Michigan Forensic Pathology Conference April 2018 The Analytical & Interpretive Challenges of Keeping Up with Fentanyl Analogs & Related New Opioids Barry K Logan PhD, F‐ABFT Executive Director, Center for Forensic Science Research and Education Chief Scientist, NMS Labs
The First Opioid Crisis… • The British East India Company promoted sales of opium into China. • By 1825 1 in 4 Chinese had an opium habit • China tried to stop British importation of opium, which led to 2 opium wars in 1839‐ 1842, and 1856‐1860.
The First Opioid Crisis… • In 1810, the Daoguang Emperor issued a decree: • Opium has a harm. Opium is a poison, undermining our good customs and morality. Its use is prohibited by law… • Recently the purchasers, eaters, and consumers of opium have become numerous… • If we confine our search for opium to the seaports, we fear the search will not be sufficiently thorough... • We should also order the general commandant of the police and police‐ censors at the five gates to prohibit opium and to search for it at all gates…
Forensic Toxicology Did Alcohol or Drugs, Cause or Contribute, to this Person’s Death or Intoxication?
Challenges for Forensic Toxicologists • Analysis: • Knowing what to test for • Access to the appropriate technology • Interpretation: • The significance of the presence of novel compounds in cases • Capacity: • Keeping up with the workload
Challenges for Forensic Toxicologists • Analysis: • Knowing what to test for • Access to the appropriate technology • Interpretation: • The significance of the presence of novel compounds in cases • Capacity: • Keeping up with the workload
Opioid Evolution • Morphine and the opium alkaloids. • Semisynthetic opioids synthesized 1914 ‐ 1920 • Meperidine, Alphaprodine synthesized in 1930’s • Anileridine 1940’s
Fentanyl • Structure of morphine elucidated in 1925 • SAR inspired by meperidine, led to Dextromoramide 1956, Piritramide then fentanyl (R4263) • Fentanyl invented in 1960 by Dr Paul Janssen
Fentanyl Analogs • More potent or longer acting analogs Alfentanil, Sufentanil, Carfentanil, synthesized by Paul Janssen in the mid 1970’s • Analgesic potencies in mouse models of 0.25 to 500 times that of fentanyl
Other μ Opioid Agonists • Opioid analgesic drugs developed at Upjohn in the 1970s. • Cyclohexyl‐N‐methylbenzamides • Mixed mu and kappa agonism • Derived from AH‐7921 • More potent than Morphine, less potent than fentanyl Right: U‐47700, U‐49900, methylenedioxy U‐47700, … U‐50488, U‐48753, U‐51754
Explosion in Prescription Opioids • 1980 Porte and Jick letter in NEJM • 1990’s Backlash to the undertreatment of pain • Availability of MS Contin and Oxycontin • Led to massive increase in painkiller prescribing • Peaking in 2011 at 219M prescriptions Porter J, Jick H. Addiction rare in patients treated with narcotics. N Engl J Med. 1980 Jan 10;302(2):123.
Explosion in Prescription Opioids • By 2014, the problem was apparent • Reduction in medical opioid prescribing led to users seeking heroin • 2014 Fentanyls emergence as a cheaper alternative • Proliferation and diversification through 2018 Time, Jun 2015
NFLIS Trend Data ‐ Fentanyl https://www.deadiversion.usdoj.gov/nflis/2016_annual_rpt.pdf
Our Latest Opioid Crisis • New York Times, June 5 th 2017 • Drug overdose deaths in 2016 most likely exceeded 59,000, the largest annual jump ever recorded in the United States. • Although the data is preliminary, the Times’s best estimate is that deaths rose 19 percent over the 52,404 recorded in 2015. And all evidence suggests the problem has continued to worsen in 2017. https://www.nytimes.com/interactive/2017/06/05/upshot/opioid-epidemic-drug-overdose-deaths-are-rising-faster-than- ever.html?mcubz=0&_r=0
Our Latest Opioid Crisis • New York Times, Sept 2 nd 2017 • Fentanyl Deaths in 2016: Up 540% in Three Years • Drug overdoses killed roughly 64,000 people in the United States in 2016. • Drug deaths involving fentanyl more than doubled from 2015 to 2016 • Synthetic opioids — primarily fentanyl and its analogues — continue to push the death count higher. https://www.nytimes.com/interactive/2017/09/02/upshot/fentanyl-drug-overdose-deaths.html
Fentanyl Analogs • Phenyl/anilinyl Propanamide Acetylfentanyl • • o‐Fluorofentanyl (Fentanyl) E • • p‐Fluorofentanyl F/Butyrylfentanyl D • • … F/Isobutyrylfentanyl • Valerylfentanyl • Tetrahydrofuranylfentanyl • Carfentanil C • 2/3‐Furanylfentanyl • Alfentanil • Acrylfentanyl • Sufentanil • Crotonylfentanyl B • Remifentanil • Methoxyacetylfentanyl • 3‐methylfentanyl • Cyclopropylfentanyl • α‐methylfentanyl • Tetramethylcyclopropylfentanyl • β‐hydroxyfentanyl A • Cyclopentylfentanyl • β‐hydroxy/Thiofentanyl • Cyclohexylfentanyl • Ethylfuranylfentanyl • … Phenylethyl piperidine
TACTICS Challenges – Knowing What to Test For • Limited real time data on seized drug trends. • No national repository for either morbidity or mortality data consolidation (toxicology or medical examiner). • No NPS Testing in ER admissions. • No standardized testing menu between forensic toxicology laboratories. • Significant inter‐laboratory gaps in scope for fentanyl analogs. • Highly variable turnaround times on fentanyl reporting.
