nine people died in Florida from fake Xanax pills with fentanyl (Parry 2016). Xanax is a benzodiazepine used for the treatment of anxiety and is not an opioid. Much of the recent increase in overdoses for benzodiazepines and cocaine has been driven by polysubstance abuse with fentanyl. In 2016 nearly 45 percent of benzodiazepine and 40 percent of cocaine overdoses also had a synthetic opioid, most likely illicit fentanyl, present at the time of death.

CBP is actively engaged in monitoring and preventing importation of illicit fentanyl. While it seized only 2 pounds in 2013, it seized 1,485 pounds (674 kg) in 2017 (CBP 2017). Moreover, total fentanyl seizures recorded by the DEA more than doubled from 14,440 in 2015 to 34,199 in 2016, the vast majority of which was fentanyl (85 percent) followed by acetyl fentanyl (4 percent) and carfentanil (3 percent) (DEA 2018). Because of its relatively small volume, the drug is frequently sent through the mail. As its annual fiscal report states, "While most illicit drug smuggling attempts occur along the Southwest border, CBP has seen a growing threat of illicit synthetic drugs smuggled to the U.S. through the international mail" (CBP 2017).

The DEA says that about 325 kg of fentanyl base were sold in 2017. As Figure 1 shows, legal sales of fentanyl have declined since 2010. However, the total size of the legal market does not seem to be that relevant to the illegal market since most of it does not appear to be diverted. In other words, illegal production makes up the vast majority of the illegal market.

The Office of Criminal Investigation at the US Food and Drug Administration (FDA) is also trying to prevent the import via the postal service of packages containing fentanyl and has had some success (Florko 2018). Similarly, UK authorities are arresting those involved in the trade through the dark web (Dearden 2018). The UK is one of the largest buyers of drugs on the dark web.

The DEA describes a key market for fentanyls: "Motivated by enormous profit potential, traffickers exploit high consumer demand for prescription medications by producing inexpensive, fraudulent prescription pills containing fentanyls" (DEA 2016). For example, in January 2016, the DEA arrested the maker of 6,000 30-milligram oxycodone tablets that were actually fentanyl-laced pills made in the counterfeiter's New York residence. And between the beginning of 2014 and end of 2015, the New England DEA office discovered 7,000 similar fake pills.

The DEA shows graphically the main transit routes for fentanyl from China (the main source country for fentanyl and the precursor chemicals) and the end market in the US (DEA 2016). Until 2017, Canadian authorities were barred from opening mail weighing less than 30 grams, which provides a bit of context as to Canada's inclusion in Figure 2 (Health Canada 2017).

There are myriad players in the provision of fentanyl in the US market, but Mexican gangs play a prominent role, in both production of the finished product and distribution. While gangs have physical transshipment points over land and sea, they also use the international courier and mail systems. The DEA says, "The combination of a chain of freight forwarders and multiple transferals of custody makes it challenging for law enforcement to track these packages. Often the package will intentionally have missing, incomplete, and/or inaccurate information" (Knierim 2018).

The DEA says that 1 kilogram (2.2 pounds) of fentanyl costs a few thousand dollars (they provide examples of $1,700 to $3,500 per kilogram actually bought from China) and can be made into hundreds of thousands of pills. With each pill selling for $10-$20, 1 kilogram would make several million dollars in revenue. Given that most illicit oxycodone pills trade for more than $20, the incentive is clear: Fentanyl products are more potent and cheaper (DEA 2016).

The CBP intercepted more than 500 kilograms of fentanyl over the physical border in 2017, and even more in years past. In Pennsylvania, where I have conducted field research on opioids, 897 pounds of fentanyl was seized between 2013 and 2015, second only to Ohio (over 3,000 pounds) in size of seizures. In 2017, 44 kilograms (92 pounds) of fentanyl was intercepted through the international mail, and the mail poses the fastest-growing threat since it is easily available to everyone.

The Rise of Fentanyl

This report aims to investigate the rise of fentanyl. In addition to the evidence presented above, I do this in two novel ways. The first is an assessment of web access and the potential delivery of fentanyl by the international mail system to the UK and the US. The second is an assessment of alleged pain patients (many of whom started as patients in need of short-run opioids due to postoperative pain but would today probably be defined as drug users or addicts) and drug dealers in Philadelphia (and surrounding counties) and the published data on drug use in the same area.

