Background Overdose

A Toxicologist’s Perspective on the National 1/13/2020 Drug Overdose Epidemic

A Toxicologist’s Perspective on the National Drug Overdose Epidemic

Presented by Demi Garvin BS, PharmD, R.Ph, F-ABFT

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Pharmacist Objectives Disclosure At the conclusion of this learning activity, pharmacists should be able to:

❖Member of Forensic Science Network LLC, a company that ❖Describe and explain factors contributing to the national drug provides clinical and forensic services, education, and training to overdose epidemic. health care practitioners and the medicolegal community. ❖Identify prescription and over-the-counter medications and novel psychoactive substances currently encountered in overdose. ❖The opinions expressed herein are those of the presenter and not ❖Explain common signs and symptoms of opioid overdose. those of any other individual or entity. ❖Identify and assess patient risk factors associated with opioid overdose. ❖Summarize community pharmacy practice behaviors that may positively impact overdose prevention and management.

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Technician Objectives At the conclusion of this learning activity, pharmacy technicians should be able to:

❖Describe and explain factors contributing to the national drug overdose epidemic. ❖Give examples of prescription and over-the-counter medications and novel psychoactive substances currently encountered in Background overdose. ❖Define the opioid triad. ❖Give examples of patient risk factors associated with opioid overdose.

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Demi Garvin, BS PharmD R.Ph F-ABFT 1 A Toxicologist’s Perspective on the National 1/13/2020 Drug Overdose Epidemic

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Drugs of Abuse

THE FAMILIAR AND THE NOT SO FAMILIAR

Stimulants Stimulants MDMA Piperazines Amphetamines Cathinones Cocaine NBOMeSeries Hallucinogens Hallucinogens Depressants TFMPP, mCPP Depressants Cannabis/THC Benzodiazepines Tryptamines Novel LSD Skeletal Muscle Benzodiazepines Mushrooms Relaxants Methoxetamine Ketamine GHB/GBL Synthetic Cannabinoids Salvia PCP 1, 4-butanediol Analgesics Analgesics Novel Synthetic Opiates Opioids Opioids Mitragynine Tramadol MT-45 Tapentadol AH-7921

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25 Most Frequently Identified Drugs* › Methamphetamine › Clonazepam › Cannabis/THC › Tramadol › Acetyl Fentanyl › Cocaine › MDMA › Heroin › FUB-AMB › Fentanyl › Psilocin/psilocybin › Alprazolam › Phencyclidine (PCP) › Oxycodone › Naloxone › Buprenorphine › Lysergic acid diethylamide (LSD) › Morphine NFLIS Midyear Report 2018 › Hydrocodone › Diazepam › Amphetamine › Gabapentin › N-Ethylpentylone › Codeine › 5F-ADB *NFLIS Annual Report 2018 11 12

Demi Garvin, BS PharmD R.Ph F-ABFT 2 A Toxicologist’s Perspective on the National 1/13/2020 Drug Overdose Epidemic

Definitions

› ó from óς (“juice of a plant”)

› Opiate – Naturally occurring › Opioid – Semi-synthetic – Synthetic › Designer Opioids – Synthetic Opioids – “Novel Psychoactive Substances” – “New Psychoactive Substances”

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The Economics of Heroin

National Drug Control Strategy-Data Supplement 2014

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From: Tracking Fentanyl and Fentanyl-Related Substances Reported in NFLIS-Drug by State 2016-2017

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Demi Garvin, BS PharmD R.Ph F-ABFT 3 A Toxicologist’s Perspective on the National 1/13/2020 Drug Overdose Epidemic

HHS Five Point Opioid Strategy

Strengthen public health surveillance Advance practice of pain management Improve access to treatment/recovery services Target availability/distribution of OD-reversing drugs Support cutting-edge research

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Definition

New psychoactive substance: a new narcotic or psychotropic drug, in pure form or in preparation, that is not controlled by the 1961 Novel Psychoactive Substances United Nations Single Convention on Narcotic Drugs or the 1971 United Nations Convention on Psychotropic Substances, but which Fentalogs & Benzodiazepines may pose a public health threat comparable to that posed by substances listed in these conventions. (Council Decision 2005/387/JHA)

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The Original The Original - modified

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Demi Garvin, BS PharmD R.Ph F-ABFT 4 A Toxicologist’s Perspective on the National 1/13/2020 Drug Overdose Epidemic

From synthesis to consumer……..

