Opioids and Children:Solving a “crisis” that we created

Cyrus Rangan MD FAAP FACMT

Medical Toxicologist, Children's Hospital Los Angeles

Assistant Medical Director, California Poison Control System

Disclosure

I have no relevant financial relationships with the

manufacturer(s) of any commercial product(s) and/or provider

of commercial services discussed in this CME activity.

I do not intend to discuss an unapproved/investigative use of a

commercial product/device in my presentation.

Opioids and Children

• 130 people die each day in the US from opioid poisonings

• Misuse of and addiction to opioids – Rx, heroin, synthetics – affects public health, social, economic welfare.

• CDC estimates "economic burden" at $78.5B, year costs (healthcare, lost productivity, addiction treatment, and criminal justice)

• How did we get here?

Dextromethorphan

• Present in numerous cough/cold preps

• Derived from codeine: may produce opioid symptoms, “false-positive” on opioid screen

• Shared chemical characteristics with PCP and ketamine: effects are similar, but less pronounced

• Toxicities seen in therapeutic dosing and abuse.

Dextromethorphan

• Robitussin DM

• Coricidin CCC

• Abuse has led to behind-the-counter and/or 18-and-over

status in many states

Kratom

7-Hydroxymitragynine

Kratom

• Origins in Malaysia, Thailand

• Primary route is ingestion, but may be smoked

• Effects within 5-10 minutes, and last 2-5 hours

• Not regulated or controlled in the U.S., easily purchased over internet, primarily opioid-like effects, with a “ceiling”

Fentanyl Patch

• Street value $25-30 per patch

• Heating the patch liberates the compound

• Fatal intravenous misuse of transdermal FentanylReeves M D and Ginifer C J, MJA 2002 177 (10): 552-554

Narcotic-containing preparations

• Allay

• Anexsia

• Anolor DH 5

• Bancap-HC

• Capital with Codeine

• Co-Gesic

• Darvocet

• DHCplus

• Dolacet

• Dolagesic

• Duocet

• E-Lor

• Endocet

• EZ III

• Hycomed

• Hyco-Pap

• Hydrocet

• Hydrogesic

• HY-PHEN

• Lorcet 10/650

• Lorcet 10/650

• Lortab

• Margesic #3

• Oncet

• Panacet 5/500

• Panlor

• Percocet

• Polygesic

• Propacet 100

• Pyregesic-C

• Roxicet

• Roxilox

• Stagesic

• Talacen

• T-Gesic

• Tylenol with Codeine

• Tylox

• Ugesic

• Vanacet

• Vendone

• Vicodin

• Wygesic

• Zydone

Opiates and OpioidsEmerging drugs

“Patients reportedly purchased yellow pills alleged to be Percocet, an opioid pain

medication. The substance has not yet been identified but it is extremely potent and

has required massive doses of naloxone (Narcan) to counteract its effects. Dozens

of patients have been hospitalized and there are reports of deaths that may be

associated with the drugs. The overdoses have been reported over a 48-hour period

in Centerville, Perry, Macon-Warner Robins, and Albany, but the drugs may also

be sold on the street in other areas of the state. Testing is being done to identify the

pills and the ingredients.”

Georgia Department of Public Health

Opiates and OpioidsEmerging drugs

“Two new fentanyl analogues, acrylfentanyl and tetrahydrofuran fentanyl, both can

be absorbed through the skin and are considered highly dangerous. Neither is

approved for human or animal use. The opioid reversal drug naloxone, may not be

effective if someone overdoses after ingesting acrylfentanyl.”

Georgia Bureau of Investigation (GBI), June 27, 2017

Opiates and OpioidsEmerging drugs

“DEA Acting Deputy Administrator Jack Riley urges any law enforcement personnel who come in contact

with fentanyl or fentanyl compounds to take the drugs directly to a lab. “Fentanyl can kill you,” Riley said.

“Fentanyl is being sold as heroin in virtually every corner of our country. It’s produced clandestinely in

Mexico, and (also) comes directly from China. It is 40 to 50 times stronger than street-level heroin. A very

small amount ingested, or absorbed through your skin, can kill you.” Two Atlantic County, NJ detectives were

recently exposed to a very small amount of fentanyl, and appeared on the video. Said one detective: “I thought

that was it. I thought I was dying. It felt like my body was shutting down.” Riley also admonished police to

skip testing on the scene, and encouraged them to also remember potential harm to police canines during the

course of duties. “Don’t field test it in your car, or on the street, or take if back to the office. Transport it

directly to a laboratory, where it can be safely handled and tested.”

Drug Enforcement Administration

Opiates and OpioidsEmerging drugs – Fentanyl hysteria?

• Dermal absorption of fentanyl– Can occur…

– Absorption and distribution is slow

– Further research is needed on newer synthetic derivatives

• Oral or inhalational exposures may be occurring simultaneously?