In previous work, with the help of drug users, I assessed the market for the prescription opioids hydrocodone and oxycodone in this part of Pennsylvania (Bate 2018). I found that as the legal market tightened, users started to look to illicit markets (web pharmacies, social media hubs, and street dealers) to feed their habit. Although I was not initially looking for fentanyl, drug users mentioned it often, and dealers were supplying it. See Figure 3 for a photo of an illicit substance, which the user claimed to be fentanyl. I found that legal prescriptions were far cheaper, especially for oxycodone, than street sources. (See Figure 4.)

As the legal market dried up for many drug users, the cost of obtaining drugs increased substantially (Figure 5), as they moved from cheaper and legal sources to more expensive, illegal ones. As a result, fake pills laced with fentanyl, which are often cheaper than illegal supplies of prescription medicines, have increased.

This happened to such an extent that in 2015 most (over 65 percent) fatal overdoses in Pennsylvania involved heroin, but by 2017, the vast majority (over 75 percent) were caused by fentanyl (Figure 6). This shift in use mirrors what has occurred nationally. Opioid overdoses were primarily driven by prescription opioids until 2011, but that shifted to heroin and now fentanyl.

Online Sources of Fentanyl

So how do drug users and dealers who are not affiliated with large gangs access fentanyl directly? The most obvious option is the internet.

Using the business-to-business trading websites Weiku and Mfrbee--the former based in the eastern Chinese city of Hangzhou and the latter elsewhere in China--it is easy to find suppliers of all sorts of chemicals. Although a search under "fentanyl" did not lead to any useful results, a little digging and contact with suppliers of other chemicals can lead to a source for fentanyl. Additionally, both sites sell a wide variety of opioids (as well as benzodiazepines and other potentially dangerous medicines).

Via Weiku and Mfrbee, it was possible to buy fentanyl, its analogues such as carfentanil, and their precursors. Some sellers would only trade in significant volumes (more than a kilogram of fentanyl), but many were happy to sell less than 100 grams of the potent product. For their own security concerns, most of the sellers are opaque, and if there are real companies, not shells, discovering the operation of them and who ultimately controls them requires far greater investigative powers than I possess.

As the Guardian found in its own investigation, both Weiku and Mfrbee claim they take down advertisements for most drugs and all narcotics, but in practice oversight of this policy is obviously lacking. Identifying the owners of companies is not likely unless Chinese authorities cooperate with Western counterparts (Marsh and Kuo 2018). In summary, fentanyls are easily available online, but that does not mean tracking down (and prosecuting) the sellers will be easy.

Although I had no intention of making the purchases, I was only one click away from doing so. I could have bought between 10 and 300 grams from various sellers. The cost reflects a basic transportation charge and a small but noticeable discount for larger purchases. Among six possible sellers and different order sizes, average fentanyl costs were just under $10 per gram for export to the US and just under $9 per gram for export to the UK.

At the larger end of purchasing, one could buy enough fentanyl to, in principle, treat tens of thousands--and cause as many overdoses. I have no idea if my purchases would have gone through without being flagged and halted by payment systems, or whether the products would have been shipped, or whether they would been intercepted by UK and US authorities once shipped, but it is eye-opening that such a lethal chemical can, in principle, be bought fairly simply online. Even if the UK and US authorities did prevent or intercept these deals, I doubt other nations would intercept them, and a motivated user or dealer could use a more circuitous path.

Whether or not drugs are available to the general public via the mail, drug dealers have domestic production and overland and sea routes and other courier services that deliver the product to the US. And below I describe what was found in Pennsylvania.

Traders and Users of Fentanyl in Philadelphia and Its Suburbs

Fentanyl is obviously available over the web and via drug gangs, but I also wanted to survey a small number of pain patients and drug dealers about fentanyl availability and use, building on my previous work (Bate 2018a). Formal interviews were not appropriate given the interviewees' nervousness about the illegality of their actions. In any event, the best one can glean are not really data but a succession of informative anecdotes.