Shipment to •China •Processing EU/US Sales •India •Packaging

•Air •Head Shops •Sea •Internet Fentanyl Product Dosage Form Indication •Nutrition Stores Fentanyl Base Sublingual Tablet Breakthrough Pain Bulk Powder Legal Highs, Research Chemical Chemicals, Dietary Fentanyl Base Transdermal System Chronic Pain (RTC) Synthesis Supplements Fentanyl Base Buccal/Sublingual Breakthrough Pain Fentanyl Base Nasal Spray Breakthrough Pain Fentanyl Base Sublingual Spray Breakthrough Pain Fentanyl Citrate IV, Intrathecal, Epidural Preop/Postop/Adjunct Anesthesia Fentanyl Citrate Transmucosal Oral Breakthrough Pain Adapted from emcdda.europa.eu Fentanyl HCl Iontophoretic Transdermal-Pt. Control Acute Postop Pain (hospital) Fentanyl HCl Clandestine manufacture NA 25 26

National Annual Estimates of Fentanyl and 2 mg = fatal dose (Fentanyl HCl) Avg. dose/tablet = 1.1 mg Fentanyl-Related Substances, NFLIS, 2015-2016 Range 0.03-2 mg/tablet › Fentanyl › Valeryl fentanyl $10-$20/tablet › Acetyl fentanyl › Acryl fentanyl › Furanyl fentanyl › p-Fluorofentanyl › Carfentanil › ANPP › 3-Methylfentanyl › o-Flurorofentanyl › Butyryl fentanyl › Beta-hydroxythiofentanyl › Fluoroisobutyryl fentanyl › Acetyl-alpha-methylfentanyl › P-Fluoroisobutyryl fentanyl › Alpha-methylfentanyl › P-Fluorobutyryl fentanyl › 4-Methoxy-butyryl fentanyl

NFLIS Brief: Fentanyl and Fentanyl-Related Substances Reported in NFLIS, 2015-2016 (rev. March 2018) 27 28

Databases Toxicology and Casework Subscriptions Peer The Role of Counterfeits Reviewed Literature

Things are not always what they seem Govt Data/NFLIS

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Demi Garvin, BS PharmD R.Ph F-ABFT 5 A Toxicologist’s Perspective on the National 1/13/2020 Drug Overdose Epidemic

Cyclopropyl Fentanyl

Janssen & Van der Eycken (1968) in Drugs Affecting the CNS

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Novel Benzodiazepines

› 3-hydroxyphenazepam › Flubromazepam › 4-chlorodiazepam › Flubromazolam › Adinazolam › Flunitrazolam › Alprazolam triazolobenzophenone derivative › Meclonazepam › Bromazolam › Metizolam › Clonazolam › Nifoxipam › Cloniprazepam › Nitrazolam › Deschloroetizolam Substance(s) being consumed is unknown › Norfludiazepam › Desmethylflunitrazepam › Phenazepam Dosage variability of active ingredient › Diclazepam › Pyrazolam Toxicity data often nonexistent (humans) › Etizolam › Zapizolam Good Manufacturing Practices?

