Fentanyl Analogs and Pre-Hospital Agitation

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

PATRICK AARONSON PHARM.D., DABAT CLINICAL PHARMACIST - EMERGENCY MEDICINE UNIVERSITY OF FLORIDA AND SHANDS – JACKSONVILLE [email protected] 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

Year Cases Deaths Year Cases

National Florida

2015 1402 47 2017 69

2014 1418 5 2016 83 Clinical Toxicology 2016;54(10): 924-1109 Clinical Toxicology 2015;53(10): 962-1146 Clinical Toxicology 2014;52(14): 1032-1283 2013 1486 12 2015 83 Annals of Emergency Medicine 2014;64(6):637-639 MMWR Morb Mortal Wkly Rep. 2013;62:703-704 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 • Fentanyl Analogs 546 • Furanylfentanyl (137)

• Synthetic Cannabinoids 477 • FUB-AMB (260)

• Cathinones 121 • N-Ethylpentylone (61)

Emerging Threat Report Mid-Year 2107 Fentanyl Exhibits in NFLIS

12x Increase 68% Increase

741% Increase

DEA-DCT-DIB-021-16 July 2016 Emerging Threat Report: DEA Drug Seizures Mid-year 2017

Fentanyl Analogs 160 137 140

120

100

80 68 60

40 18 20 10 13 14 13 2 2 3 5 0

Emerging Threat Report Mid-Year 2107 4-anilino-N-phenethylpiperidine (4-ANPP)

Psychiatry 2017 110(8):1-14 swgdrug.org/Monographs/4ANPP.pdf Designer Fentanyl Analogs Carfentanyl 1974 10,000 x

α-methyl 1978 2016 50x 2015 Acryloyl 3-methyl 100 x 1978,1988 Furanyl Cyclopentyl* 7,000 x 2012 4-methoxybutyryl Ocfentanil* Tetrahydrofuranyl* 1990

Acetyl 4-chloroisobutyryl* 80 x 4-fluoroisobutryryl butyryl 7x 4-fluorobutyryl * 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 Miosis Analgesia Headache, Relaxation dizziness

Nausea, Constipation CNS Respiratory Vomiting depression depression

Comatose Apnea Respiratory arrest

Least Common Acute Muscle Pulmonary Death rigidity – Edema, acute impair chest lung injury, wall Alveolar damage

Drug Alcohol Depend (2016) 171:107–16 Pediatrics (2015) 135:e740–3 Anal Chem 1981;53(12):1379A-1386A Treatment: Naloxone dosing

20 mg

J. Med Tox 2016;12:276-281 9/25 Ann Emerg Med 1983;12(7):438-445 Am J Dis Child 1980;134(2)156-158. Anesth Analg 1973;52(3):447-453 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

Aggression

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

KETAMINE?

Objectives: - Efficacy / Safety data for ketamine and undifferentiated agitation

- Develop algorithm for a post EMS ketamine dissociated patient

Drug Alcohol Rev. 2015 Apr 13 J Emerg Med. 2012;43:897–905 Midazolam

Ketamine

Haloperidol Bring on the Blow Dart!

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 Mechanism of Ketamine Receptors ~ Dose Effects Nicotinic Muscarinic Bronchospasm, DUMBELLS GABA > 2 mg/kg IV Sedation

> 6 mg /kg IM σ – receptor Lethargy , Coma MAOI Reuptake IH IH 5HT reuptake Agitation, Serotonin syndrome IH Da reuptake Dystonic, Dyskenesia IH NE reuptake HTN, Tachycardia NMDA Dissociation 0.7 - 1 mg/kg IV Hallucination (auditory) Receptor 3 mg/kg IM Lack of response to external Increasing Drug Concentrations DrugIncreasing Antagonist stimuli Recreational 0.2 – 0.5 mg/kg Cognition and memory Analgesia 0.1 - 0.3 mg/kg 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?

Route IV IM Clinical Onset 1 min 5 min Duration of dissociation 5 – 10 min 20 – 30 min • 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%) Ann Emerg Med 2011; 57(5): 449-461 Ketalar (ketamine hydrochloride) – Recovery agitation (1.4%) package insert. Ketamine. Micromedex® Healthcare – Hypersalivation (rare) 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

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

Academic Emergency Medicine. 2010; 17:604-611 Respiratory Depression and Ketamine – Coingestions

Respiratory Ketamine Depression 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) • Laryngospasm (0.3%) • When to intubate? • Bag-valve-mask • Refractory suctioning • Topical Laryngeal and anticholinergic lidocaine – Glycopyrrolate 0.2-0.4 mg IV – Atropine 0.5 mg IV (crosses blood brain barrier)

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

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

PATRICK AARONSON PHARM.D., DABAT CLINICAL PHARMACIST - EMERGENCY MEDICINE UNIVERSITY OF FLORIDA AND SHANDS – JACKSONVILLE [email protected]