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Synthetic Opioids – Fentanyl and its Analogues: The Unexpected Killer

Fentanyl chemical structure model

On April 21, 2016, many of us were stunned by the news of the death of rock legend Prince. Nearly 2 years later, authorities in Carver County, Minn. announced that no charges would be filed against anyone in connection with Prince’s death. Reviewing the Medical Examiner’s report, it was stated that “The decedent self-administered fentanyl”. What is fentanyl and why has it found its way into our lives and our news cycles? More importantly – what are we doing, and what could we be doing to prevent this from happening again? Equally important, what are we doing that makes this a more common cause of death, albeit inadvertently?

To understand this part of the opioid crisis, it’s important to know why Fentanyl was created and a little bit more about it. Fentanyl was first synthesized in 1959 by a Belgian chemist according to the US Drug Enforcement Agency (The DEA). It was introduced in the United States in the mid 1960s as an intravenous analgesic drug, Sublimaze. Other formulations of pharmaceutical (legal) fentanyl were developed to provide opioid pain management including a transdermal patch, flavored lollipop, sublingual tab and a nasal spray.

Fentanyl was considered a major step forward in pain treatment because it was synthetic and was 50-100 times as powerful as morphine, and yet also much shorter acting. Fentanyl is also 30-50 times as powerful as heroin. In addition to its increased potency, this drug has the potential to be absorbed into skin, injected or inhaled. It presents a very real risk to its users, their families, their friends and first responders (EMT, police, police canines, etc.). There is enough risk that the DEA has produced guidelines and videos highlighting the risk. A dose of just 2mg of fentanyl (for a non-opioid user) is usually fatal. That’s the equivalent of only a few grains of salt. This means innocent bystanders can overdose accidentally by being exposed to the powder in their environment. Time to treatment here is vital, which is what we're focused on at Medigram. Through technology and medicine (e.g., Naloxone, i.e. Trade name Narcan), we can begin to lower the deaths from opioid overdoses.

Figure 1-Fatal Dose of Fentanyl

Fatal dose of Fentanyl size relative to a penny

Over the next years, fentanyl was slightly altered to create analogues (drugs based off of fentanyl but molecularly different). There are many known analogues that are present today (and many more being created). Some of the analogues include carfentanil – which is nearly 100 times as potent as fentanyl. It’s typical use is the sedation / tranquilization of large animals such as elephants. Yes – drug users may be using an opiate engineered to tranquilize an elephant.

Tango & Cash Stamped Glassine "Branded" Fentanyl

In my first post, I discussed how in many places heroin was distributed in little glassine envelopes that had stamps on them to help identify where it came from – a ‘street brand’ if you will. I mentioned one that was particularly bad for overdoses was stamped “Tango and Cash”. In 1991, this was the first known instance of domestically produced illicit fentanyl in the United States. This heroin was found to contain approximately 12 percent fentanyl and was responsible for an estimated 126 overdose deaths. The fentanyl was produced illegally in two laboratories in Wichita, Kansas. In the mid 2000s, there was another peak in fentanyl-related deaths from fentanyl laced heroin. This was traced to a laboratory in Toluca, Mexico.

Beginning in 2013, the DEA began noting an alarming number of deaths related to opioids throughout the US. These were often the result of illicit opioids, such as counterfeit pharmaceutical products containing fentanyl. In 2016, Prince obtained some pills that he likely believed were Vicodin but was actually counterfeit pills containing fentanyl (according to the Minnesota prosecutor). Those pills killed him.

Why would drug dealers go from using heroin to fentanyl? There are a number of reasons. Primarily – profit. Secondarily, there is the ease of getting fentanyl. One single kilogram of fentanyl can provide nearly 500,000 counterfeit pills. One kilogram may only cost a few thousand dollars, but the resultant pills can be sold for $10 - $20 / pill - $5 - $10 million street value. (Source DEA). Regrettably, the quality and consistency controls on our pharmaceutical pills don’t exist for illicit counterfeits. That means that the distribution of fentanyl is usually not consistent between individual pills resulting in inconsistent dosage and a tendency to create more overdoses. The United Nations Office on Drugs and Crime in their Global Smart Update provides a great summary of both the fentanyl analogues as well as the variable dose of active substance in illicit counterfeit pills. The URL is provided below.

Fast forward to today. Most of the fentanyl that enters the country comes from China and Mexico according to the DEA. Originally, fentanyl was classified as a schedule II drug. The DEA places drugs into 5 different schedules according to their medical use and the drug’s abuse or dependency potential. A listing of the drugs and their schedules are available as part of the Controlled Substance Act. I have found the DEA’s Drugs of Abuse: “A DEA Resource Guide” an excellent resource for understanding the schedules and the associated penalties. (Link below) Penalties for abuse of schedule I drugs are typically harsher than schedule II drugs because they do not have any currently accepted medical use. On February 6, 2018, the DEA made all fentanyl-related substances that are not already scheduled (listed in an existing schedule) as Schedule I. This is important because it will support stiffer penalties for anyone working with the new fentanyl analogues that previously were not scheduled (almost a loop hole) making it difficult to identify an unknown substance and prosecute accordingly. This move should, in turn, reduce the supply. However, we regrettably have the economic principle of supply and demand.

