a toxicologist’s perspective on the national 1/13/2020 ......opiates opioids tramadol tapentadol...

A Toxicologist’s Perspective on the National

Drug Overdose Epidemic

1/13/2020

Demi Garvin, BS PharmD R.Ph F-ABFT 1

A Toxicologist’s Perspective on the National Drug Overdose Epidemic

Presented byDemi Garvin

BS, PharmD, R.Ph, F-ABFT

Disclosure

❖Member of Forensic Science Network LLC, a company that provides clinical and forensic services, education, and training to health care practitioners and the medicolegal community.

❖The opinions expressed herein are those of the presenter and not those of any other individual or entity.

Pharmacist Objectives

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

❖Describe and explain factors contributing to the national drug overdose epidemic.

❖Identify prescription and over-the-counter medications and novel psychoactive substances currently encountered in overdose.

❖Explain common signs and symptoms of opioid overdose.

❖Identify and assess patient risk factors associated with opioid overdose.

❖Summarize community pharmacy practice behaviors that may positively impact overdose prevention and management.

Technician ObjectivesAt 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 overdose.

❖Define the opioid triad.

❖Give examples of patient risk factors associated with opioid overdose.

Background

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Drugs of Abuse

THE FAMILIAR AND THE NOT SO FAMILIAR

Stimulants

Piperazines

Cathinones

NBOMe Series

Depressants

Novel Benzodiazepines

Analgesics

Novel Synthetic Opioids

Mitragynine

MT-45

AH-7921

Hallucinogens

TFMPP, mCPP

Tryptamines

Methoxetamine

Synthetic Cannabinoids

Salvia

Stimulants

MDMA

Amphetamines

Cocaine

Depressants

Benzodiazepines

Skeletal Muscle Relaxants

GHB/GBL

1, 4-butanediolAnalgesics

Opiates

Opioids

Tramadol

Tapentadol

Hallucinogens

Cannabis/THC

LSD

Mushrooms

Ketamine

PCP

NFLIS Midyear Report 2018

25 Most Frequently Identified Drugs*

› Methamphetamine

› Cannabis/THC

› Cocaine

› Heroin

› Fentanyl

› Alprazolam

› Oxycodone

› Buprenorphine

› Hydrocodone

› Amphetamine

› N-Ethylpentylone

› 5F-ADB

› Clonazepam

› Tramadol

› Acetyl Fentanyl

› MDMA

› FUB-AMB

› Psilocin/psilocybin

› Phencyclidine (PCP)

› Naloxone

› Lysergic acid diethylamide (LSD)

› Morphine

› Diazepam

› Gabapentin

› Codeine*NFLIS Annual Report 2018

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Definitions

› ó from óς (“juice of a plant”)

› Opiate– Naturally occurring

› Opioid– Semi-synthetic– Synthetic

› Designer Opioids– Synthetic Opioids – “Novel Psychoactive Substances”– “New Psychoactive Substances”

The Economics of Heroin

National Drug Control Strategy-Data Supplement 2014

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

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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

Novel Psychoactive SubstancesFentalogs & Benzodiazepines

Definition

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

The Original The Original - modified

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• China

• India

Bulk Powder Chemical Synthesis

• Air

• Sea

Shipment to

EU/US• Processing

• Packaging

Legal Highs, Research Chemicals, Dietary

Supplements

• Head Shops

• Internet

• Nutrition Stores

Sales

From synthesis to consumer……..

Adapted from emcdda.europa.eu

Fentanyl Product Dosage Form Indication

Fentanyl Base Sublingual Tablet Breakthrough Pain

Fentanyl Base Transdermal System Chronic Pain (RTC)

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

Fentanyl HCl Iontophoretic Transdermal-Pt. Control Acute Postop Pain (hospital)

Fentanyl HCl Clandestine manufacture NA

2 mg = fatal dose (Fentanyl HCl)Avg. dose/tablet = 1.1 mgRange 0.03-2 mg/tablet

$10-$20/tablet

National Annual Estimates of Fentanyl and Fentanyl-Related Substances, NFLIS, 2015-2016

› Fentanyl

› Acetyl fentanyl

› Furanyl fentanyl

› Carfentanil

› 3-Methylfentanyl

› Butyryl fentanyl

› Fluoroisobutyryl fentanyl

› P-Fluoroisobutyryl fentanyl

› P-Fluorobutyryl fentanyl

› Valeryl fentanyl

› Acryl fentanyl

› p-Fluorofentanyl

› ANPP

› o-Flurorofentanyl

› Beta-hydroxythiofentanyl

› Acetyl-alpha-methylfentanyl

› Alpha-methylfentanyl

› 4-Methoxy-butyryl fentanyl

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

The Role of CounterfeitsThings are not always what they seem Govt

Data/NFLIS

Peer Reviewed Literature

Toxicology Casework

Databases and

Subscriptions

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

Cyclopropyl Fentanyl

Substance(s) being consumed is unknownDosage variability of active ingredient

Toxicity data often nonexistent (humans)Good Manufacturing Practices?

