Update on the National Drug Overdose Epidemic: A Toxicologist’s Perspective
Demi Garvin, BS PharmD RPh F-ABFT 1
Update on the National Drug Overdose Epidemic:
A Toxicologist’s Perspective
Disclosure
• Member of Forensic Science Network LLC, a company that provides forensic services to coroners, pathologists, and the law enforcement, medical, and legal communities.
• The opinions expressed herein are those of the author and not those of any other individual or entity.
Objectives for Pharmacists
❖Discuss the impact of the opioid crisis.
❖Identify current trends in prescriptive and illicit opioid use.
❖Contrast and compare opioid prescribing guidelines for acute and
chronic pain.
❖Identify and assess patient risk factors associated with opioid
overdose.
❖Discuss non-opioid alternatives in pediatric and adult pain
management.
❖Summarize community pharmacy practice behaviors that may
positively impact opioid overdose prevention and management.
Objectives for Pharmacy Technicians
❖Discuss the impact of the opioid crisis.
❖Identify current trends in prescriptive and illicit opioid use.
❖Compare and contrast acute and chronic pain.
❖Give examples of patient risk factors associated with opioid overdose.
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Update on the National Drug Overdose Epidemic: A Toxicologist’s Perspective
Demi Garvin, BS PharmD RPh F-ABFT 2
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-butanediol
Analgesics
Opiates
Opioids
Tramadol
Tapentadol
Hallucinogens
Cannabis/THC
LSD
Mushrooms
Ketamine
PCPNFLIS 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
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”
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Update on the National Drug Overdose Epidemic: A Toxicologist’s Perspective
Demi Garvin, BS PharmD RPh F-ABFT 3
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
HHS Five Point Opioid Strategy
Strengthen public health surveillance
Advance practice of pain management
Improve access to treatment/recovery services
Target availability and 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)
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Update on the National Drug Overdose Epidemic: A Toxicologist’s Perspective
Demi Garvin, BS PharmD RPh F-ABFT 4
The Original The Original - modified
•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 (Abstral) Sublingual Tablet Breakthrough Pain
Fentanyl Base (Duragesic) Transdermal System Chronic Pain (RTC)
Fentanyl Base (Fentora) Buccal/Sublingual Breakthrough Pain
Fentanyl Base (Lazanda) Nasal Spray Breakthrough Pain
Fentanyl Base (Subsys) Sublingual Spray Breakthrough Pain
Fentanyl Citrate (Sublimaze) IV, Intrathecal, Epidural Preop/Postop/Adjunct Anesthesia
Fentanyl Citrate (Actiq) Transmucosal Oral Breakthrough Pain
Fentanyl HCl (Ionsys) Iontophoretic Transdermal-Pt. Control Acute Postop Pain (hospital)
Fentanyl HCl Clandestine manufacture NA
2 mg = fatal dose (Fentanyl HCl)
Avg. dose/tablet = 1.1 mg
Range 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 Fentany-Related Substances
Reported in NFLIS, 2015-2016 (rev. March 2018)
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Update on the National Drug Overdose Epidemic: A Toxicologist’s Perspective
Demi Garvin, BS PharmD RPh F-ABFT 5
The Role of CounterfeitsThings are not always what they seem
Janssen & Van der Eycken (1968) in Drugs Affecting the CNS
Cyclopropyl Fentanyl
Substance(s) being consumed is unknown
Dosage variability of active ingredient
Toxicity data often nonexistent (humans)
The “Hot Spot” 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
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Update on the National Drug Overdose Epidemic: A Toxicologist’s Perspective
Demi Garvin, BS PharmD RPh F-ABFT 6
Govt Data/NFLIS
Peer Reviewed Literature
Toxicology Casework
Databases and
Subscriptions
The 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
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
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 Input
Affective – Emotions
Cognitive - Thoughts
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Update on the National Drug Overdose Epidemic: A Toxicologist’s Perspective
Demi Garvin, BS PharmD RPh F-ABFT 7
Four Types of Acute and Chronic Pain
Nociceptive
Neuropathic
Central Sensitization (Wind Up)
Opioid withdrawal (Opioid Hyperalgesia)
What exactly is Central Sensitization?