Source: UNODC Early Warning Advisory on NPS, 2017 33 34

Opioid Overdose: Signs and Symptoms Awake but unable to speak Body is limp Breathing is slow, shallow, erratic, or absent Vomiting Pale or clammy face Blue-purple, gray or ashen skin tone Pinpoint pupils Opioid Practice Pearls Blue/gray/purple lips or fingernails Slow, erratic, or undetectable pulse Choking or loud snoring, gurgling noise Unresponsive to outside stimulus Loss of consciousness Respiratory depression

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Demi Garvin, BS PharmD R.Ph F-ABFT 6 A Toxicologist’s Perspective on the National 1/13/2020 Drug Overdose Epidemic

Opioids-Risk Factors to Consider

› Age › Use of >50 mg po morphine milligram › Race equivalents (MME); recent increase in dose? › Gender › Geo Location of Adverse Drug Event › Methadone/Buprenorphine Rx for Opioid Use Disorder (OUD) › Hx of opioid intoxication/overdose; substance abuse or nonmedical opioid› Recent substance abuse treatment? use › Opioid transition (risk of incomplete › Recent incarceration? Treating Pain Safely cross-tolerance) › Naloxone administered? › Smoker, COPD, Obstructive Apnea Syndrome, Asthma; Obesity; Renal, › File in a Prescription Drug Monitoring Hepatic, Cardiac disease; HIV (+) Program (SCRIPTS)? › Use of: EtOH, benzodiazepines, › OUD hx does not “impart immunity” sedatives, skeletal muscle relaxants, antidepressants, antihistamines to designer opioids

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Acute versus Chronic Pain

ACUTE PAIN CHRONIC PAIN › Less than 3 months duration › Lasts longer than 3 months › Acute tissue injury › Difficult to determine exact source

Sensory – Tissue Input Affective – Emotions Cognitive - Thoughts

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WHEN WE FIRST BEGIN TO USE OPIOIDS……

Decrease pain Increase motivation Increase confidence Increase reward Reduce depression and anxiety Increase pleasure in current activity

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Demi Garvin, BS PharmD R.Ph F-ABFT 7 A Toxicologist’s Perspective on the National 1/13/2020 Drug Overdose Epidemic

Chronic Opioid Consumption Opioid Adverse Effects

Dopamine Production ❖Mentally impairing ❖Increased fall risk

Normal Reward ❖Delayed recovery ❖Cardiac Opioid Receptors Depression ❖Increased medical costs ❖Brain changes Endorphins ❖Opioid hyperalgesia ❖Addiction Motivation ❖Disability risk doubles with Rx ≥7 days

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Consider Opioids For CDC Guidelines for Acute Pain Tx (2016) ❖ IF opioids are prescribed: Palliative care ❖End of life care Prescribe < 3 day supply ❖Acute (severe) trauma – short term only More than 7 days will rarely be required Counsel Patients ❖Safe storage ❖Proper disposal of unused opioids

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NALOXONE-OPIOID REVERSAL AGENT

WHO Model List of Essential Medicines Pure competitive opioid antagonist , ,  receptors High affinity for -opioid receptor Naloxone Onset of Action 2 minutes (IV) 2 minutes (IN) 5 minutes (IM) Duration of Action: 30-60 minutes June 2014-SC Overdose Prevention Act (SC Code §44-130) Extensive first-pass metabolism

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Demi Garvin, BS PharmD R.Ph F-ABFT 8 A Toxicologist’s Perspective on the National 1/13/2020 Drug Overdose Epidemic

NALOXONE USE

Prescriptions doubled between 2017-2018

Estimated that for every 70 Rx’s for high- dose opioid therapy, only 1 Rx for naloxone is being dispensed

Source: National Institute of Drug Abuse (NIDA) https://www.eeti.training/ 49 50

Candidates for Naloxone › History of opioid intoxication/overdose or substance use disorder Naloxone Rescue- Adverse Effects? › Current use (or history) of illicit or nonmedical opioid use › Confusion › Diaphoresis › Methadone or buprenorphine use (MAT for OUD) › Headache › Tremor › Use of  50 mg oral morphine or MME daily, or long acting opioid › Opioid therapy transition (due to incomplete cross-tolerance) › Gastrointestinal › Seizures problems › Opioid Rx in Presence Of › Naloxone sensitivity – Smoker, respiratory compromise (COPD, sleep apnea, asthma) › Aggressiveness – Renal, hepatic, cardiac disease › Cardiac arrest – HIV/AIDS › Tachycardia › Pulmonary edema – Ethanol, Benzodiazepine, Sedative, Skeletal Muscle Relaxant, Antidepressant use › Shivering › Renarcotization