Novel Benzodiazepines › 3-hydroxyphenazepam

› 4-chlorodiazepam

› Adinazolam

› Alprazolam triazolobenzophenone derivative

› Bromazolam

› Clonazolam

› Cloniprazepam

› Deschloroetizolam

› Desmethylflunitrazepam

› Diclazepam

› Etizolam

› Flubromazepam

› Flubromazolam

› Flunitrazolam

› Meclonazepam

› Metizolam

› Nifoxipam

› Nitrazolam

› Norfludiazepam

› Phenazepam

› Pyrazolam

› Zapizolam

Source: UNODC Early Warning Advisory on NPS, 2017

Opioid Practice Pearls

Opioid Overdose: Signs and SymptomsAwake 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

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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Opioids-Risk Factors to Consider› Age

› Race

› Gender

› Geo Location of Adverse Drug Event

› Hx of opioid intoxication/overdose; substance abuse or nonmedical opioid use

› Opioid transition (risk of incomplete cross-tolerance)

› Smoker, COPD, Obstructive Apnea Syndrome, Asthma; Obesity; Renal, Hepatic, Cardiac disease; HIV (+)

› Use of: EtOH, benzodiazepines, sedatives, skeletal muscle relaxants, antidepressants, antihistamines

› Use of >50 mg po morphine milligram equivalents (MME); recent increase in dose?

› Methadone/Buprenorphine Rx for Opioid Use Disorder (OUD)

› Recent substance abuse treatment?

› Recent incarceration?

› Naloxone administered?

› File in a Prescription Drug Monitoring Program (SCRIPTS)?

› OUD hx does not “impart immunity” to designer opioids

Treating Pain Safely

Acute versus Chronic Pain

ACUTE PAIN

› Less than 3 months duration

› Acute tissue injury

CHRONIC PAIN› Lasts longer than 3 months

› Difficult to determine exact source

Sensory – Tissue InputAffective – EmotionsCognitive - Thoughts

WHEN WE FIRST BEGIN TO USE OPIOIDS……

Decrease painIncrease motivationIncrease confidenceIncrease rewardReduce depression and anxietyIncrease pleasure in current activity

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Dopamine Production

Normal Reward

Opioid Receptors

Endorphins

Motivation

Chronic Opioid Consumption

Depression

Opioid Adverse Effects

❖Mentally impairing

❖Delayed recovery

❖Increased medical costs

❖Opioid hyperalgesia

❖Disability risk doubles with Rx ≥7 days

❖Increased fall risk

❖Cardiac

❖Brain changes

❖Addiction

CDC Guidelines for Acute Pain Tx (2016)

IF opioids are prescribed:

Prescribe < 3 day supplyMore than 7 days will rarely be requiredCounsel Patients ❖Safe storage ❖Proper disposal of unused opioids

Consider Opioids For

❖Palliative care

❖End of life care

❖Acute (severe) trauma – short term only

Naloxone

NALOXONE-OPIOID REVERSAL AGENT

WHO Model List of Essential Medicines

Pure competitive opioid antagonist

, , receptors

High affinity for -opioid receptor

Onset of Action2 minutes (IV)2 minutes (IN)5 minutes (IM)

Duration of Action: 30-60 minutes

Extensive first-pass metabolismJune 2014-SC Overdose Prevention Act (SC Code §44-130)

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https://www.eeti.training/

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)

Candidates for Naloxone› History of opioid intoxication/overdose or substance use disorder

› Current use (or history) of illicit or nonmedical opioid use

› Methadone or buprenorphine use (MAT for OUD)

› Use of 50 mg oral morphine or MME daily, or long acting opioid

› Opioid therapy transition (due to incomplete cross-tolerance)

› Opioid Rx in Presence Of– Smoker, respiratory compromise (COPD, sleep apnea, asthma)

– Renal, hepatic, cardiac disease– HIV/AIDS

– Ethanol, Benzodiazepine, Sedative, Skeletal Muscle Relaxant, Antidepressant use

