FLAKKA : The Pharmacology, Pathophysiology, and Presentation of the Excited-Delirious Patient

1. FLAKKA : The Pharmacology, Pathophysiology, and Presentation of the Excited-Delirious Patient Rich Lammers, DO and Kristin Dimond, PharmD, BCPS

2. Objectives • Discuss the history of Flakka and cultural evolution • Define the pharmacology of Flakka • Recognize signs and symptoms of Flakka ingestion • Outline treatment for life-threatening ingestion sequelae • Describe risk to pregnant population

3. FLAKKA • Chemical Name: Alpha pyrrolidinopentiophenone (𝞪-PVP) • Has no legitimate medical use • Chemically similar to amphetamines, cocaine, MDMA • A synthetic cathinone (stimulant) www.google.com/flakka Kaizaki, Tanaka, Numazawa. New recreational drug 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (alpha-PVP) activates central nervous system via dopaminergic neuron. The Journal of Toxicological Sciences. Vol. 39, No.1, 1-6, 2014.

4. History of FLAKKA • 𝞪-PVP (though not called that) patented in several US and European patents between 1963-1967 as CNS stimulant and pressor • Was never marketed as having therapeutic potential • 2006-Meltzer et al. began studying for possible cocaine addiction treatment • This study showed the NET/DAT blocking effects • World Health Organization data indicates ingestion may be occuring inadvertently when purchasing items online sold as ‘ecstasy’ -https://www.who.int/medicines/access/controlled-substances/5.3_Alpha-PVP_CRev.pdf accessed Aug 13, 2019 -Glennon RA, Young R. Neurobiology of 3,4-methylenedioxypyrovalerone (MDPV) and α-pyrrolidinovalerophenone (α-PVP). Brain Res Bull. 2016;126(Pt 1):111-126. -Castellanos D, Menendez B, Logan BK, Mohr ALA, Ayer D, et al. (2018) “Flakka” Intoxication: What have We Learned? J Drug Abuse Vol.4 No.1:4

5. History of FLAKKA • Europe and America both report increased seizures of Flakka in ~2011 • 2015 WHO Critical Review Report listed 130 deaths (in Europe) from 𝞪-PVP • Broward County, Florida experiences flakka “outbreak” 2011-2015 • 1872 emergency room visits from July-December 2015 https://www.who.int/medicines/access/controlled-substances/5.3_Alpha-PVP_CRev.pdf accessed Aug 13, 2019 Glennon RA, Young R. Neurobiology of 3,4-methylenedioxypyrovalerone (MDPV) and α-pyrrolidinovalerophenone (α-PVP). Brain Res Bull. 2016;126(Pt 1):111-126. Castellanos D, Menendez B, Logan BK, Mohr ALA, Ayer D, et al. (2018) “Flakka” Intoxication: What have We Learned? J Drug Abuse Vol.4 No.1:4

6. Current Rates • US DEA states >20,000 emergency visits in the US in 2011 • often reported as “bath salts” • 80 deaths in Florida attributable to FLAKKA between 9/14 and 12/15 • Florida Emergency visits 2014/15 • mean age 34 • under 25 approximately 15% Palamar JJ, Rutherford C, Keyes KM. "Flakka" use among high school seniors in the United States. Drug Alcohol Depend. 2019;196:86-90.

7. Current rates • No current epidemiologic data on use patterns among adolescents, however this is an age of concern • “Monitoring the Future” study (representative, self-reporting study of seniors in high school) approximate 1% of American students have used in the past year • Associated with using 4 or more drugs in the past year • Associated with having lower socioeconomic status, not residing with parents, or parents with lower education • Likely an UNDERESTIMATE of adolescent use (ingestion/usage may not be known) • common adulterants, thought to be ‘ecstacy’ Palamar JJ, Rutherford C, Keyes KM. "Flakka" use among high school seniors in the United States. Drug Alcohol Depend. 2019;196:86-90.

8. Review Question #1 True or False Current rates of usage are likely inaccurate due to the products being sold as “ecstacy” and under other names. Answer: True

9. Pharmacokinetics/Dynamics • A norepinephrine & dopamine reuptake inhibitor • “Feel good” side effects → can go to extremes • May be sniffed, snorted, taken orally, rectal administration, smoked, or made into a solution and injected • Effects occur within 30-34 minutes of administration • Peak at 1.5 hours • Total “desirable” effects last 6-8 hours • Undesirable effects may last days • Highly lipophilic with a high BBB penetration/transition • Up to 20% of users will have negative effects - https://www.drugabuse.gov/publications/drugfacts/synthetic-cathinones-bath-salts accessed April 29, 2019 - https://www.dea.gov/factsheets/flakka-alpha-pvp accessed April 29, 2019 - Katselou, Maria & Papoutsis, Ioannis & Nikolaou, Panagiota & Spiliopoulou, Chara & Athanaselis, Sotiris. (2015). α-PVP (“flakka”): a new synthetic cathinone invades the drug arena. Forensic Toxicology. 34. 10.1007/s11419-015-0298-1. -https://www.jems.com/articles/print/volume-40/issue-7/features/treatment-considerations-for-patients-using-so-called-legal-recreational-drugs.year=2014.html accessed April 29,2019

