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Home , Acetylfentanyl, Alfentanil, Butyrfentanyl, Remifentanil, Sufentanil

Dinosaurs, Elephants and – Oh, My! Updates on novel synthetic substances

Dominique Delagnes, Chief Operating Officer averhealth

1 Fentanyl used in

2 What is It?

• Fentanyl is an “” – acts like an in the body but chemically not an opiate • Used since 1963 as an adjunct to surgery • 50 – 100x as potent as • Half-life is 3 – 12 hr • Oral doses: 100 – 1600 mg for breakthrough pain for cancer patients • Patches: 25 – 100 mg/hr for 72 hrs, surgical breakthrough pain • Injections: 2 mg/ml for epidural infusion or 25 – 100 mg for IV infusion • Nasal spray: 100 – 400 mg/spray, up to 800 mg/day

3 Fentanyl Blood Levels

Method Dose Peak Blood Levels Delayed Levels

Oral 400 mg 1-2 ng/ml 1.8 ng/ml after 1 hour Patch 25 – 100 mg/hr 0.3 – 3.8 ng/ml -- Spray 400 mg 1.6 ng/ml 0.8 ng/ml after 1.5 hours IV 2 mg/kg 11 ng/ml 1 ngml after 1 hour IV (surgery) 75 mg/kg 50 ng/ml --

• Loss of consciousness above 34 ng/ml (serum). • Up to 6% excreted as unchanged drug, most of rest norfentanyl; other metabolites also.

4 Fentanyl Toxicity

• Severe respiratory depression, muscle rigidity, seizures, hypotension, coma. • Fatal Overdoses: Blood 3 – 28 ng/ml (average 8.3) Urine 5 – 93 ng/ml (average 28)

• Beginning around 2005, begin to see fentanyl-laced . Why? - cheaper to produce than heroin - increases potency, gives more of a kick to heroin - stretches supplies out • Originally attributed to one lab in Mexico, but it caught on elsewhere. • People died but - Marketing!!!

5 Increased Deaths

• Prince died at the age of 57. • He was addicted to and thought he was buying Vicodin. • The Vicodin was laced with Fentanyl and the dose of Fentanyl was lethal.

Street Names China Girl China White Goodfella Opioid Death Increases 2015-2016

7 Fentanyl Involvement in Opioid Deaths

8 Increases

9 March 5, 2018 Issue

10 Typical Case – Michigan

Delivery Of Controlled Substance Causing Death

• Subject uses heroin, collapses. Found dead some time later. - Morphine 18 ng/ml - No 6-MAM - Fentanyl 12 ng/ml – in potentially fatal range. - Alprazolam 97 ng/ml - 19 ng/ml - THC, THC-COOH, caffeine, cotinine

• Alprazolam, morphine not likely fatal in isolation. • Fentanyl in toxic/fatal range. • All together, fatal OD. Death is listed as mixed-drug overdose

11 Manufacturing “Progress”

• All major drug classes now have synthetic versions • Majority manufactured in China • Purchased over the internet • Arrive by plane – FedEx facility in Memphis • Usually see new drugs in Europe first –about six months later, US • Western governments complain to the Chinese government (sometimes at the UN) – they crack down on the offending drug – clandestine chemists change formulas – cycle begins again…

12 How do we identify drugs being consumed?

• Pills, powders, liquids seized by law enforcement • Structure identified by crime lab analytical chemists: LC-MS/MS, GC/MS, FTIR • Internet sources such as Erowid, Bluelight • Emergency room admissions provide initial toxicology data • After standards made – animal studies for pharmacokinetic data • Very few controlled human studies generally done

13 How do we identify drugs being consumed?

Who is using? Waste-water analysis and public urinal studies

14 Analog Treadmill

1. Authorities crack down on existing drug 2. Clandestine chemists tweak the structure – now considered legal! 3. New drug found on street by LE in pill, liquid or powder form 4. ODs, OWIs, ER admissions 5. News stories, public attention 6. Vendors make reference standards 7. Labs develop tests 8. Research done, scientific data published 9. Legislature controls 10. Back to Step 2

Yeah, but Steps 6-7…how do we figure out what these things even are?