› Those who request it

› Those who live in remote locations

Naloxone Rescue- Adverse Effects?› Confusion

› Headache

› Gastrointestinal problems

› Aggressiveness

› Tachycardia

› Shivering

› Diaphoresis

› Tremor

› Seizures

› Naloxone sensitivity

› Cardiac arrest

› Pulmonary edema

› Renarcotization

1. Symptoms presumed to be due to naloxone result from opioid withdrawal

2. Long term drug misuse/abuse may increase likelihood of ADE due to underlying morbidity-not naloxone ADE

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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Case Studies

The Opioid Triad

Pulmonary congestion and edema

Cerebral edema

Urine retention

› Respiratory depression

›Miosis

› Stupor

PM Opioid Triad

Clinical Opioid Triad

Case Study All Too Common

Case Study “Poor Man’s Methadone”

Loperamide› Oral opioid-like agent› Anti-secretory effect and decreased gut motility› Poor blood-brain barrier penetration → lacks CNS effects (tx)

› Dosing– LD: 4 mg followed by 2 mg q episode of diarrhea– Max Dose: 12 mg/day x 48 h or 16 mg/day x 5 days– Abuse: reports of up to 800 mg/day

› Tx-insignificant accumulation in the systemic circulation

› “Super doses”→ CNS accumulation/abuse/dependence

› [Blood] = 1-3 ng/mL (tx)

› [Blood] > 10-1000 ng/mL (toxic/lethal)

› Toxicity → Cardiotoxin → Dysrhythmias → Arrhythmias – QT Interval– Torsades de Pointes Normal 400 ms

Abnormal > 450 ms

Loperamide Opiate Withdrawal Protocol› Day 1: Take 400 mg of cimetidine followed by 24-30 mg of

loperamide or less washed down with a glass of grapefruit juice (GFJ) every 5-8 hours, or as needed.

› Day 2: Take 400 mg of cimetidine followed by 20 mg of loperamide every 5-8 hours, or as needed, all washed down with GFJ.

› Day 3: Take 400 mg of cimetidine followed by 18 mg of loperamide every 5-8 hours, or as needed, all washed down with GFJ.

› Day 4: Begin to lower your loperamide dosage by half, but continue to take with 400 mg of cimetidine and wash down with GFJ.

http://opiateaddictionsupport.com/how-to-use-loperamide-for-opiate-withdrawal/

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Opioids and CardiotoxicityLoperamideMethadoneBuprenorphineOxycodone

Risk FactorsCongenital QTc

Heart DiseaseOlder Age > 65 yearsFemalesHypokalemia/HypomagnesemiaBradycardiaHepatic DiseaseHigh Dose Opioid, Significant Dose IncreasesCYP450 Inhibitors (CYP3A)Drugs known to increase QTc

Drugs cause electrolyte changes

QTc >470 ms postpubertal malesQTc >480 ms postpubertal females

Long QT Interval Syndrome

Case Study Opioids and the Pediatric Population

Pediatric Opioid Poisoning Hospitalizations

JAMA Pediatr. 2016; 170 (12): 1195-1201

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).Pediatrics. 2018; 141(4): e20173335.

Buprenorphine Indications and FormulationsI. Medication Assisted Therapy

Sublingual Tablets› Buprenorphine + Naloxone › Buprenorphine

Sublingual Film› Buprenorphine + Naloxone

Buccal Film› Buprenorphine + Naloxone

Injectable› Buprenorphine

Subdermal Implant› Buprenorphine

II. PainTransdermal System

› Buprenorphine

Pain

Transdermal System › Buprenorphine

Medication Assisted Therapy

Sublingual Tablets› Buprenorphine + Naloxone › Buprenorphine

Sublingual Film› Buprenorphine + Naloxone

Buccal Film› Buprenorphine + Naloxone

Injectable› Buprenorphine

Subdermal Implant› Buprenorphine

Buprenorphine Formulations and Indications

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Newborn or neonate < 1 month oldPreterm or premature < 36 weeks gestation

Term ≥ 36 weeks gestationInfant: < 1 year oldToddler: 1-3 yearsChild: 4-11 yearsAdolescent: 12-19 years

Ages and Stages

Decreasing Potency Increasing Potency

MORPHINE

1:1

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.› May require higher total dose vs. adult

– Exposure to buprenorphine› “Ceiling effect”-not observed

*Methadone, fentanyl transdermal, ER opioid formulations

Case Study Intrauterine Fetal Demise

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

Case Study Update: Mitragynine (kratom)

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What is kratom?

