PATRICK AARONSON PHARM.D., DABAT CLINICAL PHARMACIST - EMERGENCY MEDICINE

UNIVERSITY OF FLORIDA AND SHANDS – JACKSONVILLE

AARONSON@POISON.UFL.EDU

Trending in the Emergency Department: Fentanyl Analogs and Pre-hospital agitation

Goals and Objectives

Pharmacist:

– Recognize the most recent drug abuse crisis - Fentanyl Analogs

– Recognize the challenges of naloxone dosing for Fentanyl analogs

– Evaluate the risks and benefits of pre-hospital Ketamine for undifferentiated agitation

Goals and Objectives

Technician:

– Discuss the Fentanyl analog crisis trajectories

– Recognize the pharmacological effects of Ketamine for undifferentiated agitation

Disclosure

I do not have a vested interest in or affiliation with any corporate organization offering financial support or grant monies for this continuing education activity, or any affiliation with an organization whose philosophy could potentially bias my presentation.

DEA: 2013: 700 Fentanyl deaths nationally

CDC.gov/drugoverdose/pdf/pbss/PBSS-Report-072017.pdf

Mortality Weekly Report (MMWR), 64(50–51), 378–1382

statnews.com/2016/09/29/fentanyl-heroin-photo-fatal-doses/

dea.gov/divisions/hq/2016/hq092216_attach.pdf

Poison Center / Emergency Department Data

• Lag time between experimentation and academic outlet

• Poison center data less useful (disguised substances, familiar toxidrome)

• Nonfatal fentanyl cases attributed to heroin

• ELISA reports Fentanyl unless GC/MS was utilized to detect analogs

Clinical Toxicology 2016;54(10): 924-1109

Clinical Toxicology 2015;53(10): 962-1146

Clinical Toxicology 2014;52(14): 1032-1283

Annals of Emergency Medicine 2014;64(6):637-639

MMWR Morb Mortal Wkly Rep. 2013;62:703-704

Year Cases Deaths

National

2015 1402 47

2014 1418 5

2013 1486 12

Year Cases

Florida

2017 69

2016 83

2015 83

Fentanyl Crisis: Hidden Toll

• ↑ Cost for Emergency Room Visits

• ↑ Cost for Medical examiner bills

– Toxicology Costs (GC/MS): Pennsylvania

• Overcrowded court rooms

• Overcrowded Jails / Prisons

– Mercer county, West Virginia

• ↑ Foster care (parents with opioid addiction)

– Columbia, Ohio

msn.com/en-us/money/markets/how-the-opioid-crisis-is-blowing-a-hole-in-small-town-americas-finances/ar-AAscLb5

Fentanyl Crisis: Trajectories

• Early recreational use of drugs

• Intergenerational use of opioids

• Opioid prescriptions for pain management

• Drug Trafficker profitability

– Less to smuggle

– Pills for broader access

National Drug Early Warning System: New Hampshire Hotspot study September 2017

Enormous Profit Potential

• Fentanyl Powder (1,000 g) = $2,000.00

• ~ 1 mg fentanyl/pill = 1 million pills

• $10-20/pill = $10-20 million dollars

DEA-DCT-DIB-021-16 July 2016

dea.gov/divisions/hq/2016/hq092216_attach.pdf

Counterfeit Pills

• March 2016: 9 deaths from counterfeit alprazolam (Pinellas County FL)

• March 2016: 500 pills from counterfeit oxycodone 30 mg but really U-47700 (recently scheduled)

• April 2016: 52 deaths from counterfeit hydrocodone/acetaminophen (Sacramento, Ca)

• June 27, 2017: 5 deaths, 30 hospitalized Cleveland, GA. Counterfeit oxycodone/acetaminophen 10/325 mg

ajc.com/news/crime--law/gbi-two-fentanyl-analoguesdea.gov/divisions/hq/2016/hq092216_attach.pdf

Fentanyl Analogs: Global Supply

DEA-DCT-DIB-021-16 July 2016

Precursor: 4-ANPP

4-anilino-N-phenethylpiperidine

DEA-DCT-DIB-021-16 July 2016

Pill Press

DEA-DCT-DIB-021-16 July 2016

Dark Web: Drug Culture Growth

• Not registered vs surface web

– Encrypted Networks (TOR browser)

– Grams “Google of Darknet”

• Anonymous communication

– Cryptocurrencies: (i.e. Bitcoin, Litecoin, Zerocoin)