Common phenomenon in chronic pain
Pain modulating systems in CNS are dysfunctional-
Pain is always enhanced
Even minor nociceptive input is enhanced to cause severe pain
Often seen in-
TMJ syndrome
Fibromyalgia
Chronic low back pain
Chronic headaches
Irritable Bowel Syndrome
When we first begin to use opioids……
Decrease painIncrease motivationIncrease confidenceIncrease rewardReduce depression and anxietyIncrease pleasure in current activity
Opioid Adverse Effects
• Mentally impairing
• Delayed recovery
• Increased medical costs
• Opioid hyperalgesia
• Risk of disability doubles with Rx ≥7 days
• Increased fall risk
• Cardiac
• Brain changes
• Addiction
Dopamine Production
Normal Reward
Opioid Receptors
Endorphins
Motivation
Chronic Opioid Consumption
Depression
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Update on the National Drug Overdose Epidemic: A Toxicologist’s Perspective
Demi Garvin, BS PharmD RPh F-ABFT 8
CDC Guidelines for Acute Pain Tx (2016)
• IF opioids are prescribed:
❖Prescribe < 3 day supply
❖More than 7 days will rarely be required
•
• Counsel patients about
❖Safe storage
• Proper disposal of unused opioids
Alternatives to Opioid Pharmacotherapy
Acute Pain
• Acetaminophen
• NSAIDS
• [Opioids]
• Topical agents
• Nonpharmacologic Physical therapy
• Ice• Heat……
Oral Opioids vs. Nonopioid Analgesics in ED
• Randomized control trial in the emergency department for patients with acute strains, sprains, and fractures
• Acetaminophen 1000 mg and ibuprofen 400 mg equivalent to opioids in treating acute pain
Chang A. et al., JAMA. 2017; 318(17): 1661-1667.
Post-op/Dental Acute Pain Studies
• Single dose oral analgesics for acute post-op pain• 200mg ibuprofen plus 500mg acetaminophen effective
• Third molar extractions• Ibuprofen + acetaminophen effective
• Greater analgesia with fewer side effects
Webster BS. et al., Spine. 2007; 32(19): 2127-2132.
Moore PA. et al., J. Am Dens Association. 2013; 44(8): 898-908.
Consider Opioids For
Palliative care
End of life care
•Acute (severe) trauma – short term only
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Update on the National Drug Overdose Epidemic: A Toxicologist’s Perspective
Demi Garvin, BS PharmD RPh F-ABFT 9
Naloxone
Naloxone-Opioid Reversal Agent
WHO Model List of Essential Medicines
Pure competitive opioid antagonist
, , receptors
High affinity for -opioid receptor
Onset of Action
2 minutes (IV)
2 minutes (IN)
5 minutes (IM)
Duration of Action: 30-60 minutes
Extensive first-pass metabolism(typically not given orally)
June 2014-SC Overdose Prevention Act (SC Code §44-130)
Naloxone Use
Rxs 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 opioid use disorder)
• Use of 50 mg oral morphine or MME daily, or long acting opioid
• Opioid therapy transition (due to incomplete cross-tolerance)
• Opioid Rx and concomitant• 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
• Renarcotization1. Symptoms presumed to be due to naloxone
result from opioid withdrawal2. 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
2 mg naloxone blocks 80% of μ receptors
1 mg naloxone blocks 50% of μ receptors
50% of μ receptors must be blocked to reverse OD
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Update on the National Drug Overdose Epidemic: A Toxicologist’s Perspective
Demi Garvin, BS PharmD RPh F-ABFT 10
The Opioid Triad
Pulmonary congestion and edema
Cerebral edema
Urine retention
• Respiratory depression
• Miosis
• Stupor
PM Opioid Triad
Clinical Opioid Triad
Loperamide (“Poor Man’s Methadone”)• 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 alternatively 16 mg/day x 5 days
• Abuse: reports of up to 800 mg/day
• Insignificant accumulation in the systemic circulation (tx)
• Can be taken in “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 msAbnormal > 450 ms
Loperamide Opiate Withdrawal Protocol
• Day 1: Take 400 mg of Tagamet 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 Tagamet followed by 20 mg of loperamide every 5-8 hours, or as needed, all washed down with GFJ.
