trending in the emergency department: fentanyl analogs ......frontiers in psychiatry...
TRANSCRIPT
PATRICK AARONSON PHARM.D., DABAT CLINICAL PHARMACIST - EMERGENCY MEDICINE
UNIVERSITY OF FLORIDA AND SHANDS – JACKSONVILLE
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
Trending in the Emergency Department: Fentanyl Analogs and Pre-hospital agitation.