“OTC” Drug Abuse Recent Experiences of the Arkansas Poison & Drug Information Center

Keith McCain, Pharm.D., DABAT krmccain@uams.edu

Arkansas Poison & Drug Information Center

• Service unit of the UAMS College of Pharmacy • Free, confidential, and expert resource to citizens,

healthcare providers, public health officials, law enforcement agencies of Arkansas

• Available 24 hours a day, 7 days a week, 365 days a year

1 Board certified medical toxicologist (Henry Simmons Jr., M.D., Ph.D.) 2 Board certified clinical toxicologists (Pharm.D.) 10 Certified specialist in poison information (5 RN/4 Pharm.D./1 Rph) 1 Certified health education specialist

Disclosure

• I have no financial interest associated with the topic of this presentation.

• Comments are solely the responsibility of Keith McCain and do not represent the official views or positions of the University of Arkansas System, University of Arkansas for Medical Sciences, UAMS College of Pharmacy, or the Arkansas Poison & Drug Information Center.

• I tend to be a “Drugs are bad” person

Over-The-Counter/OTC

• FDA Center for Drug Evaluation and Research Division of Nonprescription Drug Products regulates OTC products.

• 91 Therapeutic categories of OTC drugs

• 800 active ingredients; >100,000 drug products

Source: Food and Drug Administration

Contributing Factors to OTC Abuse

• Misperception of Safety

• Ease of access

• Ease of concealment

• “How to” Internet sites

www.erowid.org

Dextromethorphan • Cough Suppressant approved in 1958

• Chemical similarity to codeine, but does not possess same opioid receptor activity

• When taken as directed side-effects are rarely observed

Codeine Dextromethorphan

Dextromethorphan • Found in more than 120

OTC Products • Available in liquid,

tablet, gel capsules, strips, lozenges

• Marketed alone or in combination with other active pharmaceutical ingredients

• Immediate and Extended Release formulations

• 235 million packages of DXM containing OTC produced each year

Dextromethorphan Abuse (DXM, Robo, CCC, Triple C, Skittles, Poor Man’s PCP)

The “Plateaus” of “Robotripping” PLATEAU DOSE (mg) EFFECT

1st 100-200 mg (1.5-2.5 mg/kg) 4-6 pills or 30-60 ml of syrup

Mild Stimulation, Restlessness, Euphoria

2nd 200-500 mg (2.5-7.5 mg/kg) 7-18 pills or 60-185 ml of syrup

Euphoria, Exaggerated auditory/visual sensations, Closed-eye hallucinations

3rd 500-1000 mg (7.5-15 mg/kg) 18-33 pills or 185-375 ml of syrup

Distorted visual perceptions, ataxia, Delayed reaction time, Partial dissociation

4th >1000 mg (>15 mg/kg) >33 pills or >375 ml of syrup

Hallucinations, Delusions, Ataxia, Complete dissociation

Source: Antoniou T, Juurlink DN. Dextromethorphan Abuse. CMAJ. 2014;186(16): E631. UpToDate. Dextromethorphan abuse and poisoning.

UNDESIRED CLINICAL EFFECTS

Common Less Common

Vomiting Abnormal Movements

Increased Heart Rate Seizures

Sweating Respiratory Depression

Agitation, Panic/Mania Coma

Mechanism of Toxicity

NMDA-Receptor Antagonist • Dextromethorphan and more so its active metabolite

dextrorphan, antagonize the actions of glutamate the primary central nervous system excitatory neurotransmitter.

- Phencyclidine (PCP) and ketamine are NMDA Antagonist Serotonin Reuptake Inhibitor • Increased serotonin levels can induce a spectrum of adverse

clinical effects known as serotonin syndrome (altered mental state, autonomic instability, and neuromuscular dysfunction)

NMDA Receptor Signaling

Glutamate (excitatory)

NMDA receptor

Mg++

Glycine (inhibitory)

Na+

Ca++

Activates Cellular Processes

Effect of Dextromethorphan on NMDA Receptor Signaling

Glutamate (excitatory)

NMDA receptor

Mg++

Glycine (inhibitory)

Na+

Ca++

Cellular Processes Activated

DXM

Cellular Processes Blocked

Age-Specific Annual Rate of Single-Substance Dextromethorphan Intentional Abuse Exposure Calls

American Association of Poison Control Centers 2000-2015

Source: Karami S, et. Al, Trends in dextromethorphan cough and cold products: 2000–2015 National Poison Data System intentional abuse exposure calls, Clinical Toxicology, 2018; 56:7, 656-663