› Those who request it 1. Symptoms presumed to be due to naloxone result › Those who live in remote locations from opioid withdrawal 2. Long term drug misuse/abuse may increase likelihood of ADE due to underlying morbidity-not naloxone ADE 51 52

1 mg naloxone blocks 25 mg heroin for 1 hour 1 mg naloxone blocks 50% of μ receptors 50% of μ receptors must be blocked to reverse OD 2 mg naloxone blocks 80% of μ receptors

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Demi Garvin, BS PharmD R.Ph F-ABFT 9 A Toxicologist’s Perspective on the National 1/13/2020 Drug Overdose Epidemic

The Opioid Triad

Pulmonary congestion and edema Cerebral edema PM Opioid Triad Urine retention Case Studies › Respiratory depression › Miosis Clinical Opioid Triad › Stupor

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Case Study Case Study All Too Common “Poor Man’s Methadone”

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Loperamide Loperamide Opiate Withdrawal Protocol › Oral opioid-like agent › Day 1: Take 400 mg of cimetidine followed by 24-30 mg of › Anti-secretory effect and decreased gut motility loperamide or less washed down with a glass of grapefruit › Poor blood-brain barrier penetration → lacks CNS effects (tx) juice (GFJ) every 5-8 hours, or as needed. › Dosing – LD: 4 mg followed by 2 mg q episode of diarrhea › Day 2: Take 400 mg of cimetidine followed by 20 mg of – Max Dose: 12 mg/day x 48 h or 16 mg/day x 5 days loperamide every 5-8 hours, or as needed, all washed down – Abuse: reports of up to 800 mg/day with GFJ. › Tx-insignificant accumulation in the systemic circulation › Day 3: Take 400 mg of cimetidine followed by 18 mg of › “Super doses”→ CNS accumulation/abuse/dependence loperamide every 5-8 hours, or as needed, all washed down › [Blood] = 1-3 ng/mL (tx) with GFJ. › [Blood] > 10-1000 ng/mL (toxic/lethal) › Day 4: Begin to lower your loperamide dosage by half, but › Toxicity → Cardiotoxin → Dysrhythmias → Arrhythmias continue to take with 400 mg of cimetidine and wash down –  QT Interval with GFJ. – Torsades de Pointes Normal  400 ms Abnormal > 450 ms http://opiateaddictionsupport.com/how-to-use-loperamide-for-opiate-withdrawal/ 59 60

Demi Garvin, BS PharmD R.Ph F-ABFT 10 A Toxicologist’s Perspective on the National 1/13/2020 Drug Overdose Epidemic

Opioids and Cardiotoxicity Loperamide Methadone Buprenorphine Long QT Interval Syndrome Oxycodone Risk Factors Congenital QTc Heart Disease Older Age > 65 years Females Case Study Hypokalemia/Hypomagnesemia QTc >470 ms postpubertal males Bradycardia QTc >480 ms postpubertal females Opioids and the Pediatric Population Hepatic Disease High Dose Opioid, Significant Dose Increases CYP450 Inhibitors (CYP3A) Drugs known to increase QTc Drugs cause electrolyte changes

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Pediatric Opioid Poisoning Hospitalizations

Rate of hospital admissions for opioid ingestion per 10,000 hospitalizations and the rate of PICU admissions for opioid ingestion per 10,000 PICU hospitalizations from 2004 through quarter 3 of 2015. Trends in the rate change over time were significant (P < 0.001). JAMA Pediatr. 2016; 170 (12): 1195-1201 Pediatrics. 2018; 141(4): e20173335.