10. Daniel J, Owen A. Trends in Substance Use Across the Nation and South Dakota. S D Med. 2016;No:13-16.

11. Street Names Gravel Bliss Cloud Nine Lunar Wave Vanilla Sky White Lightning Meow Meow Ocean Burst Pure Ivory Purple Wave Red Dove Snow Leopard Star Dust White Dove White Knight https://www.google.com/url?sa=i&source=images&cd=&ved=2ahUKEwivrI6bwc7jAhUQV80KHXXqBV8QjRx6BAgBEAQ&url=https%3A%2F%2Fwww.rehabcommunity.org%2Fwhat-is-flakka-its-short-term-and-long-term-effects%2F&psig=AOvVaw3P_Y27iO-_k-pY-leZJNCx&ust=1564090458462272 https://www.drugabuse.gov/publications/drugfacts/synthetic-cathinones-bath-salts accessed April 29, 2019

12. Availability • Predominantly manufactured in China, India, and Pakistan where it is legal • available online for $3-5/dose • Legal for retail sale and can be purchased in smoke shops, head shops, convenience stores, adult book stores, gas stations, and on Internet sites • white or brown powder and are • sold in small plastic or foil packages labeled "not for human consumption" • In order to circumvent the Controlled Substance Analog Enforcement Act they are labeled: "bath salts," "plant food," "jewelry cleaner," or "phone screen cleaner." • Known to be for sale locally and in the surrounding area • Use can be addictive - https://www.drugabuse.gov/publications/drugfacts/synthetic-cathinones-bath-salts accessed April 29, 2019. -https://www.dea.gov/factsheets/flakka-alpha-pvp accessed April 29, 2019

13. Signs/Symptoms of Ingestion/Overdose • Rapid heartbeat; hypertension; hyperthermia; prolonged dilation of the pupil of the eye teeth grinding; sweating; headaches; palpitations; seizures -Kaizaki, Tanaka, Numazawa. New recreational drug 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (alpha-PVP) activates central nervous system via dopaminergic neuron. The Journal of Toxicological Sciences. Vol. 39, No.1, 1-6, 2014. -https://www.drugabuse.gov/publications/drugfacts/synthetic-cathinones-bath-salts accessed April 29, 2019 -Katselou, Maria & Papoutsis, Ioannis & Nikolaou, Panagiota & Spiliopoulou, Chara & Athanaselis, Sotiris. (2015). α-PVP (“flakka”): a new synthetic cathinone invades the drug arena. Forensic Toxicology. 34. 10.1007/s11419-015-0298-1.

14. Review Question #2 Patients with ingestion of 𝞪-PVP will be expected to have which of the following side effects?

15. Local Experience Typical Presentation: • EMS call: “40’s male, altered, agitated, hypertensive, tachy, breathing fast. ETA 5 min.” • Patient is agitated, grinding teeth, moving around in the bed. • Patient says “I gotta go, it’s my birthday and I just want to be with my girlfriend! Unhook me and get me out of this hospital!”

16. Typical Presentation Physical Exam: • Vitals: Temp 99.0, BP 180/95, HR 110, Respirations 25, Pulse Ox 100% • HEENT: No head trauma appreciated, “crazy eyes,” pupils slightly dilated. • Cardiovascular: tachycardic, no abnormal heart sounds. • Pulmonary: Tachypnic. Breath sounds present throughout. • Abdomen is soft, no tenderness

17. Typical Presentation Physical Exam - Continued • Neuro Exam: • Alert and Oriented x3 (person, place, time) • Pupils dilated, EOMI. Crazy eyes, tracking from object to object. • No focal weakness, no tremors or twitching. • Can re-direct him. Answers questions one-at-a-time, but loses focus between questions.

18. Typical Presentation Assessment\Plan\Treatment: • 40’s male, agitated and slightly altered. Likely stimulant use • Continued redirecting, patient allows IV placement of cardiac monitor • Ativan 2mg IV push • Normal saline 1L IV bolus ED Course: • With treatment, patient improves. Vitals normalize. After 3 hours, patient markedly more appropriate. Full re-examination. Girlfriend contacted, discharged home.