› Mitragyna speciosa is a tropical evergreen tree from SE Asia native to Thailand, Malaysia, Indonesia, and Papua New Guinea

› kratom, the original name used in Thailand, is a member of the Rubiaceae family (includes coffee and gardenia)

› Leaf veins greenish-white or red (possible difference in potency)

› Principle psychoactives

Mitragynine

7-OH-mitragynine

Routes of Administration› Leaves used by

Thai/Malaysian natives and workers for centuries

› May be chewed or a tea is prepared from boiling the leaves

› Leaves are also dried and smoked; placed into capsules or made into extracts

Dose Dependent-Pharmacological Effects› High dose – Opioid-like respiratory depression and euphoria

Mitragynine and 7-OH-mitragynine Interact with opioid receptors (CNS) Sedation, pleasure, decreased pain

› Low dose – CNS stimulation (coca-like)Mitragynine also interacts with other receptorsIncreased energy, sociability, mental alertness

› Uses: chronic pain, opioid withdrawal, mild stimulation

Initial Onset: 10-20 minutesPeak Effects: up to 2 hoursDuration: 5-7 hours

CURRENT STATUS

August 2016

DEA announces intent to Schedule (I)

October 2016

DEA withdraws intent

October 2017

FDA, NIDA recommend Schedule I status

February 2018

FDA announces opioid-activity

June 2018

https://nccih.nih.gov/news/kratom

November 2018

No clinical studies to date

Current 2019 Status

“Drug of Concern”

Case Study Driving Under the Influence of Drugs (DUID)

Case StudyAdulterants

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› Antiemetics

› Antihistamines

› Skeletal Muscle Relaxants

› Diphenoxylate

› Loperamide

› Mitragynine

› Buprenorphine

› Methadone

› Licit/Novel Benzodiazepines

› Sedative/Hypnotics

› Fentanyl/Novel Fentanyls

› Gabapentin

› Pregabalin

› Propylhexadrine

Compounds of Concern

Opioid Substitutes

MAT

Gabapentinoids

Questions? CE CODE

P7U6ZG

References and Suggested Resources▪ Gummin DD, Mowry JB, Spyker DA, Brooks DE, Osterthaler KM, et al. 2017

Annual Report of the American Association of Poison Control Centers' National Poison Data System (NPDS): 35th Annual Report. Clin Toxicol (Phila). 2018 Dec 21;:1-203. PubMed PMID: 30576252.

▪ European Monitoring Centre for Drugs and Drug Addiction, European Drug Report: Trends and Developments 2017.

▪ European Monitoring Centre for Drugs and Drug Addiction, New Psychoactive Substances: Innovative Legal Responses June 2015, doi: 10.2810/90544.

▪ Growing threat from counterfeit medicines. World Health Organization. April 2010. http://www.who.int/bulletin/volumes/88/4/10-020410/en/

▪ Poisons found in counterfeit medicines. The Partnership for Safe Medicines. http://www.safemedicines.org/2012/03/no-drugs-at-all.html

▪ Garrett L. Ensuring the safety and integrity of the world’s drug, vaccine, and medicines supply. Policy Innovation Memorandum No. 21. Council on Foreign Relations. http://www.cfr.org/pharmaceuticals-and-vaccines/ensuring-safety-integrity-worlds-drug-vaccine-medicines-supply/p28256

▪ Kelly S, Thomson L, Frick C, Heidari K, Sen N. Opioid Prescriptions in South Carolina. S.C. Department of Health and Environmental Control. October 2018.

▪ Mackey TK, Nayyar G. Digital danger: a review of the global public health, patient safety and cybersecurity threats posed by illicit online pharmacies. Br Med Bull. 2016; 118:110-126.

▪ CDC. Vital Signs: Overdoses of Prescription Opioid Pain Relievers-United States,1999-2008. MMWR 2011; 60:1-6.

▪ Substance Abuse and Mental Health Services Administration. Results from the 2012 National Survey on Drug Use and Health: volume 1: summary of national findings. Rockville, MD: Substance and Mental Health Services Administration, Office of Applied Studies; 2011. http://oas.samhsa.gov/NSDUH/2k10NSDUH/2k10Results.htm#2.16

▪ Shah A, Hayes CJ, Martin BC. Characteristics of Initial Prescription Episodes and Likelihood of Long-Term Opioid Use — United States, 2006–2015. MMWR MorbMortal Wkly Rep 2017;66:265–269.

