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Fentanyl Analogs and Pre-Hospital Agitation

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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.
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