19. Assessment Question #3 What should the top priority in the previous case be? Keeping the patient and staff free from harm

20. Emergency Management/Treatment Excited delirium syndrome (ExDS) • Potentially life-threatening, is in a psychotic and extremely agitated state • Psychomotor agitation and often with violent behavior • Unable to process rational thoughts or to focus his/her attention • NOT a mere psychiatric behavioral condition but is an extreme condition with neurologic, metabolic and cardiovascular features • Extreme agitation, confusion and hallucinations, erratic behavior, diaphoresis, tachycardia, dilated pupils, hyperthermia, hyper-aggression, unexplained strength and endurance and making unintelligible sounds

21. Emergency Management/Treatment 2 Life-threatening sequelae: • Malignant Hyperthermia • Hyponatremia

22. Emergency Management Malignant Hyperthermia • Oxygenation • Dantrolene • per facility protocol • Cool patient • cool fluids, body cavity lavage, ice packs • Hyperkalemia *treat if present* • calcium, insulin, bicarb, glucose, diuretics, dialysis (if needed) • Dysrhythmias • follow ACLS protocols

23. Emergency Management Hyponatremia • Treatment is oral water restriction • Be aware that hyponatremia may be a side effect of the sympathomimetic toxidrome • Seizures, hypertension, tachycardia and altered level of consciousness, tachydysrhythmias, excited delirium, renal/hepatic failure, hyperthermia, cerebral edema and acute psychosis may occur, diaphoresis, and overhydration with water following vasopressin secretion can lead to hyponatremia • Restrict oral water intake where hyponatremia is suspected

24. Emergency Management/Treatment • No antidote • Treatment of overdose is the same as that of amphetamines • Hyperthermic patients--aggressive cooling (benzodiazepines may help with shivering) • Supportive care with benzodiazepines • Cardiac support with low-dose norepinephrine • may be indicated to normalize blood pressure and heart rate • Excited Delirium Syndrome • Treatment of Malignant Hyperthermia, if indicated • Substance abuse/treatment placement, if indicated 5.https://www.jems.com/articles/print/volume-40/issue-7/features/treatment-considerations-for-patients-using-so-called-legal-recreational-drugs.year=2014.html accessed April 29,2019

25. Review Question #4 Treatment of the Excited Delirium Syndrome patient may include • Benzodiazepines • Aggressive cooling and Dantrolene • Cardiac support • All of the above

26. Laboratory Testing • Diagnostic labs available • Tested in the Bath Salts test at ARUP Laboratories, test code is 2011411 • Blood for acute exposure (test 2011411) • Urine test is preferred for long-term exposure (test 2008651) • 7-10 day turn around • LabCorps has a Synthetic Designer Drug Urine test, test code 701110 • 9-14 day turn around • cannabinoids, methcathinone, cathinone, mephedrone, MDPV, methylone, and salvinorin -Prosser JM, Nelson LS. The toxicology of bath salts: A review of synthetic cathinones. J Med Toxicol. 2012;8(1):33–42 -Palamar JJ, Rutherford C, Keyes KM. "Flakka" use among high school seniors in the United States. Drug Alcohol Depend. 2019;196:86-90.

27. Risk in Pregnancy • Risk of premature rupture of membranes, placental abruption, placenta previa, decreased infant and infant head circumference (with other stimulant abuse)-little data/studies in particular on 𝞪-PVP • Hypertension risk puts the fetus at risk, should be avoided in pregnancy -Prosser JM, Nelson LS. The toxicology of bath salts: A review of synthetic cathinones. J Med Toxicol. 2012;8(1):33–42 -Winstock AR, Mitcheson L. New recreational drugs and the primary care approach to patients who use them. BMJ. 2012;344:e288.

28. Review Question #5 True or False 𝞪-PVP presents a health risk to both the pregnant female and the fetus?

29. Dramatic Presentation • 0200 hrs, Police called to scene by neighbors regarding a woman screaming at a tree • On arrival, police find a 30’s female, partially clothed, screaming and fighting with a tree • Upon approach, police are charged by woman, taser deployed effectively, restrained • Continued agitation, 3 male police restraining, but difficult • EMS dispatched for extremely agitated and altered patient, assistance with sedation and transfer to trauma center for evaluation

30. Dramatic Presentation • 0300: On arrival ED, 3 police still restraining patient • No IV established • 2mg IM Ativan administered, 3mg intranasal Versed without change • Paramedic with redness and swelling to face, punched by patient • Police with multiple scratches, one with bite to arm

31. Dramatic Presentation Physical Exam: • Vitals: Not obtainable due to thrashing...she is warm, tachycardic, tachypnic, bounding pulses in all distal extremities • HEENT: No trauma to head, pupils are markedly dilated, eyes darting around • Cardiovascular: Tachy (150’s-160’s), bounding pulses throughout. • Pulmonary: CTAB, tachypneic • Abdomen: Soft • Skin: injection marks to bilateral arms, various ages