• Deep web segment: Vendors

– Silk Road, Alphabay, Hansa, Dream market, Outlay market,

python market, apple market. Hum Psychopharmacol Clin Exp. 2017; 32:2573

Annals of Emergency Medicine 2014;64(6):637-639

Emerging Threat Report: DEA Drug Seizures Mid-year 2017

546

• Fentanyl Analogs

• Furanylfentanyl (137)

477

• Synthetic Cannabinoids

• FUB-AMB (260)

121

• Cathinones

• N-Ethylpentylone (61)

Emerging Threat Report Mid-Year 2107

Fentanyl Exhibits in NFLIS

68%

Increase

741% Increase

12x Increase

DEA-DCT-DIB-021-16 July 2016

Emerging Threat Report: DEA Drug Seizures Mid-year 2017

2 2 3 510 13 14 18

13

68

137

0

20

40

60

80

100

120

140

160

Fentanyl Analogs

Emerging Threat Report Mid-Year 2107

4-anilino-N-phenethylpiperidine (4-ANPP)

Psychiatry 2017 110(8):1-14

swgdrug.org/Monographs/4ANPP.pdf

Carfentanyl 1974

10,000 x

4-chloroisobutyryl*

4-fluoroisobutryryl

4-fluorobutyryl

4-methoxybutyryl

butyryl 7x

Cyclopentyl*

α-methyl 1978 50x

3-methyl 1978,1988

7,000 x

Ocfentanil* 1990

Acryloyl 100 x

Acetyl 80 x

Tetrahydrofuranyl*

Furanyl

Designer Fentanyl Analogs

2012

2015

2016

* Analog not scheduled

Fentanyl Analogs: Potency

Fentanyl Therapeutic levels: 0.3 – 3.9 ng/ml

Fentanyl Postmortem levels: 9 – 30 ng/ml

Potency: Drug Morphine Heroin Fentanyl

Fentanyl 100 x 50 x

Carfentanil 10,000 x 4,000 x 100 x

3-α-methylfentanyl 7,000 x

Acetylfentanyl 80 x 15 x

Butrylfentanyl 7 x

Acryloylfentanyl 100 x

dea.gov/druginfo/fentanyl-faq.shtml

Frontiers in Psychiatry 2017;8:article110

Journal of Analytical Toxicology, 27(7), 499–504

Journal of Analytical Toxicology, 24(7), 627–634

Fentanyl Analogs: Pharmacokinetics

Drug Onset Duration

Morphine IV 1 min 2 - 4 h

Heroin IV 5 min 4 - 5 h

Fentanyl IV 1 min 30 - 60 min

Fentanyl IN 7 min 1 - 2 h

Acetylfentanyl oral 1 - 10min 1 - 2 h

Acryloylfentanyl IN 1 - 5 min 10 - 30 min

Butyrylfentanyl oral 15 - 30 min 3 - 4 h

4-fluorobutyrylfentanyl IN 1 min 30 - 60 min

Furanylfentanyl oral 1 - 10 min 1 - 3 h

U-47700 oral 15 min 1 - 2 h

Naloxone IV 2 min 45 – 90 min

dea.gov/druginfo/fentanyl-faq.shtml

Frontiers in Psychiatry 2017;8:article110

Ann Emerg Med 1983;12:438-45

Sublimaze (fentanyl citrate injection) package insert 2016

Carfentanil

• Veterinary Use for large animals

• Special DEA license for procurement

• 10,000 x morphine, 4,000 x heroin, 100 x fentanyl

• 2002 hostage crisis in Moscow: 120 deaths

• 42 y/o splashed 1.5 mg in mouth

– Symptoms in 2 min

– Naltrexone 100 mg IV = 200 mg of Naloxone

Am J Emerg Med (2010) 28(4):530–2

zoopharm. net/products.php. Accessed Seot 28, 2017

Ann Emerg Med 2003;41(5):700-5

Carfentanil

• 10/6/17 23 y/o M had 55 grams in home

– Sarasota County

• 10 mg could kill 500 people

• 1 g could kill 50,000 people

• 55 g could kill 2.7 million people

heraldtribune.com/news/20171006/sarasota-man-gets-12-years-for-selling-Carfentanil

heraldtribune.com/news/20170511/sarasota-men-accused-of-selling-carfentanil-10000-times-stronger-than-morphine

Int J Addict. 1969;4:1–24

Gov. Rick Scott: “Opioid Epidemic”