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Buprenorphine Indications and Formulations Buprenorphine Formulations and Indications I. Medication Assisted Therapy Sublingual Tablets Medication Assisted Therapy Pain › Buprenorphine + Naloxone › Buprenorphine Sublingual Tablets Transdermal System Sublingual Film › Buprenorphine + Naloxone › Buprenorphine › Buprenorphine + Naloxone › Buprenorphine Buccal Film › Buprenorphine + Naloxone Sublingual Film Injectable › Buprenorphine + Naloxone › Buprenorphine Buccal Film Subdermal Implant › Buprenorphine › Buprenorphine + Naloxone Injectable II. Pain › Buprenorphine Subdermal Implant Transdermal System › Buprenorphine › Buprenorphine

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Demi Garvin, BS PharmD R.Ph F-ABFT 11 A Toxicologist’s Perspective on the National 1/13/2020 Drug Overdose Epidemic

Ages and Stages Newborn or neonate < 1 month old Preterm or premature < 36 weeks gestation Term ≥ 36 weeks gestation Infant: < 1 year old Toddler: 1-3 years M Child: 4-11 years O Adolescent: 12-19 years R Decreasing Potency P Increasing Potency H I N E

1:1

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Opioid Toxicity in Pediatrics

› Features – Delayed onset of toxicity – Severe poisoning – Prolonged toxicity › Children < 3 years of age* – Admit/Observe 24 hours – Initial Naloxone: 0.1 mg/kg body wt. Case Study › May require higher total dose vs. adult – Exposure to buprenorphine Intrauterine Fetal Demise › “Ceiling effect”-not observed

*Methadone, fentanyl transdermal, ER opioid formulations

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Case Study Update: Mitragynine (kratom)

Honein et al. Pediatrics 2019; Wilkelman et al. Pediatrics 2018; Haight et al. MMWR 2018

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Demi Garvin, BS PharmD R.Ph F-ABFT 12 A Toxicologist’s Perspective on the National 1/13/2020 Drug Overdose Epidemic

› Mitragyna speciosa is a tropical evergreen tree from SE Asia Routes of Administration native to Thailand, Malaysia, What is kratom? › Leaves used by Indonesia, and Papua New Thai/Malaysian natives Guinea and workers for › kratom, the original name used centuries in Thailand, is a member of the › May be chewed or a tea Rubiaceae family (includes is prepared from boiling coffee and gardenia) the leaves › Leaf veins greenish-white or red › Leaves are also dried (possible difference in potency) and smoked; placed into › Principle psychoactives capsules or made into Mitragynine extracts 7-OH-mitragynine

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Dose Dependent-Pharmacological Effects August 2016 DEA announces intent to Schedule (I) CURRENT STATUS › High dose – Opioid-like respiratory depression and euphoria October 2016 Mitragynine and 7-OH-mitragynine DEA withdraws intent Interact with opioid receptors (CNS) October 2017 Sedation, pleasure, decreased pain FDA, NIDA recommend Schedule I status › Low dose – CNS stimulation (coca-like) February 2018 Mitragynine also interacts with other receptors FDA announces opioid-activity Increased energy, sociability, mental alertness June 2018 › Uses: chronic pain, opioid withdrawal, mild stimulation https://nccih.nih.gov/news/kratom November 2018 Initial Onset: 10-20 minutes Peak Effects: up to 2 hours No clinical studies to date Duration: 5-7 hours Current 2019 Status “Drug of Concern” 75 76

Case Study Case Study Driving Under the Influence of Drugs (DUID) Adulterants

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Demi Garvin, BS PharmD R.Ph F-ABFT 13 A Toxicologist’s Perspective on the National 1/13/2020 Drug Overdose Epidemic

Compounds of Concern

› Licit/Novel Benzodiazepines › Antiemetics › Sedative/Hypnotics › Antihistamines › Fentanyl/Novel Fentanyls › Skeletal Muscle Relaxants › Diphenoxylate

› Gabapentin › Loperamide Opioid Substitutes Gabapentinoids › Pregabalin › Mitragynine

› Propylhexadrine › Buprenorphine › Methadone MAT

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Questions? CE CODE P7U6ZG

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