32. Dramatic Presentation Physical Exam, Continued: • Neuro: Awake, but not oriented. Unable to interact or redirect patient • No strength deficits….one staff per limb, one laying across pelvis, another attempting to hold head (6 staff in total) • 2 other staff attempting IV placement

33. Dramatic Presentation Assessment\Plan\Treatment • 30 female, acute agitated-delirium • Differential Diagnoses: Stimulant overdose, multidrug overdose, Thyrotoxicosis • Plan: Keep staff and patient safe • Sedation patient, obtain vitals, obtain labs and imaging

34. Dramatic Presentation ED Course: • 2 mg Ativan IM, 10 mg Haldol IM without effect. IV established after 15 minutes • IV: Ketamine IV (2 doses of 200 mg, 400 mg total 5-10 minutes apart) Some improvement with this, but still requiring restraint. 1 L NS bolus • Vitals now obtainable: • Temp 104, HR 202, BP 217\101, Resp 34, Pulse Ox 100%

35. Dramatic Presentation ED Course: • Patient continues to need retraining, decision to intubate for both patient and staff safety. • Intubated using 10 mg Etomidate, 200 mg succinylcholine. • Labs: • CBC: WBC 17,000 • CMP: Na 129, K 6.8, glucose 324 • Gas: pH normal\low normal, PCO2 low • Lactate 17 • CK\Myoglobin: High • TSH\Free T3\4 normal • Imaging: CT head normal, Chest X-RAY: lungs normal, left shoulder dislocation

36. Dramatic Presentation ED\Hospital Course: • 3 min after intubation, agitated and requiring restraints again • High dose propofol drip, rocuronium • Aggressive IVFs, shoulder reduction, hyperkalemia treatment, ICU admission. • Within 12 hours, normalization of labs and vitals • Extubated, asking “What happened and where am I?”

37. Recap • Severely agitated, everyone at risk • Safety • self • staff • patient • Aggressive treatment of agitation, especially in a restrained patient. This led to rhabdomyolysis, dislocated shoulder, injured first responders.

38. References • Kaizaki, Tanaka, Numazawa. New recreational drug 1-phenyl-2-(1-pyrrolidinyl)-1-pentanone (alpha-PVP) activates central nervous system via dopaminergic neuron. The Journal of Toxicological Sciences. Vol. 39, No.1, 1-6, 2014. • https://www.drugabuse.gov/publications/drugfacts/synthetic-cathinones-bath-salts accessed April 29, 2019 • https://www.dea.gov/factsheets/flakka-alpha-pvp accessed April 29, 2019 • Katselou, Maria & Papoutsis, Ioannis & Nikolaou, Panagiota & Spiliopoulou, Chara & Athanaselis, Sotiris. (2015). α-PVP (“flakka”): a new synthetic cathinone invades the drug arena. Forensic Toxicology. 34. 10.1007/s11419-015-0298-1. • https://www.jems.com/articles/print/volume-40/issue-7/features/treatment-considerations-for-patients-using-so-called-legal-recreational-drugs.year=2014.html accessed April 29,2019 • Prosser JM, Nelson LS. The toxicology of bath salts: A review of synthetic cathinones. J Med Toxicol. 2012;8(1):33–42 • Winstock AR, Mitcheson L. New recreational drugs and the primary care approach to patients who use them. BMJ. 2012;344:e288. • Klega AE, Tickal Keebauch J, Stimulant and Designer Drug Use: Primary Care Management. American Family Physician, Vol 92, No. 2, accessed April 29 • https://www.labcorp.com/test-menu/38896/synthetic-designer-drug-profile accessed July 24, 2019 • Takeuchi A, Ahern TL, Henderson SO. Excited delirium. West J Emerg Med. 2011;12(1):77–83. • https://www.who.int/medicines/access/controlled-substances/5.3_Alpha-PVP_CRev.pdf accessed Aug 13, 2019 • Glennon RA, Young R. Neurobiology of 3,4-methylenedioxypyrovalerone (MDPV) and α-pyrrolidinovalerophenone (α-PVP). Brain Res Bull. 2016;126(Pt 1):111-126. • Castellanos D, Menendez B, Logan BK, Mohr ALA, Ayer D, et al. (2018) “Flakka” Intoxication: What have We Learned? J Drug Abuse Vol.4 No.1:4 • Palamar JJ, Rutherford C, Keyes KM. "Flakka" use among high school seniors in the United States. Drug Alcohol Depend. 2019;196:86-90. • Daniel J, Owen A. Trends in Substance Use Across the Nation and South Dakota. S D Med. 2016;No:13-16.

39. Questions?