14-17 years

18-21 years

30+ years

Prevalence of Annual Use for 8th, 10th, and 12th Graders, 2017

8th Grade 10th Grade 12th Grade

Any Illicit Drug 15.8% 29.1% 41.2%

Any Illicit Drug excluding inhalants and marijuana

5.8% 9.4% 13.3%

Alcohol 18.2% 37.7% 55.7%

Marijuana/Hashish 10.1% 25.5% 37.1%

Any Prescription Drug - - 10.9%

Amphetamines - - 5.9%

Tranquilizers 2.0% 4.1% 4.7%

Hallucinogens 1.1% 2.8% 4.4%

Narcotics other than Heroin - - 4.2%

Over-the-Counter Cough/Cold Medication 2.1% 3.6% 3.2%

Cocaine 0.8% 1.4% 2.7%

Inhalants 4.7% 2.3% 1.5%

Source: 2017 Monitoring the Future, Institute for Social Research, University of Michigan

Estimation of Peer Substance of Abuse Use

Source: Partnership for a Drug Free America, 2013 Partnership Attitude Tracking Survey (PATS)

Most commonly abused single-substance dextromethorphan cough and cold brands

American Association of Poison Control Centers 2000-2015

Source: Karami S, et. Al, Trends in dextromethorphan cough and cold products: 2000–2015 National Poison Data System intentional abuse exposure calls, Clinical Toxicology, 2018; 56:7, 656-663

Coricidin

Robitussin Mucinex

Perceived Availability of Substances of Abuse

Source: Partnership for a Drug Free America, 2013 Partnership Attitude Tracking Survey (PATS)

• 2007 - DEA request FDA to schedule DXM • 2009 - Consumer Healthcare Products Association

initiated an abuse mitigation plan • 2010 - FDA Drug Safety and Risk Management

Committee voted 15 to 9 against scheduling DXM

Source: Spangler DC, et Al. Dextromethorphan: a case study on addressing abuse of safe and effective drug. Subst Abuse Treat Prev Policy. 2016;11:22.

• California January 2012 • New York March 2014 • Arizona July 2014 • Louisiana August 2014 • Virginia January 2015 • Kentucky June 2015 • Washington July 2015 • Tennessee January 2016

• New Jersey February 2016 • Alaska June 2016 • Florida January 2017 • Delaware June 2017 • Nevada October 2017 • Oregon January 2018 • Colorado August 2018 • Wisconsin April 2019

Source: Consumer Healthcare Products Association / www.congress.gov

Regulatory Efforts

States with legislation prohibiting the sale of dextromethorphan products to minors

2005 - First federal legislation filed to restrict sale of “unfinished” DXM; did not become law. 2011 - First federal legislation filed to restrict sale of all DXM products to minors; efforts ongoing to pass legislation

Source: Karami S, et. Al, Trends in dextromethorphan cough and cold products: 2000–2015 National Poison Data System intentional abuse exposure calls, Clinical Toxicology, 2018; 56:7, 656-663

Annual Rate of Dextromethorphan Intentional Abuse Exposure Calls American Association of Poison Control Centers 2000-2015

Loperamide

• 1975 - Approved as prescription medication to help control symptoms of diarrhea. (16 mg/day)

• 1988 – Gained OTC status (8 mg/day) • Available as generic, store brand and Imodium

A-D; tablet/caplet, solution, suspension, chewable tablet, capsule, softgel

• Acts on opioid receptors in the intestinal wall to slow motility, and increase density and viscosity of feces

Source: U.S. Food and Drug Administration

ATP (energy)

Loperamide

Blood

Intestinal wall P-Glycoprotein Opioid Receptor

Intestinal lumen

“Normal” Processing of Loperamide by the Body

At therapeutic dose, p-glycoprotein limits loperamide concentrations from becoming high enough to result in systemic effect.

Processing of “Supratherapeutic” Loperamide by the Body

ATP (energy)

At high dose, loperamide exceeds the capacity of p-glycoprotein to limit systemic effect.

Brain

www.bluelight.org

Figure 2

Journal of the American Pharmacists Association 2017 57, S45-S50DOI: (10.1016/j.japh.2016.12.079)

Source: Miller H, et. Al., Loperamide Misuse and Abuse. J Am Pham Assoc 2017; 57(2), S45-S50

Published Case Reports of Loperamide Toxicity (1985-2016)

Clinical Effects of Loperamide Overdose

• Small pupils • Sedation • Slowed Breathing • Opioid Euphoria • Syncope or fainting • Unresponsiveness • Chest pain • Irregular heartbeat • QT/QRS prolongation • Torsades de pointes • Ventricular arrhythmia • Cardiac arrest

www.loperamidesafety.org

• Have you been taking loperamide? • How much loperamide do you take and how often? • Are you aware of the severe heart risks associated with overuse,

misuse, and abuse of loperamide?

