A Toxicologist’s Perspective on the National 1/13/2020 ......Opiates Opioids Tramadol Tapentadol...
Transcript of 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
1 2
3 4
5 6
A Toxicologist’s Perspective on the National
Drug Overdose Epidemic
1/13/2020
Demi Garvin, BS PharmD R.Ph 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-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
7 8
9 10
11 12
A Toxicologist’s Perspective on the National
Drug Overdose Epidemic
1/13/2020
Demi Garvin, BS PharmD R.Ph F-ABFT 3
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
13 14
15 16
17 18
A Toxicologist’s Perspective on the National
Drug Overdose Epidemic
1/13/2020
Demi Garvin, BS PharmD R.Ph F-ABFT 4
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
19 20
21 22
23 24
A Toxicologist’s Perspective on the National
Drug Overdose Epidemic
1/13/2020
Demi Garvin, BS PharmD R.Ph F-ABFT 5
• 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
25 26
27 28
29 30
A Toxicologist’s Perspective on the National
Drug Overdose Epidemic
1/13/2020
Demi Garvin, BS PharmD R.Ph F-ABFT 6
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
31 32
33 34
35 36
A Toxicologist’s Perspective on the National
Drug Overdose Epidemic
1/13/2020
Demi Garvin, BS PharmD R.Ph F-ABFT 7
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
37 38
39 40
41 42
A Toxicologist’s Perspective on the National
Drug Overdose Epidemic
1/13/2020
Demi Garvin, BS PharmD R.Ph F-ABFT 8
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)
43 44
45 46
47 48
A Toxicologist’s Perspective on the National
Drug Overdose Epidemic
1/13/2020
Demi Garvin, BS PharmD R.Ph F-ABFT 9
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
49 50
51 52
53 54
A Toxicologist’s Perspective on the National
Drug Overdose Epidemic
1/13/2020
Demi Garvin, BS PharmD R.Ph F-ABFT 10
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/
55 56
57 58
59 60
A Toxicologist’s Perspective on the National
Drug Overdose Epidemic
1/13/2020
Demi Garvin, BS PharmD R.Ph F-ABFT 11
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
61 62
63 64
65 66
A Toxicologist’s Perspective on the National
Drug Overdose Epidemic
1/13/2020
Demi Garvin, BS PharmD R.Ph F-ABFT 12
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)
67 68
69 70
71 72
A Toxicologist’s Perspective on the National
Drug Overdose Epidemic
1/13/2020
Demi Garvin, BS PharmD R.Ph F-ABFT 13
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
73 74
75 76
77 78
A Toxicologist’s Perspective on the National
Drug Overdose Epidemic
1/13/2020
Demi Garvin, BS PharmD R.Ph F-ABFT 14
› 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.
79 80
81 82
83 84
A Toxicologist’s Perspective on the National
Drug Overdose Epidemic
1/13/2020
Demi Garvin, BS PharmD R.Ph F-ABFT 15
▪ 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.
85 86
87