• State of emergency: 27 million in federal money

• Controlled Substance Act legislation (HB 477) 7/2017

– Fentanyl Analogs

• More than 4 grams = 3 years prison

• More than 14 grams = 14 years prison

• More than 28 grams = 25 years in prison

news4jax.com/news/politics/florida-legislature/new-bill-would-close-loopholes-for-synthetic-drugs

news4jax.com/health/opioid-crisis/gov-rick-scott-poised-to-act-on-fentanyl-trafficking-bill

New Generation of Synthetic Opioids

• AH – 7921

• U – 47700: 7.5 x morphine

• MT – 45

Frontiers in Psychiatry 2017;8:article110

Forensic Toxicol (2013) 31(2):223–40

“Grey Death”

• Mixture: Fentanyl, Heroin, Carfentanil, U-47700

• Cement mix like powder

news4jax.com/health/gray-death-is-newest-street-drug-worrying-officials

Fentanyl Analog Clinical Effects

Most Common Euphoria Relaxation

Miosis Analgesia

Headache, dizziness

Nausea, Vomiting

Constipation CNS depression

Respiratory depression

Comatose Apnea

Respiratory arrest

Least Common Acute Muscle rigidity – impair chest wall

Pulmonary Edema, acute lung injury, Alveolar damage

Death

Drug Alcohol Depend (2016) 171:107–16

Pediatrics (2015) 135:e740–3 Anal Chem 1981;53(12):1379A-1386A

Treatment: Naloxone dosing

J. Med Tox 2016;12:276-281 Ann Emerg Med 1983;12(7):438-445 Am J Dis Child 1980;134(2)156-158. Anesth Analg 1973;52(3):447-453

9/25

20 mg

Fentanyl Analogs: Treatment

• 1st responders: dermal absorption unlikely

– Carfentanil: nitrile gloves, N95 respirator

• 20% ED physicians feel prepared

• Respiratory support

• Naloxone: “Mega doses” (up to 10 – 20 mg)?

– Repeat every 20 min, consider Drip

• Supportive care for acute withdrawal

Clin Tox 2017 Sept ahead of print

West J Emerg Med. 2013;14:467-470 J. Med Tox 2016;12:276-281

Fentanyl Analogs: Acute Withdrawal Effects after Naloxone

Pros Cons

Am J Emerg Med 2003;21(1):32-34 Oral Surg Oral Med Oral Pathol 1981;52(6):602-603

Aggression

Fentanyl Analogs: Assessment Question 23 y/o male comes to the ED with obtunded mental status, miotic pupils, and RR 8 (currently protecting his airway). EMS states the patient admits to heroin use prior transportation. Naloxone 0.4 mg was administered with no response. What is your recommendation?

A. Intubate

B. Naltrexone 380 mg IM x 1

C. Titrate naloxone up to 2 mg to avoid withdrawal

D. Titrate naloxone up to 10 – 20 mg

Objectives:

- Efficacy / Safety data for ketamine and undifferentiated agitation

- Develop algorithm for a post EMS ketamine dissociated patient

KETAMINE?

Prehospital agitation/aggression

Drug Alcohol Rev. 2015 Apr 13

J Emerg Med. 2012;43:897–905

Midazolam

Ketamine

Haloperidol

Ann of Emerg Med. 2016;67(5):588-590 Prehosp Disaster Med. 2015;30(5):491-495 Prehosp Emerg Care 2003;7:48-55 J Emerg Med 1998;16(4):567-73

Bring on the Blow Dart!

Receptors ~ Dose Effects

Nicotinic

Muscarinic Bronchospasm, DUMBELLS

GABA > 2 mg/kg IV > 6 mg /kg IM

Sedation

σ – receptor Lethargy , Coma

MAOI Reuptake IH

IH 5HT reuptake Agitation, Serotonin syndrome

IH Da reuptake Dystonic, Dyskenesia

IH NE reuptake HTN, Tachycardia

NMDA Receptor Antagonist

Dissociation 0.7 - 1 mg/kg IV 3 mg/kg IM

Hallucination (auditory) Lack of response to external stimuli

Recreational 0.2 – 0.5 mg/kg Cognition and memory

Analgesia 0.1 - 0.3 mg/kg

Mechanism of Ketamine In

crea

sin

g D

rug

Co

nce

ntr

atio

ns

Ann Emerg Med. 2011;57:449–461 Adapted: Goldfrank’s Toxicologic Emergencies, 9th ed. New York NY, McGraw-Hill, 2011 Emupdates.com

Ketamine for Agitation/Aggression?

