1. The Value of Early-Warning: Carfentanil Deaths in Europe
Helgi Danielsson
The EMCDDA recently conducted a joint investigation into carfentanil with Europol, which led to the request from the council for a formal risk-assessment, to take place in November.
24 October 2017
Lisbon Addictions

2. Source: Van Bever et al. (1976)
What is carfentanil?
A highly potent synthetic opioid, analogue of fentanyl
Developed by Paul Janssen and Co in the 70’s
Significantly higher potency vs. fentanyl and morphine.
Licenced veterinary medicine in the US; tranquilizing agent for the immobilisation of large animals.
Analgesic activity in rats (tail-flick assay)
ED50(mg/g)
Potency ratio
Morphine
3.21 1
Fentanyl
0.011
290
Carfentanil
10300
Source: Van Bever et al. (1976)
Fentanyl
Carfentanil
Carfentanil is a synthetic opioid of the fentanyl family. Potency can be measured in many ways, the table on the right indicates analgesic potency in rats.
It was developed by Janssen and co-workers in the 70’s and so unlike some of the recently detected fentanils, it is not a new analogue and it has been studied in some detail.
It is regarded as one of the most potent opioids known to man, and as an indication of this, we see here on the right results from an experiment with rats, where in terms of the measured analgesic effect, carfentanil was found to be around times more potent than morphine. This does not directly translate to an equally high potency in terms of respiratory depression; the main mechanism involved in cases of acute poisonings and death
It has found it’s way into veterinary medicine and zoological practices, as an animal tranquilizer and an anaesthetic agent.
The structure of carfentanil retains the fentanyl core, but with an addition of a carbomethoxy group on the piperidine ring, which is responsible for the increase in activity.

3. Potency & Associated Risks
How much pure drug to make 10,000 doses?
When talking about potency, we see here a rough estimate of how much pure substance is needed to make doses for different drugs; some better known drugs like cocaine and amphetamine and some NPS type substances. The amount for carfentanil, 0.1 grams, is an estimate from a test on a single person, where only 9 micrograms were found to be enough to elicit an effect.
So, even though this represents a ballpark figure, this has some serious implications in terms of potential risks.
First of all, we can imagine that such small amounts are easy to ship and traffic, and therefore difficult to intercept.
Also, as doses may be in the microgram range, drug concentrations are expected to be very low in biological samples, and could therefore go undetected, and I will discuss this in more detail a bit later on.

4. Health Risks
As with other fentanils, the most serious health risk from carfentanil use is life-threatening respiratory depression.
Has been sold and used as a ‘legal’ replacement for heroin and Rx opioids, and sold as, or in, heroin;
Difficulties in cutting and dosing properly
Unfamiliarity with the substance and its properties
High-risk opioid users may not be aware of using the substance
Fentanils (in general) sold as counterfeit medicines – benzodiazepines, Rx opioids or other analgesics;
Again, inadvertent ingestion; opioid naïvety (lack of tolerance) and a high risk of accidental poisoning
The most serious health risk associated with carfentanil use, is likely to be life-threatening respiratory depression.
Similar to other synthetic opioids, and fentanils in particular, carfentanil is known to be sold and used as a legal substitute for prescription opioids.
Refering back to the previous slide, the potency of carfentanil is likely to lead to difficulties in cutting the substance and dosing correctly. How easy can it be to consistently measure and mix doses in the microgram range?
- Unfamiliarity can lead to improper handling and accidental exposure. Even within the fentanil class of opioid, the properties of individual substances can vary considerably so the exact properties of new fentanils may not be understood.
- In cases where heroin has been cut with carfentanil, users may not be aware of what they are actually taking.

5. Health Risks - continued
Poly-drug use;
Additional and synergistic effects with other CNS-depressants
Other opioids, ethanol, benzodiazepines frequently detected in PM samples.
Using alone
Inability to call for help or administer naloxone in case of an overdose.
Increased risk of accidental exposure;
Law enforcement, emergency personnel, custodial, family members, postal workers and laboratory settings.
When using opioids, taking other CNS depressants will increase the risk of overdose and harms, and this is exactly what we have seen frequently in our post-mortem data.
From our investigations into fentanil related deaths, we see that these often occur in a private setting, where the deceased is found alone at home. Using alone leaves the person unable to call for help or administer the antidote, naloxone.
Due to the nature of the substance – both its high potency but also its ability to permeate the skin – there is an elevated risk of accidental exposed to the substance to, for example, first responders such as the police and emergency personnel, as well as postal workers, lab technicians and family members, to name a few.