Kratom (thang, kakuam, thom, ketum, biak)

• Plant-based substance (Mitragyna speciosa)

native to South-East Asia • >40 alkaloids (mitragynine primary alkaloid) • Typically brewed into a tea, chewed, smoked, or

ingested in capsules

Source: DEA Office of Diversion Control

Kratom

• CDC reported 10 fold increase in calls to poison centers from 2010 (n=26) to 2015 (n=263).

• Low dose = stimulant effects – Increased alertness, physical energy, talkativeness

and sociable behavior

• High dose = opioid-like effects – Sedation and euphoria

Source: CDC MMWR / July 29, 2016 / Vol. 65 / No. 29 DEA Office of Diversion Control

Kratom

• Mitragynine and 7-hydroxymitragynine placed on Arkansas CSL October 22, 2015

• DEA announced intent to list as Schedule I on August 31st, 2016

• DEA announced withdrawal of Notice of Intent on October 13, 2016 after public and congressional objections

• FDA issued public health advisory of 36 deaths linked to kratom products on November 14, 2017

• February 6, 2018; FDA releases analysis characterizing some compounds within kratom to be opioids and updated deaths “associated” with kratom to 44.

• Released FDA case files show all but one case involve kratom products laced/contaminated with other active ingredients or decedents that had evidence of additional drug use.

• May 24, 2018 CDC designates a multi-state outbreak of salmonella linked to tainted kratom as complete (199 patients in 41 states)

Kratom

Source: U.S. Food and Drug Administration Centers for Disease Control and Prevention

Kratom

• American Kratom Association: Kratom can provide increased energy, minor pain relief and many find relief from a variety of other mental and physical ailments.

• FDA: there have been no adequate and well-controlled scientific studies involving the use of kratom as a treatment for opioid use withdrawal or other diseases in humans. (09/11/2018)

Tianeptine • Tianeptine (marketed as Coaxil or Stablon) is an

atypical tricyclic drug used as an antidepressant in 66 countries across Europe, Asia, and Latin America.

• Not approved for use in the U.S., but easily available via the Internet as a “dietary supplement” or “research chemical”

• At high dose opioid receptors are activated • 2014-2017 statistically significant increase in calls

to U.S. poison control centers

Source: CDC MMWR / July 13, 2018 / Vol. 67 / No. 27 CDC MMWR / August 3, 2018 / Vol. 67 / No. 30

Tianeptine

Clinical Effects and Therapies Performed following TIANEPTINE exposures (N=114)

SYMPTOM

Increased Heart Rate 25.4%

Agitation 21.9%

Drowsiness 16.7%

Confusion 13.2%

Increased Blood Pressure 11.4%

Nausea 7.9%

Sweating 7%

Vomiting 4.4%

Coma 4.4%

Source: CDC MMWR / August 3, 2018 / Vol. 67 / No. 30

THERAPY

I.V. Fluids 35.1%

Benzodiazepine 27.2%

Oxygen 10.5%

Naloxone 9.7%

Sedation 7.9%

Antiemetic 6.1%

Intubation 4.4%

Ventilator support 4.4%

Tianeptine • Short half-life and evidence of significant dose

escalation among users. • Users predominantly 21-40 y/o and male • Associated with withdrawal syndrome:

Source: CDC MMWR / August 3, 2018 / Vol. 67 / No. 30

Symptom N=21

Agitation 33.3%

Nausea 33.3%

Increased heart rate 19.1%

Vomiting 19%

Diarrhea 9.5%

Tremor 9.5%

Sweating 9.5%

Phenazepam

• USSR developed benzodiazepine (1974)

• Never marketed in the U.S. • Not specifically listed on U.S.

CSA • ~60 hour half life

Etizolam

• Benzodiazepine developed in Japan and India • Not specifically listed on U.S. CSA • Placed on AR CSL December 2014

Benzodiazepines • Flubromazepam • Flubromazolam • Clonazolam • Pyrazolam • Nitrazolam • Adinazolam • Diclazepam • 3-hydroxyphenazepam • Deschloroetizolam • Meclonazepam • Nifoxipam • Metizolam

KRMCCAIN@UAMS.EDU