15 Testing Challenges

• Initially no reference standards to use for test development

• Metabolism unknown: - Compounds may be extensively metabolized. If reference standard is of parent drug and drug is completely converted to metabolites then you might miss it. - Which metabolites? Do some closely related drugs metabolize to the same thing? If we find a metabolite, how do we know which drug it came from?

• Doses usually not known – may be extremely low

• Half-life not usually known – how long can it be detected?

• What do screening panels detect, and at what efficiency?

• What transitions (instrument settings) do we use for LC/MS/MS?

16 Fentanyl Analogs

- Alphamethylfentanyl - 4-fluorobutyrlfentanyl - - - - Furanylethylfentanyl - - - Benzocarfentanil - Octafentanil - Benzodioxole fentanyl - Remifentanyl - Beta-hydroxyfentanyl - - Beta-methylfentanyl - Tetrahydrofuranfentanyl - - Thienylfentanyl - - - Cyclopentanylfentanyl -

17 Structures

Fentanyl Carfentanil

Acetylfentanyl

Alpha-Methylfentanyl

Burtyfentanyl

18 Carfentanil

• Trade name Wildnil. Used since 1975 for deer, elk, moose and other large animals. • All pharmacokinetic data are in goats or elands. • Half-life (in goats) is 3 – 20 hours. • 60 mg/kg dose gives peak serum 8 ng/ml (in goats). • 169 mg/kg dose gives a peak plasma level of 13 ng/ml (in elands). • Adverse effects: nausea, vomiting, dizziness, drowsiness, bradycardia, respiratory depression, muscle rigidity, coma and death (in people).

Elands are really big.

19 Would 10 mg Carfentanil Sedate a T-Rex?

Jurassic Park 2: The Lost World

20 Or a Pachycephalosaurus?

21 Carfentanil Use in Humans

• Suspected in the Moscow theater crisis in October, 2002. • 40 to 50 armed Chechen terrorists seized the theater, about 850 people held hostage. • Russian Federal Security Service forces pumped an unnamed chemical into the building’s ventilation system, presumably to sedate occupants and allow a rescue operation. • Aerosol exposure – dose cannot be controlled • Approximately 130 people died due to gas exposure. • One survivor had 0.1 ng/ml urinary norcarfentanil 5 days post-exposure • Carfentanil and found on clothing of another.

22 And Now We Have Carfentail and

Opioid toxidrome: the toxic effects were those of carfentanil, not cocaine.

Grenoble Alpes, France; reported at SOFT/TIAFT, Boca Raton, Jan 2018

23 Alpha MethylFentanyl

• Methylfentanyl, China White • First seen in CA in late 1979. • No pharmacokinetic data • Similar side effects to other • Fatalities: blood 2 – 11 ng/ml (average 7) urine 5 – 151 ng/ml (average 47) • Possibly 10x potency of fentanyl (400 – 6000x morphine)

24 AcetylFentanyl

• Increased use since 2013 • No pharmacokinetic data in humans. • No antemortem studies or live subject data. • ~ 15x potency of morphine • 52 confirmed fatalities involving acetylfentanyl from 2013-2015 (DEA). • Toxic effects – respiratory depression, seizures, coma

Another fatal day in Tuscola Co…

Clonazepam 8.9 ng/ml 7-aminoclonazepam 130 ng/ml Cocaine 46 ng/ml Benzoylecgonine 540 ng/ml Paroxetine 170 ng/ml 6-monoacetylmorphine (free) 1.1 ng/ml Morphine (free) 17 ng/ml Fentanyl 4.7 ng/ml Acetylfentanyl 3.6 ng/ml Positive

25 Alfentanil, Sufentanil, Remifentanil

Pharmaceutical compounds developed by Glaxo and as surgical agents.

Alfentanil (Alfenta), used since 1980 • Roughly similar to morphine in potency • Faster-acting, shorter duration than fentanyl (half-life 1-2 hours)

Sufentanil (Sufenta), used since 1976 • 5 – 10 times as potent as fentanyl, 500 – 800 times as potent as morphine. • Doses usually low (below 30 mg/kg), given by IV or epidural (patch form in Europe) • Two ODs reported (by IV): 1 and 78 ng/ml in blood

Remifentanil (Ultiva), used since 1996 • Very fast-acting – half life 6 – 16 minutes • Available only in injectable form • High incidence of respiratory depression and apnea • Thought to be used in the Moscow theater crisis

26 Other Fentanyls

Butyrfentanyl – seen since 2012 • Doses 0.5 – 3.0 mg, • Effects last 1 – 4 hours • Somnolence, muscle rigidity, respriratory depression, seizures and coma • Blood levels and metabolism in man unknown

Furanylfentanyl – seen since 2014 • Doses 0.15 – 10 mg • Effects last 1 – 3 hours • Toxicity same as butyrfentanyl • Blood levels and metabolism in man unknown

Effects expected to be similar to fentanyl itself. Some degree of respiratory depression should occur - potentially life-threatening.