6. Detections in Europe
First detection in Europe in 2012, in Latvia, where the substance has been frequently detected, usually in heroin.
To date: detections in 9 countries
Latvia & Lithuania
+ Finland & Estonia 2016
+ Belgium, Germany, Norway, Sweden & United Kingdom in 2017
Produced and shipped from China, Hong Kong
Confirmed exposure to carfentanil in at least 60 deaths in Europe since November 2016.
The first detection in Europe was in 2012, reported by Latvia, and it has since been regularly detected there in heroin samples.
Between 2012 and 2015, carfentanil detections were limited to Latvia and Lithuania, where it is frequently used to cut heroin. Subsequently, it was detected in the neighbouring countries Estonia and Finland in And in 2017, a further 5 countries detected the substance for the first time (Belgium, Germany, Norway, Sweden and the United Kingdom).
Detections have mostly been of small amounts of powders, at street level.
Like most NPS, carfentanil is known to be produced by chemical and pharmaceutical companies based in China, and shipped directly to Europe. The increase in availability of carfentanil can be seen as a consequence of how easy it has now become to order NPS online, directly from the manufacturer and delivered to your doorstep.
We see that the substance has been around since 2012, but there has been a large increase in its availability from around the end of 2016, and coupled with that, a simultaneous increase in deaths (at least 60 with confirmed exposure)
These have mostly been seizures at street level in powder form, with additional seizures of liquids. Seizures: Estonia, Germany, Finland, Latvia, Lithuania, Sweden, United Kingdom.
Collected samples: Belgium (apparent suicide), United Kingdom (Wedinos samples submitted as Fentanyl + mannitol mixtures) and Norway (death case)
Based on reports to the EMCDDA and Europol, the substance has been ordered from China and Hong Kong, with Russia mentioned as well as Germany and UK to a lesser extent. (Trafficking: information from Lithuania, United Kingdom and Sweden)

7. Confirmed deaths in Europe
First reported death:
Finland November 2016
Outbreak in the UK:
31 deaths (Feb-May 2017)
Many geographically linked
High-risk opioid users (heroin injectors)
Other cases:
Lithuania: Heroin injectors
Belgium: Apparent suicide
Norway: 15 year old psychonaut 16 31
Looking at the deaths that have been reported to the EMCDDA associated with carfentanil, we see that they all of the cases come from Northern-Europe.
We have little information on the deaths from Estonia, but are aware of it being mixed with heroin in the Baltic states, and our reports from Lithuania support this.
Belgium: a user, presumably aware of the strength of the substance, ordered carfentanil online and used it as a means of taking his own life.
Norway: young boy ordered the substance online, and was found dead by his computer. At the time of death, he was writing a user experience post on carfentanil in a drug users forum.
We see that the bulk of the deaths come from the UK, so we will take a closer look at those cases and the characteristics of the outbreak.

8. Epidemiology
The epidemiological curve certainly shows the evident outbreak in the UK, with all of the reported deaths taking place in a concentrated 4-month period.
What we notice that there is an abrupt decline from May to June, from 6 deaths in May to none reported since. We are aware of a few more possible cases that are still under investigation, with the dates unknown, but his sharp decrease is still quite telling.
We can add that, towards the end of April, the UK police raided the premises of a known supplier and distributor of carfentanil, and other fentanils. He had been selling his products online using the darknet, both within the UK and internationally. This investigation is still on-going.
There have not been any reported deaths since those that took pace in May.
There are 22 deaths, in purple and pink on the right, that also took place in 2017, but no exact date or month has been reported.