• Side Effect profile: – Emergence Reactions (0 - 30%)

– Emesis (8.4%)

– Transient apnea or respiratory depression (0.8%)

• Likely to occur following rapid administration or high doses of ketamine

– Transient Laryngospasm (0.3%)

– Recovery agitation (1.4%)

– Hypersalivation (rare)

Route IV IM

Clinical Onset 1 min 5 min

Duration of dissociation 5 – 10 min 20 – 30 min

Ann Emerg Med 2011; 57(5): 449-461 Ketalar (ketamine hydrochloride) package insert. Ketamine. Micromedex® Healthcare Series [database online]. Accessed 10/07/17

I thought ketamine had preserved respiratory drive?

Ketamine (n = 47) Propofol (n = 50) p value

Dose 1 mg/kg 1 mg/kg

Subclinical Respiratory depression 63.8% 40% 0.019

Pulse Oximeter < 92% 12.7% 14%

ETCO2 change from 10 mmHg 44.7% 30%

Apnea / Hypoxia

Capnogram wave absent at anytime 23% 18%

Clinical interventions 40% 52% 0.253

Academic Emergency Medicine. 2010; 17:604-611

• Ketamine has a higher rate for subclinical respiratory depression • Ketamine and Propofol have the same rate of apnea / hypoxia

Respiratory Depression and Ketamine – Coingestions

Respiratory Depression

Ketamine

Emergency Medical Services: South Florida Miami – prehospital • Retrospective Screened Runsheets (n = 52)

• Ketamine 4 mg/kg then 2 – 2.5 mg/kg midazolam for emergency reaction

• Medication control 2 minutes

• Respiratory depression 6%

• Intubation rate (3.8%)

• Maintained sedation until hospital (~19 min)

Western J Emerg Med 2014;15(7):736-741

Emergency Medical Services: Adelaide, South Australia - prehospital

• Retrospective study of new protocol (n=22)

• Transportation of psychiatric patients (no intentional overdoses)

• Premedicated with benzodiazepine or antipsychotic or combination

• Ketamine 0.5 mg/kg then 1-2 mg/kg/hr infusion

• Intubated (9%)

• No emergence phenomenon

Emerg Med Australasia 2017;29:291-296

Emergency Medical Services: San Francisco, CA - prehospital • Prospective Observational Study (n = 24)

• Ketamine 0.8 mg/kg IV or 3 mg/kg IM

• Intubation rate (8.3%)

• Mean time to sedation was 5 min

Am J Emerg Med 2017;35:1000-1004

Emergency Medical Services: Duval County, FL - prehospital • Data Inquiry for 90 days (June – Sept 2017)

• n = 44 (19 substance abuse/ psychiatric)

• Ketamine 4 mg/kg IM

– Midazolam 2 – 5 mg IV if additional sedation needed

• Intubations: (4.5%)

Special thanks to Dr. Andrew Schmidt and Lt Rowley

Duval County EMS SOG April 18 2016

EMS Intubation rates post-ketamine seems comparable to Haloperidol / Benzos…… What about in the Emergency Department?

Emergency Medical Services: Minneapolis, MN – ED • n = 49

• 0% intubated prehospital

• 29% Intubated in the ED

– n = 14 intubated mean dose (6.16 mg/kg)

– n = 35 no intubation mean dose (4.9 mg/kg)

• p = 0.02

Am J Emerg Med 2015;33:76-79

Emergency Medical Services: Minneapolis, MN – ED • Reasons for intubation: airway protection (n=69), ongoing

violence (n=16), Provider comfort and clinical course

• Intubation was associated with:

– Late night presentation (11pm – 11am) OR 1.91

– Not associated with dose (< 5 vs > 5 mg/kg)

• IQR = 4.59 – 6.07 mg/kg?????

Ketamine (n = 135)

Dose 5.2 mg/ kg

Intubation Prehospital 2.96%

Intubation ED 63%

Prehospital and Disaster Medicine 2016;31(6): 593-602

Emergency Medical Services: Minneapolis, MN – ED

Ketamine (n = 64) Haloperidol (n = 82)

Dose 5 mg/ kg 10 mg

Adequate sedation 95% 65%

Time to sedation 5 min 17 min

Intubation Prehospital 0% 0%

Intubation ED 38% 4%

Complications 49% 5%

Hypersalivation 38% 0%

Emergence 10% 0%

Laryngospasm 5% 0%

Apnea 4.7% 0%

Clin Tox 2016:54(7): 556-562

Am J Emerg Med 2015;33:76-79

Ketamine IM: Intubation Takeaway

• Prehospital: 0 – 9%

• In hospital: 29 – 63%

• Comfort level with dissociated state

– Subjectively apply the GCS: “3K”?

