Opioid-Involved Fatal Overdoses and the Role of Higher Dosage Strength Opioid Products: What We Do and Don’t Know

Bruce A. Goldberger, Ph.D. Division of Forensic Medicine Department of Pathology, Immunology and Lab Medicine University of Florida College of Medicine

1 What is there that is not poison? All things are poison and nothing is without poison. Solely the dose determines that a thing is not a poison. – Paracelsus (1493-1541)

A poison in a small dose is a medicine, and a medicine in a large dose is a poison. – Alfred Swaine Taylor (1859)

2 3 4 5 Medicolegal Death Investigation – Drugs in Decedents

− Volatiles − Over-the-Counter Drugs − Prescription Drugs − Illicit Drugs

6 Opioids Benzodiazepines • Buprenorphine • Alprazolam • Codeine • Clonazepam • Fentanyl • Diazepam • Hydrocodone • Lorazepam • Temazepam • Hydromorphone • Methadone Stimulants • Morphine • Amphetamines • Oxycodone • Cocaine • Oxymorphone • Tapentadol • Tramadol

7 Illicit Drugs and NPS

− Cannabis, cocaine, heroin, methamphetamine and phencyclidine − New psychoactive substances (NPS) including aminoindanes; synthetic cannabinoids; synthetic cathinones; phenethylamines; piperazines; plant- based substances; tryptamines; other substances

8 Synthetic Opioids FENTANYL ANALOGS OTHER SYNTHETIC OPIOIDS Acetylfentanyl AH-7921 Acrylfentanyl MT-45 4-ANPP U-47700 Butyrylfentanyl U-49900 Carfentanil U-50488 ortho-Fluorofentanyl para-Fluorobutyryl fentanyl para-Fluorofentanyl Furanylfentanyl Isobutyrylfentanyl Methoxyacetylfentanyl 4-Methoxybutyrylfentanyl 4-Methylphenethylacetylfentanyl 3-Methylfentanyl Beta-hydroxythiofentanyl Valerylfentanyl 9 Polysubstance Use

− Fatal intoxication is common amongst prescription and illicit drug users − Number of drugs ingested is directly related to incidence of fatal overdose − Fatal overdoses include accidental and intentional overdose

10 Common Opioid Drug-Drug Combinations

− Opioids + Alcohol − Opioids + Benzodiazepines − Fentanyl/Fentanyl Analog + Cocaine − Fentanyl/Fentanyl Analog + Methamphetamine

11 Toxicological Considerations

− Predominant drug effect • depressant and stimulant − Combined drug effect • additive and synergistic − Frequency of drug administration • acute and chronic (tolerance) − Use of an antagonist

12 Polysubstance Use Among Drug- Caused Deaths in Florida (2017)

In Combination with Drug Deaths Most Common Other Drugs (excluding metabolite) Cocaine 2012 88.2% Fentanyl Fentanyl 1743 92.8% Cocaine Fentanyl Analogs 1588 91.6% Cocaine Morphine 1285 97.8% Cocaine Heroin 944 99.0% Cocaine Alprazolam 791 97.7% Cocaine Oxycodone 610 95.2% Alprazolam Methamphetamine 464 95.7% Fentanyl Methadone 247 91.5% Alprazolam Hydrocodone 226 95.1% Alprazolam Diazepam 178 98.9% Morphine Tramadol 102 90.2% Alprazolam Carisoprodol 23 100.0% Oxycodone

Florida Drug-Related Outcomes Surveillance and Tracking System (FROST), 2019

13 − CNS depression with loss of consciousness − Respiratory depression and apnea − Miosis

14 The ME/C should correlate the constellation of signs and symptoms associated with the ingestion of a specific drug or drug class.

15 − Pulmonary edema and hyperemia − Bronchopneumonia − Cerebral edema − Congestion in liver and other organs − Retention of urine − Other pathology including cardiomyopathy and coronary artery disease

16 − Potency of drug and consideration of drug- drug interaction(s) − Significance of autopsy and toxicological findings − Interaction of natural disease and drugs − Consideration of MDI findings

17 MDI Utilization of the PDMP

— Establish prescription drug use history — Compare PDMP data with decedent’s medication inventory from scene — Evaluate evidence of drug use – with and without a prescription — Identify health care providers from whom the decedent's medical history can be obtained — Assess likelihood for tolerance to psychoactive drugs including benzodiazepines and opioids — Establish the role of drugs in a drug intoxication death — Identify drug treatment programs, if these data are available in the jurisdiction

Adapted from Uniform Standards and Case Definitions for Classifying Opioid-Related Deaths: Recommendations by a SAMHSA Consensus Panel – Goldberger et al., J Addict Dis. 2013 Jul; 32(3): 231–243. 18 Fentanyl-Caused Deaths and Fentanyl Rx in Florida

80 40

70 35 Thousands 60 30

50 25

40 20

Deaths,No. 30 15 Prescriptions, No. Prescriptions,

20 10

10 5

0 0 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Fentanyl (Death) Fentanyl (Rx) 19 Surveillance Opportunities: Time

160 450 PDMP Implementation 140 400 Thousands 350 120

300 100 250 80 200 Deaths, No. Deaths, 60 150 No. Prescriptions,

40 100

20 50

0 0 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 Alprazolam (Deaths) Oxycodone (Deaths) Alprazolam (Rx) Oxycodone Long Acting (Rx) Oxycodone Short Acting (Rx)

20 Unadjusted death rates for drug overdose by benzodiazepine prescription history and daily opioid dose.

Tae Woo Park et al. BMJ 2015;350:bmj.h2698

21 ©2015 by British Medical Journal Publishing Group BMJ 2018;362:k3207 23 MMWR / November 4, 2011 / Vol. 60 / No. 43 In conclusion, we found that a higher daily dose of opioids is associated with large relative and absolute increases in opioid-related mortality, and that daily doses of 200 mg or more of morphine (or equivalent) are associated with a particularly high risk. Our findings have important implications, largely because most opioid- related deaths were avoidable and occurred in young people. We believe physicians should carefully assess the appropriateness of long-term use of opioids to treat chronic, noncancer-related pain, particularly at high doses.

24 Arch Intern Med. 2011;171(7):686-691 Figure 4 Incidence rates and incidence rate ratios for overdose deaths involving opioid analgesics, by average daily ...

25 Figure 5 Incidence rate ratios for overdose deaths involving opioid analgesics, by benzodiazepine prescription status. ...

26 27