• Day 3: Take 400 mg of Tagamet 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 Tagamet and wash down with GFJ.
http://opiateaddictionsupport.com/how-to-use-loperamide-for-opiate-withdrawal/
Opioids and Cardiotoxicity
LoperamideMethadoneBuprenorphineOxycodone
Risk FactorsCongenital QTc
Heart DiseaseOlder AgeFemalesHypokalemia/HypomagnesemiaBradycardiaHepatic DiseaseHigh Dose Opioid, Significant Dose IncreasesCYP450 Inhibitors (CYP3A)Drugs known to increase QTc
Drugs cause electrolyte changes
QTc >470 ms
postpubertal males
QTc >480 mspostpubertal females
Long QT Interval Syndrome
(LQTS)
Pediatric Opioid Poisoning Hospitalizations
JAMA Pediatr. 2016; 170 (12): 1195-1201
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Update on the National Drug Overdose Epidemic: A Toxicologist’s Perspective
Demi Garvin, BS PharmD RPh F-ABFT 11
Buprenorphine Indications and Formulations
• Medication Assisted Therapy• Sublingual Tablets
• Buprenorphine + Naloxone (Zubsolv®, generic)• Buprenorphine (Subutex®)
• Sublingual Film• Buprenorphine + Naloxone (Suboxone®)
• Buccal Film• Buprenorphine + Naloxone (Bunavail®)
• Injectable• Buprenorphine (Sublocade®)
• Subdermal Implant• Buprenorphine (Probuphine®)
• Pain• Transdermal System
• Buprenorphine (Butrans®)
Newborn or neonate < 1 month old
Preterm or premature < 36 weeks gestation
Term ≥ 36 weeks gestation
Infant: < 1 year old
Toddler: 1-3 years
Child: 4-11 years
Adolescent: 12-19 years
Ages and Stages
Decreasing Potency Increasing Potency
M
O
R
P
H
I
N
E
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
Honein et al. Pediatrics 2019; Wilkelman et al.
Pediatrics 2018; Haight et al. MMWR 2018
What is kratom?• Mitragyna speciosa is a tropical
evergreen tree from Southeast 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 psychoactivesMitragynine
7-OH-mitragynine
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Update on the National Drug Overdose Epidemic: A Toxicologist’s Perspective
Demi Garvin, BS PharmD RPh F-ABFT 12
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
Pharmacological Effects• High dose – Opioid-like respiratory depression and euphoria
Mitragynine and 7-hydroxy-mitragynine (7-OH-mitragynine) interact with opioid receptors (CNS)
Sedation, pleasure, decreased pain
• Low dose – CNS stimulation (coca-like)
Mitragynine also interacts with other receptors > stimulant Increased energy, sociability, mental alertness
• Uses: chronic pain, opioid withdrawal, mild stimulation
Initial Onset: 10-20 minutes
Peak Effects: up to 2 hours
Duration: 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”
Compounds of Concern
• Licit/Novel Benzodiazepines
• Sedative/Hypnotics
• Fentanyl/Novel Fentanyls
• Gabapentin
• Pregabalin
• Antiemetics
• Antihistamines
• Skeletal Muscle Relaxants
• Diphenoxylate
• Loperamide
• Mitragynine
• Buprenorphine
• Methadone
Opioid Substitutes
MAT
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
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Demi Garvin, BS PharmD RPh F-ABFT 13
• Seya M-J, Gelders SF a M, Achara OU, Milani B, Scholten WK. A first
comparison between the consumption of and the need for opioid
analgesics at country, regional, and global levels. J Pain Palliat Care
Pharmacother. 2011;25(1):6-18. doi:10.3109/15360288.2010.536307.
• Shah A, Hayes CJ, Martin BC. Characteristics of Initial Prescription
Episodes and Likelihood of Long-Term Opioid Use — United States,
2006–2015. MMWR Morb Mortal 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.
• 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.
• 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/co
untry_files/morphine_equivalence/unitedstatesofamerica_me_methadon
e.pdf. Published 2015. Accessed November 27, 2017.
• Pain & & Policy Study Group, American Caner 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.
• Paulozzi LJ, Baldwin G. CDC Grand Rounds: Prescription Drug Overdoses
— a U.S. Epidemic. MMWR. 2012;61(1):10-13.
• Webster BS, Verma SK, Gatchel RJ. Relationship between early opioid
prescribing for acute occupational low back pain and disability duration,
medical costs, subsequent surgery and late opioid use. Spine (Phila Pa
1976). 2007;32(19):2127-2132. doi:10.1097/BRS.0b013e318145a731.
• 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.
• 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.
• 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.
• 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.
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