9. Raid on supplier in the UK
Epidemiology
Raid on supplier in the UK
To add to that, towards the end of April, the UK police raided the premises of a known supplier and distributor of carfentanil, and other fentanils. He had been selling his products online using the darknet, both within the UK and internationally. This investigation is still on-going.
Need to UPDATE with most recent confirmed cases and details:
16 total deaths from Lithuania (little details but 9 new cases are from the 2017 progress report, so some of them might be recent.
31 total deaths from UK – 2 new cases from Alere Forensics, both with heroin metabolites detected and drugs found at the scene, powder and foil, respectively.
21 have history of drug use (opiates mostly, heroin)

10. Case Study: UK deaths
Geographically linked: Yorkshire, Nottinghamshire and Lincolnshire
High risk opioid users (heroin injectors):
Heroin metabolites were identified in 81% of the deaths
Syringes and other paraphernalia found in a high number of cases
Many were known drug users to the police or other services.
Other substances detected:
Fentanyl – 19 cases (65%)
Fentanyl, butyrfentanyl and 4F-BF (or -iBF) - 10 cases (34%)
Other opioids, FU-F, alfentanil, diazepam, THC and other cannabinoids
Carfentanil PM blood concentrations: range pg/mL
Possibly underreported as sensitive techniques required. Routinely screened?
There is a strong geographic link between the cases, with most deaths taking place in Yorkshire (Hull, Bradford, Leeds), and in the neighbouring counties of Nottinghamshire and Lincolnshire, areas in the East of England and East-midlands.
Analyses of postmortem samples from the UK cases revealed that a large majority of the users had taken heroin. With the main metabolites, 6-MAM and morphine, identified in 25 of the deaths.
Syringes and other paraphenalia were found in many cases on, or near, the deceased and many were known to the police as problem drug users.
Additionally, in 19 cases fentanyl was also detected and in 10 cases, a quite specific combination of fentanils was identified. Fentanyl, butyrfentanyl, which is now internationally controlled, and 4F-butyrylfentanyl, or its isomer.
This same combination of substances strongly indicates a common source of the substance or product used.
It is somewhat unlike other previous outbreaks involving fentanils, as in the examples of acetyl-, acryloyl- and furanylfentanyl, the users were not typically heroin users, and injecting was less frequently reported. There, new dosage forms, such as nasal sprays played a big part and those substances were also sold openly on the surface web; something we have not seen to such an extent with carfentanil.
We see that the PM blood contrations were very low, down to the picograms per millilitre, which means these cases might be underreported as very sensitive techniques are required.

11. Other substances detected in PM blood
Case 10 had 8 opioids (methadone, tramadol and codeine), plus diazepam, EtOH
32% of the cases had 5 or more different opioids detected
68% of the cases had 1 or more benzodiazepine detected
45% of the cases had cocaine or metabolites detected
Difficulties in establishing the role of each substance in specific death cases.
What role did carfentanil play int he deaths – say if there were 8 potent opioids detected in the matrix.
Highn number of psychoactive substances detected with both additative and synergistic effects, most of which are CNS-depressants

12. Importance of Early Warning
Opioid overdoses are on the rise in Europe and in many other parts of the world.
Timely communication:
Understanding the risks associated with new substances.
Effective communication to and within the network to prevent additional harms.
Signals and trends:
Increase in availability of carfentanil resulted in a simultaneous increase in overdoses and deaths.
The importance Early-warning lies in the fact that outbreaks like the one seen in the UK, can take tak place in any country.
Quick exchange of information, in the form of first detections in countries and reporting of results from acute intoxications and deaths can help relevant parties to better prepared for these types of outbreaks.
Analytical and forensic services can be made aware of potential new substances that appear, and thus start looking for them specifically.

13. Summary
Carfentanil poses a high risk of fatal overdose Used to cut heroin. Likely ingested in some cases unknowingly by high-risk opioid users. Significant increase in availability from around the end of 2016, and a subsequent increase in deaths. Risk of outbreaks. High potency and small doses have implications for its detection; both in terms of trafficking and in biological samples. Importance of routinely screening for the substance, as it represents a serious threat to individual and public health.
Carfentanil poses a high risk of a fatal overdose.
It has been used to cut heroin, and we’ve seen the severe consequences this has had in the UK.
As soon as the availability increased, we saw an increase in deaths.
We’ve seen outbreaks with several fentanils previously and it has become easy to order substances straight from the manufacturer, so all that is really needed for this to happen is for a person to order a few grams and mix them irresponsibly into the drug supply.
Only small amounts are needed for multiple doses, so detection is inherently difficult.
As underreporting is likely, I would like to stress the importance of routinely screening for this substance, as it represents a serious threat to individual health.

14. Thank you!
@helgidanielsson;