Demand is now being met by the creation of new fentanyl analogues, but also analogues of other ‘new’ synthetic drugs. For example, in November 2016, a new drug known as U-47700 was scheduled by the DEA as a schedule I drug (it was already responsible for 46 confirmed fatalities). In the past few weeks, a new analogue has appeared on cybermarkets on the dark web. It’s cost – about USD $6,500 / kg.

Why is it that Prince and others end up with counterfeit pills? Why is it that people end up going from prescription opioids to seeking illicit ones? When weighing the pain of an injury or disease versus the relief of an opioid – especially when factoring in the impact of withdrawal – many are drawn to look for alternative sources when the prescription runs out and their doctors either won’t or can’t prescribe more. As we know, if there is a demand, there will be a supply. If the two are mismatched – the cost of the supply could be much higher – but there will be people to pay it – enough to consume the available demand. We must not lose focus on how to reduce the demand for opioids. Reducing the supply is simply going to drive prices up, reduce availability and drive individuals to new or multiple drugs. A recent study from the Nation Drug Early Warning System (NDEWS) recently announced the results of a study in New Hampshire showing a sharp increase in overdose deaths in 2016. Equally as troubling, 20% of the toxicology tests showed 10 or more drugs with the average number of drugs in each decedent’s blood was 6.2. This “polydrug” complexity is important as it makes the identification of the drug causing death more difficult and makes detox and treatment much more difficult. In many ways – the more complex we make the supply chain; the more ingenuity is demanded of the drug suppliers and the more difficult it becomes to stop.

With the dramatic use of, and potency of, illicit synthetic opioids, our immediate focus must be on ensuring we have the capabilities to recognize and treat overdoses. Next week, we’ll focus on Naloxone - the drug that Surgeon General VADM Jerome Adams issued an advisory about earlier this month - “knowing how to use naloxone and keeping it within reach can save a life”.

In these blogs, I want to provide you with some additional media that will help you better understand the problem. Today’s video was actually curated by Zach – the recovering heroin addict I introduced last week. It is exceptionally personal to me as I lived for many years in Calgary, Canada where this video was filmed. It’s currently received about 6 million views on YouTube. It’s appropriately entitled Fentanyl: The Drug Deadlier than Heroin.

A second video (not solely focused on fentanyl) exceptionally well produced by the Cincinnati Enquirer looks at the opioid epidemic over one week locally in Ohio. 180 overdoses and 18 deaths. Take the time to watch this one. In one of the hardest hit states, there is a level of ‘normal’ with the heroin crisis there. We simply can’t think of this as ‘normal’. It’s not. It’s a problem that we’ve created and it’s ours to solve.

By: Dean Shold VP, Technology at Medigram

Dean Shold is the VP of Technology for Medigram. Before his current role, Dean was the VP of Infrastructure and Chief Technology Officer for Stanford Health Care, and was previously the VP of Global Data Operations for Zephyr Health. With a degree in computing science and a passion for social good, real time data analysis and mobile computing, he brings a unique background and perspective to the healthcare industry. At Medigram, Dean drives enterprise customer complete solution development, implementation, support, and customer success. At Stanford Health Care, he led a global team of 180+ personnel at 24x7 support to 50+ locations including multiple hospitals. He managed the technology and support budgets and built and reorganized teams to drive performance and reliability. He built a command center based on FEMA's (Federal Emergency Management Agency Guidelines) and oversaw data center performance and builds.

Dean also has deep passion for practically addressing the opioid crisis. His interests are in the scientific and the social sides of the opioid crisis bridging the addict with the researcher and the lawmaker. He is fascinated by how the worlds of legal and illegal opioids intertwine and how our societal biases impact treatment and recovery. In his work, he brings a vision of how Health IT can be leveraged to better understand and address the crisis. This includes examining the following key dimensions in addition to Health IT such as fentanyl, naloxone, harm reduction, detox, treatment and recovery.

Outside of the office, Dean also co-founded a non-profit organization to create novel ways to donate to charities. Dean is an instrument rated pilot and avid music lover. He and his wife, Pauline recharge by exploring harm-reduction organizations, the arts, craft beer and music scenes.

Links to check out:

United States Drug Enforcement Agency – Fentanyl Drug Information

United Nations Office on Drugs and Crime – Global Smart Update – Fentanyl and its analogues – 50 years on

Prince Investigation – Carver County Sherriff

(** NOTE – this report contains many files with very graphic images that may be disturbing)

United States Drug Enforcement Agency – Drug Scheduling

United States Drug Enforcement Agency – Drugs of Abuse: A DEA Resource Guide – 2017 Edition

United States Drug Enforcement Administration Diversion Control Division – Title 21 Code of Federal Regulations – Part 1308 – Schedules of Controlled Substances

United States Drug Enforcement Administration Diversion Control Division – Rules – 2018 – Temporary Placement of Fentanyl-Related Substances in Schedule I.

eDarkTrends: Monitoring cryptomarkets to identify emerging trends of illicit synthetic opioids use

National Drug Early Warning System – HotSpot Report – New Hampshire 2016

YouTube VICE video – Fentanyl: The Drug Deadlier than Heroin

Cincinnati Enquirer: Video: 180 ODs, 18 deaths, 1 week; how the heroin crisis is normal now

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