27 Other Synthetic Opioids: Escaped Research Chemicals

MT-45 Dainippon Pharmaceutical Co, Japan, 1970’s

W-15 University of Alberta , Canada, 1980’s. Series W-1 to W-32 W-18

AH-7921 Allen and Hanburys, UK (now part of Glaxo), 1970’s)

U-49900 Upjohn, MI, (now part of Pfizer), 1970’s. U-50488 U-51754 U-47700 Isomer of AH-7921 U-51754

• Research chemicals developed during drug research. • Never made it out of the lab into clinical trials. • Expected to have some opiate-like activity, but little data in humans

28 Krokodil

Desomorphine

• Roche Pharmaceuticals, developed in 1932 • 8-10x more potent than morphine. • Not used clinically since 1981.

• Clandestine production from , similar to from pseudoephedrine. When this happens, the drug becomes contaminated with various chemicals, which causes damage to skin, liver, bone and kidneys through infections and gangrene.

• Krokodil – Russian for “crocodile”; may refer to damaged skin of users. • “Flesh-eating” or “zombie” drug due to infections from contaminants

29 Synthetic Opioid Structures

Desomorphine Morphine Alpha-Methylfentanyl

U-47700 MT-45 W-18

30 The Latest

• Typically pharmaceutical compounds not for sale in the US. Frequently sold in Europe or Asia and may be purchased over the internet. Black market rather than clandestine chemists – easier to identify.

• Around since 2008, increasing in use since about 2015, although not as many as other synthetics.

- Etizolam - Phenazepam - Halazepam - Meclonazepam

• Effects are similar to those of other benzodiazepines (Xanax, Valium, Ativan). • Pharmacokinetic data typically available.

31 Synthetic

• Since around 2000. First ones called “Spice” or “K2”. • 14 different chemical families known, based on chemical structures • 168 compounds and counting • Newest: the FUBINACA/CHMINACA/PINACA series • Naming convention would be a whole separate lecture

32 Effects of Synthetic Cannabinoids

• Higher affinity for receptors than itself: - More potent - Longer-lasting - Prolonged effects

• Some effects cannabis-like, some more typical of stimulants or hallucinogens, including agitation, seizures, hypertension, violent behavior

• Physical Effects: extremely high (stroke, cardiac arrests reported), dilated pupils, rapid , kidney failure

33 Synthetic Stimulants (Synthetic Cathinones)

• Sold as “bath salts” • Increased use from around 2010 • Several chemical classes (phenethylamines, tryptamines, cathinones, piperazines)

- Methylenedioxypyrovalerone (MDPV) - Flakka (alpha-PVP) – (“zombie drug”) - Methylone - Pentylone - Benzylpiperazine (BZP) - TFMPP - - 2-DPMP (Ivory Wave) - 3-methylmethcathinone (3MMC) - 4-methylethcathinone (4MEC) - Buphedrone - Ethylcathinone - Dimethyltryptamine (DMT) - Alphamethytryptamine (AMT)

34 Synthetic Stimulants

• Meant to be Methamphetamine or MDMA (Ecstasy) –like.

• Stimulant Effects:

- Increased alertness - - Agitations - Hallucinations - Tachycardia - Hyperthermia - Insomnia - Seizures/Tremors

35 Bath Salts Timeline

Justin Brower, SOFT, Boca Raton Jan 2018

36 Conclusion

• Suite of drugs used ever-changing

• Pharmacology of most designer drugs not well known

• Many testing challenges

• Laboratories need to continue to update testing panels to cover the synthetic drugs being manufactured in clandestine laboratories

37 Questions?

Dominique Delagnes Chief Operating Officer [email protected] 804-285-0413

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