TACTICS Knowing What to Test For • Seized drug casework • Toxicological Casework • Government Data/NFLIS • Electronic Databases and Subscriptions • Peer review literature monitoring • Conference proceedings • Collaborations with vendors • International conferences and networking • Drug user forums, chat rooms and events • Metabolomics Lab work
Opioids Testing Scope 2018 Opiates Morphine, codeine Semi-synthetics Heroin, oxycodone, oxymorphone, hydrocodone, hydromorphone Synthetics (meperidine, propoxyphene) methadone Fentanyl derivatives Fentanyl, Remifentanil, Sufentanil, Carfentanil, Alfentanil, and precursors Lofentanil, Ocfentanil, Acetylfentanyl, F/Butyrylfentanyl, F/Isobutyrylfentanyl, Valerylfentanyl, Tetrahydrofuranylfentanyl, 2/3-Furanylfentanyl, Acrylfentanyl, Crotonylfentanyl, Methoxyacetylfentanyl, Cyclopropylfentanyl, Tetramethylcyclopropylfentanyl, Cyclopentylfentanyl, Cyclohexylfentanyl, 3-methylfentanyl, α -methylfentanyl, β - hydroxyfentanyl, β -hydroxy/Thiofentanyl, Ethylfuranylfentanyl, Fluorofentanyl, 4-ANPP, Benzylfentanyl… Cyclohexyl-N- U-47700, U-49900, U-48800… methylbenzamides Arylcyclohexylamines Tramadol, Tapentadol, Bromadol…
TACTICS Knowing What to Test For
Challenges for Forensic Toxicologists • Analysis: • Knowing what to test for • Access to the appropriate technology • Interpretation: • The significance of the presence of novel compounds in cases • Capacity: • Keeping up with the workload
Analytical Approach Sample Received Review History Blood Alcohol Immunoassay Chromatography MS Screening Screening Special testing + + Confirmatory/ - - Quantitative Testing + Report Interpret
Cross‐reactivity: Fentanyl Analogs Propanamide Analyte % Cross Reactivity Acetylfentanyl 111% Fentanyl 100% Butyrylfentanyl 88% Furanylfentanyl 74% p‐Fluorofentanyl 61% +trans‐3‐methylfentanyl 50% α‐methylfentanyl 19% +cis‐3‐methylfentanyl 3% Alfentanil <1% 4‐ANPP (precursor/met.) <1% Phenylethyl piperidine
Analytical Challenges Fentanyl/Opioid Immunoassay Limitations Limitation Outcome Immunoassays for opioids False Negative do not cross‐react with Screens fentanyl , its analogs or any emerging opioids. Immunoassays for Some False fentanyl do not cross‐ Negative react with all fentanyl Screens analogs or any emerging opioids. Confirmatory LCMSMS Unconfirmable assays may not include Positive most current fentanyl Screens analogs.
Analytical Approach Sample Received Review History Blood Alcohol Immunoassay Chromatography MS Screening Screening Special testing + + Confirmatory/ - - Quantitative Testing + Report Interpret
Technology ‐ The Past Gas Chromatography/Mass Spectrometry Non‐Targeted: Flags unknowns, but limited tools for their identification. Forensically significant concentrations of NPS drugs are often too low to detect by traditional GCMS screening methods. Out of date libraries and databases do not include the most current NPS drugs. The chemistries of many NPS compounds are not amenable to GCMS.
Technology ‐ The Present Liquid Chromatography/Tandem Mass Spectrometry Targeted analysis assumes we know what we are looking for. Metabolites of most novel compounds are not known. Sensitivity is appropriate for typical NPS drug categories. Diversity of chemical structures limits scope in any given analysis.
Technology ‐ The Near Future Liquid Chromatography/TOF/QTOF Non‐targeted data acquisition of accurate mass, retention time, and fragmentation Targeted reporting but with data‐mining capabilities. Full spectrum data acquisition. QTOF adds structural elucidation tools. Retrospective analysis of data files allows for pharmacoepidemiology. Q1 Q1 CID CID TO TOF Analyzer Analyzer
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