▪ Solanki DR, Koyyalagunta D, Shah R V, Silverman SM, Manchikanti L. Monitoring opioid adherence in chronic pain patients: assessment of risk of substance misuse. Pain Physician. 2011;14(2):E119-E131. http://www.ncbi.nlm.nih.gov/pubmed/21412377.

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http://www.safemedicines.org/2012/03/no-drugs-at-all.html

http://www.cfr.org/pharmaceuticals-and-vaccines/ensuring-safety-integrity-worlds-drug-vaccine-medicines-supply/p28256

http://oas.samhsa.gov/NSDUH/2k10NSDUH/2k10Results.htm#2.16

http://www.ncbi.nlm.nih.gov/pubmed/21412377



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▪ Paulozzi LJ, Baldwin G. CDC Grand Rounds: Prescription Drug Overdoses — a U.S. Epidemic. MMWR. 2012; 61(1):10-13.

▪ Miller M, Stu ÃT, Azrael D. Opioid Analgesics and the Risk of Fractures in Older Adults with Arthritis. J Am Geriatr Soc. 2011;59:430-438. doi:10.1111/j.1532-5415.2011.03318.x.

▪ Odgers CL, Caspi A, Nagin DS, et al. Is it important to prevent early exposure to drugs and alcohol among adolescents? Psychol Sci. 2008;19(10):1037-1044. doi:10.1111/j.1467-9280.2008.02196.x.

▪ Miech R, Johnston L, O'Malley P, Keyes K, Heard K. Prescription opioids in adolescence and future opioid misuse. Pediatrics. 2015;136:e1-e9. doi:10.1542/peds.2015-1364.

▪ Overbeek DL, Abraham J, Munzer BW. Kratom (Mitragynine) ingestion requiring naloxone reversal. Clin Pract Cases Emerg Med. 2019 Feb; 3(1):24-26.

▪ Ray WA, Chung CP, Murray KT, et al. Prescription of Long-Acting Opioids and Mortality in Patients With Chronic Noncancer Pain. JAMA. 2016;315(22):2415. doi:10.1001/jama.2016.7789.

▪ Warner M, Chen LH, Makuc DM, Anderson RN, Miniňo AM. Drug poisoning deaths in the United States, 1980-2008, NCHS data brief, no 81. Hyattsville, MD: National Center for Health Statistics, 2011.

▪ NFLIS Annual 2018 Report.▪ https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates▪ https://crediblemeds.org/healthcare-providers/▪ United States of America Opioid Consumption in Morphine Equivalence (ME), mg

per person. Pain & Policy Study Groups. http://www.painpolicy.wisc.edu/sites/www.painpolicy.wisc.edu/files/country_files/morphine_equivalence/unitedstatesofamerica_me_methadone.pdf. Published 2015. Accessed November 27, 2017.

▪ Pain & & Policy Study Group, American Cancer Society, American Cancer Society Cancer Action Network. Achieving Balance in State Pain Policy: A Progress Report Card (CY 2015) . Carbone Cancer Center. July 2016:1.

▪ Martell B, O’Connor P, Kerns R, et al. Systematic review: opioid treatment for chronic back pain: prevalence, efficacy, and association with addiction. Ann Intern Med. 2007; 146(2):116-127. http://annals.org/article.aspx?articleid=732048. Accessed August 9, 2014.

▪ Tisdale JE, Jaynes HA, Kingery JR, et al. Development and Validation of a Risk Score to Predict QT Interval Prolongation in Hospitalized Patients. Circ Cardiovasc Qual Outcomes. 2013; 6:479-487.

▪ NHS Greater Glasgow and Clyde Medicines Information Service. Drug Induced QT Prolongation. Issue 21, December 2012.

▪ Pharmacist’s Letter/Prescriber’s Letter. Drug-Induced Long QT Interval. Detail-Document #280111, January 2012.

▪ Boyer, EW. Management of Opioid Analgesic Overdose. N Engl J Med. 2012; 367:146-155.

▪ Kane JM, Colvin JD, Bartlett AH, et al. Opioid-Related Critical Care Resource Use in US Children’s Hospitals. Pediatrics. 2018; 141(4): e20173335.

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https://www.drugabuse.gov/related-topics/trends-statistics/overdose-death-rates

https://crediblemeds.org/healthcare-providers/

a toxicologist’s perspective on the national 1/13/2020 ......opiates opioids tramadol tapentadol...

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