The first point to note is that fentanyl went from being a relatively new street drug in 2014 to one of the main drugs by mid-2018. Even as recently as in March 2018, most of the dealers I spoke with were selling oxycodone and other prescription medication, and none openly advertised they could sell fentanyl (even though some were selling fake oxycodone pills that were probably laced with fentanyl). Six months later, all six of the dealers I spoke with were openly selling fentanyl.

The impact on users was obvious. Drug-seeking patients overwhelmingly responded that it was almost impossible not to get offered fentanyl. In some instances, users were unable to buy anything else, or at least unable to buy their first-choice drug (notably, oxycodone or hydrocodone) that they were familiar with and would not likely cause them to overdose. And that is ignoring that an increasing amount of allegedly prescription productions, such as oxycodone, are probably fakes--chalk or sugar pills laced with a tiny amount of fentanyl.

When I spoke to pain patients in March 2018, none sought out fentanyl, and none acknowledged buying any. Two users were now using it, one regularly. I was not the first person to tell them of the risks.

One of the users I spoke with said there was a practice of stealing or buying discarded fentanyl patches from hospitals or hospices. People were combing through medical waste and, in one instance I am told, breaking into the hospital to get to the waste before it was dumped "to beat the competition." After a cancer patient uses a patch for three days, it is discarded, but there is still fentanyl that can be extracted from the patch, which then can be sold and ingested.

Other diversion practices probably also occur. But compared to imported illicit fentanyl, these diversions of legal products are likely minimal.

Discussion

Government data (from the DEA, FDA, CBP, CDC, etc.) show that fentanyl use in the illicit market has expanded, probably as illicit supply of prescription opioids has dried up. My own field research supports this and demonstrates an alarming sign that fentanyl is in both fake pills and openly sold. Street markets in the city of Philadelphia probably adopted fentanyl earlier than in the suburbs, so use may have peaked in 2017, whereas the experiences of the suburban users with whom I spoke probably displayed a lag. Regardless of timing, it is arguable that policies to drive oxycodone and other prescription opioids from the illicit market are the main cause of the rise of fentanyl in these markets, and regrettably the resulting spike in fatal overdoses.

This mirrors what happened in Estonia a decade ago. Drug addicts in Estonia were hooked on heroin coming via Russia from Afghanistan. As the war against the Taliban in Afghanistan began in 2002, the heroin trade dried up. Fentanyl from Russia replaced it quickly. Fatal overdoses spiked.

Interestingly, dealers liked how easy it was to transport fentanyl, and, much as I found in Philadelphia, users who wanted other opioids simply could not get them. In short, the dealers totally controlled what users could get and pushed them to buy fentanyl. Estonian authorities prioritized arresting the mid- and high-level dealers in 2017 and successfully dried up fentanyl trade. How long that lasts and its broader impacts are not certain yet (Hoskins 2018).

US government agencies have made considerable efforts to interdict fentanyl and its precursors from entering the US market, but the combination of its small size and high value makes this difficult. The DEA only scheduled one fentanyl precursor, 4-Anilino-N-phenethyl-4-piperidine, in 2010 (DEA 2010). Additionally, Mexican gangs and Chinese criminal enterprises find it easy to hide the products through a variety of transit methods. The international mail also provides opportunity to trade in fentanyl, as described in the original research above. The ease with which I was able to find fentanyl to buy for export to the US and UK shows that it will be difficult to shut down this expanding source of product.

There is also another reason to look at sales into the UK. While the US may come to an agreement with Beijing about closing down sales to the US from business sites such as Weiku, it is unlikely to be fully successful. And even if it managed to stop 100 percent of direct sales to the US, enterprising dealers will simply sell into nations such as the UK, repackage the product, and then resell it into the US. Intercepting all packages from the UK and other EU nations to the US will not be possible. One UK gang made about $225,000 in five months in early 2017 "by mixing the drugs with bulking agents and sending them to customers in the UK, US, Germany, Norway, Canada, Australia, Argentina, Canada, France, Singapore, Holland and Spain" (Dearden 2018). Also, as I found in research into internet sales of nonnarcotic medicines (Bate 2012), Russian gangs are active participants and, given their sales into neighboring Estonia, could easily act as global traders via mail (if they are not already).