– Objectively for airway

• Possible predictors

– Late night arrival (11p-7a)

– Acute ethanol intoxication

– Dose: 4 mg/kg vs 5 mg/kg

Prepare to intubate for rare complications • Hypersalivation (rare)

• When to intubate?

• Refractory suctioning and anticholinergic

– Glycopyrrolate 0.2-0.4 mg IV

– Atropine 0.5 mg IV (crosses blood brain barrier)

• Laryngospasm (0.3%)

• Bag-valve-mask

• Topical Laryngeal lidocaine

Ann Emerg Med 2011;57(5): 449-461 Ann Emerg Med. 2009;54:158-168

Ketamine Tolerance

Emergence

Phenomenon

Recovery Agitation

Recovery agitation (1.4%) / Emergence Phenomenon (0-30%)

• ↓ Excessive stimulation (anecdotal)

• Psychiatric antipsychotics

– Haloperidol 5-10 mg IM/IV

– Atypical antipsychotic (i.e. ziprasidone 10-20 mg IM

• Sympathomimetic benzodiazepines

– Midazolam 2-5 mg IM

– Lorazepam 2 mg IM/IV

Ann Emerg Med 2011;57(5): 449-461 Ann Emerg Med. 2011;57:109-114 Ann Emerg Med. 2000;36:579-588

What about Intracranial Pressure?

• Newer evidence (n = 953)

– No difference in ICP, ICU LOS, mortality

– Pressure increases are minimal with normal ventilation

– Ketamine has cerebral vasodilatory effects

• Structural barriers to cerebrospinal flow.

Ann Emerg Med 2015;65(1):43-51 Anesth Analg. 2005;101:524-534

Cardiovascular effects (rare) but…

• Indirect sympathomimetic effects

– Inhibits biogenic amine reuptake

• Direct negative inotropic properties

– Diminished myocardial contractility

• Bradycardia, hypotension, cardiac arrest possible

Saudi J Anaesth 2011;5:395-410 Pediatr Clin North Am 1994;41:1269-1292

Take home Points: Post Ketamine

• Telemetry (SpO2/ETCO2)

• Avoid intubating a dissociated patient

– Objective exam for apnea

– Co-ingestions

• Low threshold:

– Follow-up benzodiazepines / antipsychotics

– Follow-up Glycopyrrolate

Wrap-up

Haloperidol Ketamine

Onset 17 min 5 min

Sedation Prehospital 65% 95%

Redosing 20% 5%

Complications 5% 49%

Intubations 4% 39%

Clin Tox 2016;54(7):556-562 Ann Emerg Med. 2016;67:581-587 aviacionargentina.net megamagtest.blogspot.com/2014/03/j-16-fighter-bomber

Prehospital Ketamine: Assessment Question EMS transports a 23 y/o M and states he was given 4 mg/kg of ketamine due to being combative, violent, and uncooperative upon arrival. Patient is currently a Glasgow Coma Scale of 5. Patient is protecting his airway, pulse oximetry is 98% with an End-Tidal CO2 of 41 mmHg (normal range). What is your recommendation?

A. Intubate

B. Administer Haloperidol 5 mg IM

C. Symptomatic support with continued monitoring

D. Administer Glycopyrrolate 0.2 mg IV

Push-Dose Pressors

• EMCrit.org Podcast 205

• Key Articles – Bolus-Dose Vasopressors in the Emergency Department: First, Do No Harm;

Second, More Evidence Is Needed. Ann Emerg Med. 2017 Jul 26.

– Safety Considerations and Guideline-Based Safe Use Recommendations for "Bolus-Dose" Vasopressors in the Emergency Department. Ann Emerg Med. 2017 Jun 7

– The impact of push-dose phenylephrine use on subsequent preload expansion in the ED Am J Emerg Med 2016;(34(12):2419-2422

PATRICK AARONSON PHARM.D., DABAT CLINICAL PHARMACIST - EMERGENCY MEDICINE

UNIVERSITY OF FLORIDA AND SHANDS – JACKSONVILLE

AARONSON@POISON.UFL.EDU

Trending in the Emergency Department: Fentanyl Analogs and Pre-hospital agitation.