In all my research into fake medicines in other parts of the world, it is rare for counterfeiters to make fake pills that contain any correct active ingredients. Far less than 1 percent of fakes had active ingredients (Bate 2012). Making pills with real ingredients is more expensive and often more dangerous to the counterfeiter's safety due to potentially lethal chemicals such as fentanyl. It is also harder to formulate real drugs than chalk pills. And in emerging markets, those selling fakes are unlikely to know where they end up and hence cannot expect repeat business, so there is no point in adding real ingredients.

Sales of fake analgesics in the US may differ because of the likelihood of repeat business with the same individuals, who will not buy again if they get no impact from the pills. As such, dealers make pills with some fentanyl since it mimics real pills. (Or they add some fentanyl to massively diluted heroin--for those willing to inject themselves.)

As the DEA found, even people not buying opioids may get lethal doses of fentanyl in other medicines. So fatal overdoses may even increase outside of the opioid market itself, which is a significant concern.

Policy Suggestions and Questions

This June, the FDA held a meeting called "FDA Online Opioid Summit: Reducing Availability of Illicit Opioids Online" with major internet and payment companies in an effort to limit the import of opioids into the US. If companies such as Visa, Mastercard, and PayPal did not accept payment for narcotics from China, it would limit the trade. It would not stop trade in fentanyl into the US, but it is still probably worth doing.

The Synthetics Trafficking and Overdose Prevention Act, signed into law in October 2018, takes this approach further by requiring detailed advance electronic information on all packages coming from abroad through the United States Postal Service. Not only is this action expensive, but it may also prevent the importation of other medications that millions rely on.

While lowering the number of prescription opioids in circulation is the right policy--assuming that preventing new opioid addicts is of paramount importance--the finding that fentanyl has caused a massive increase in fatal overdoses may mean that limiting prescription opioids broadly might be a better-targeted approach. Existing drug seekers who are already addicted and are unable to access prescription medication are likely to overdose on fentanyl. Is it possible to identify those most at risk and provide an extended weaning off period rather than making them go "cold turkey," perhaps pushing them to street sources with fatal consequences? New Mexico is hearing testimony on evaluating such an idea (State of New Mexico 2018).

Given the lethal nature of fentanyls, perhaps dealers of other opioids should be given more lenient sentencing, with harsher sentencing for fentanyls (and traders of its precursors), so as to drive dealers toward better tolerated drugs. Perhaps a variant of this is following Estonia's lead and targeting mid- and high-level traffickers in fentanyls.

Providing first responders with fentanyl testing strips seems like a sound policy, so that they are better protected against handling unknown white powders. Furthermore, making sure first responders and others, such as fast food workers, are equipped with naloxone would also save lives. Tales of baristas and the like administering naloxone are present across the media (Fadulu 2018).

Perhaps the best solutions are not anything to do with fentanyl but more funding of mental health and drug programs so that fewer people become addicted and those that do are helped in drug programs. Drugs such as Vivitrol, which block the fentanyl molecule from binding to receptors on the brain, might work better than more traditional medications for opioid use disorder such as buprenorphine or methadone.

Designing a project to assess the best interventions makes sense because, given scarce resources, the above cannot all be done, or may even be contradictory. Moreover, increased and improved data collection would also help establish the foundation for future policy efforts. Current surveillance programs do not distinguish between overdoses caused by legal or illegal substances, and fentanyl is folded into the larger category of synthetic opioid deaths. A better system would require a coordinated effort on the parts of medical examiners, law enforcement, and state health departments, but more precise measures would help.

Conclusions

Assessing the international mail and Philadelphia pain patients and drug dealers, I found easy availability and use of the potentially deadly fentanyl analgesics. Efforts by the US government to interdict fentanyls and their precursors have had some success, but by making prescription opioids harder to come by, government policy has probably driven illicit actors to supply--and drug users to ingest--fentanyls.

References

Bate, Roger. 2012. Phake: The Deadly World of Substandard and Falsified Medicines. Washington, DC: AEI Press.

--. 2018a. "A Field Study of the Opioid Market: Authenticity and Price from Pharmacy to Street." AEI Economics Working Paper Scries, October 9. http://www.aci.org/publication/a-field-study-of-the-opioid-market-authcnticity-and-price-from-pharmacy-to-street/.

--. 2018b. "New Data on Effective Opioid Drug Prices for Actual Pain Patients in Philadelphia--and What It May Mean." AEIdcas, October 9. http://www.aci.org/publication/new-data-on-effective-opioid-drug-prices-for-actual-pain-patients-in-philadelphia-and-what-it-may-mean/.

CDC (Centers for Disease Control and Prevention). National Vital Statistics System. 2018. "Data Brief 294. Drug Overdose Deaths in the United States, 1999-2016." https://www.cdc.gov/nchs/data/databriefs/db294_table.pdf.

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Hoskins, Ryan. 2018. "What Canada Can Learn from Tiny Estonia's Huge Fentanyl Problem." Globe and Mail. May 16. https://www.thcglobcandmail.com/ncws/national/cstonias-cautionary-fcntanyl-talc-fbr-canada/articlc30512811/.

Knierim, Paul E. 2018. "Tackling Fentanyl: The China Connection." US Department of Justice. September 6. https://www.dea.gov/sites/default/files/2018-09/DEA%20Testmony%20-%20China%20and%20Fentanyl%20HFAC_0.pdf.

Marquardt, Kathy A., R. Steven Tharratt, and Nabil A. Musallam. 1995. "Fentanyl Remaining in a Transdermal System Following Three Days of Continuous Use." Annals of Pharmacotherapy 29, no. 10 (October): 969-71.

Marsh, Sarah and Lily Kuo. 2018. "Fentanyl for Sale to UK Users Through Chinese Websites." Guardian. August 27. https://www.theguardian.com/society/2018/aug/27/fcntanyl-for-salc-to-uk-users-through-chincse-websites.

McLaughlin, Kathleen. 2017. "Underground Labs in China Are Devising Potent New Opiates Faster Than Authorities Can Respond." Science. March 29. https://www.sciencemag.org/news/2017/03/underground-labs-china-are-devising-potent-new-opiates-faster-authorities-can-respond.

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Parry, Hannah. 2016. "Watch Out Spring Breakers! Fake Xanax Pill Which Is 50 Times Stronger Than Heroin Kills Nine in Florida." DailyMail.com. March 22. https://www.dailymail.co.uk/news/article-3505025/Watch-spring-breakers-Fake-Xanax-pill-50-timcs-strongcr-hcroin-kills-9-Florida.html.

State of New Mexico. 2018. https://nmlegis.gov/Sessions/18%20Regula17final/HM056.pdf.

Szalavitz, Maia. 2018. "You Can't Overdose on Fentanyl by Touching It." March 21. Tonic. https://tonie.vice.com/en_us/article/8xk4jk/touching-fcntanyl-absorbcd-through-skin.

Whelan, Aubrey. 2018. "How Fentanyl, the Deadly Synthetic Opioid, Took over Pennsylvania." Inquirer. October 24. http://www2.philly.com/philly/health/fentanyl-synthetie-opioid-drug-overdoses-philadelphia-pennsylvania-20181024.html.

White House. 2018. "President Donald J. Tramp's Initiative to Stop Opioid Abuse and Reduce Drag Supply and Demand." March 19. https://www.whitehouse.gov/briefings-statements/president-donald-j-trumps-initiative-stop-opioid-abuse-reduce-drug-supply-demand/.

Arthur C. Brooks, President; Michael R. Strain, Director of Economic Policy Studies; Stan Veuger, Editor, AEI Economic Perspectives

By Roger Bate

About the Author

Roger Bate is an economist who researches international health policy, with a particular focus on tropical disease and substandard and counterfeit medicines. He also writes on general development policy in Asia and Africa.
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Title Annotation:ECONOMIC PERSPECTIVES
Author:Bate, Roger
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Geographic Code:1USA
Date:Dec 1, 2018
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