• Minimal data on cases of deaths or severe symptoms

Opiates and OpioidsPresentation

• Opiate syndrome

– Hypothermia, bradycardia, apnea, hypotension

– Mental status: sedation, obtundation, coma

– Small pupils

Opiates and OpioidsTreatment

• One of few street drugs with an effective antidote

• Naloxone – antagonizes opiate receptors

• Can work within seconds

• Watch for withdrawal; may need to treat aggressively with

benzodiazepines

Background on the “Opioid Crisis”

Late 1990s – pharmaceutical companies reassured medical community opioid pain relievers don’t cause addiction

NEJM: http://www.nejm.org/doi/pdf/10.1056/NEJM198001103020221

• Unrelieved pain major, yet an avoidable, public health problem

• 1997, collaborative project initiated to integrate pain assessment

and management into standards

• 2001, all patient care organizations accredited by JCAHO - Pain

Management became the “5th vital sign”

• Prescription opioids purported and perceived to be “safe” “non-

addicting”

Overprescribing: “The 5th Vital Sign”

Opioids and Children

• Healthcare providers began prescribing at greater rates, leading to widespread diversion and misuse before it became clear that Rx use led to high levels of addiction.

• Opioid overdose rates: 2017, >47,000 died in US from opioid overdose – Rx, heroin, synthetics – 1.7 million with substance use disorders related to prescription opioid pain relievers; 652,000 suffered from a heroin use disorder

The “Public Health Crisis”

• 21-29% of patients prescribed opioids for chronic pain misuse them

• 8-12% develop an opioid use disorder

• 4-6% who misuse prescription opioids transition to heroin

• 80% who use heroin misused prescription opioids first

• 30% overall opioid increase, 2016-2017 across US (Midwest 70%)

Consequences of the “public health crisis”

• Increase opioid misuse and overdoses

• Increase neonatal abstinence syndrome

• Increase in spread of HIV and HepC in areas of higher use

• 10-15% of HS seniors report having misused prescription opioids (general adult population =5%)

• Non-medical use has largely followed trends in medical use.

• United States biggest consumer globally of opioids, accounting for almost 100% of world total for hydrocodone (e.g., Vicodin) and 81% for oxycodone (e.g., Percocet)

• Number of prescriptions for opioids (like hydrocodone and oxycodone products) escalated from 76 million in 1991 to 207 million in 2013

International Narcotics Control Board Report 2008. United Nations Pubs. 2009. p. 20

NATIONAL OPIOID OD DEATHS: BY SEX

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

*Includes heroin, illicit synthetic opioids, and opioid analgesics

Trends in lifetime medical and nonmedical use of prescription opioids among high school seniors, 1976–2015.

Sean Esteban McCabe et al. Pediatricsdoi:10.1542/peds.2016-2387

©2017 by American Academy of Pediatrics

Joint Commission requirement

to address pain

Opioids and Pediatrics

• 2013: 750,000 patients treated for nonmedical use of prescription pain relievers

• 18,893 Opioid analgesic overdose deaths in 2014 (5x increase since1999)

• 7,000 people treated daily in EDs for incorrect opioid use

• 17% of ED patients are prescribed opioids at discharge

Children and Adolescents, Age 0-20yNational Poison Data System 2000 -2015

• 188,468 prescription opioid exposures: Increased early, declined after 2009. Buprenorphine increased during the last 3 study years

• Hydrocodone: largest proportion (28.7%)

• 47.1% of buprenorphine exposures admitted (90% in children 0-5y)

• Odds of being admitted to HCF higher in teens vs children 0-5y(OR: 2.86; 95% CI: 2.78–2.94) or 6-12 (OR: 6.62; 95% CI: 6.06–7.02)

• Serious outcomes greater in teens vs. children 0-5y(OR: 3.03; 95% CI: 2.92–3.15) or 6-12 (OR: 4.59; 95% CI: 4.21–5.00)

• Prescription opioid–related teen suicide rate increased by 52.7%

In the ED, we…

• Treat patients with severe pain

– Physical injury

– Sickle cell pain crises

– Breakthrough pain in chronic-disease patients

• Drug overdoses

Opioids and Pediatrics

• Children < 18y = 25% of US population

• Rate of Opioid prescriptions in adolescents 15-19 years doubled

from 1994-2007

• By 2013, 2M Americans > 12 years either abused or were dependent

on opioid painkillers

Opioids and Pediatrics – Research Needs

• Surprisingly poor data on pediatric PK/PD– Drug absorption, metabolism and elimination

– Drug efficacy

– Drug adverse reactions

• Long-term issues– No data on growth and development

– Few clinical trial study designs in pediatrics

– Few studies on long-term efficacy of opioids for chronic pain

Opioids and Pediatrics – Research Needs

• Most studies are industry-generated – pharmaceutical companies have

little incentive to obtain or publish pediatric data on opioid safety and

efficacy

• General reluctance to publish negative data

• Pediatric exclusivity studies occur late into research cycle, if at all

• Marketing protection of sales to adults morphs into economic

benefits for all ages

• Sponsors may not see publication as worthwhile, after marketing

protection

Opioids and Pediatrics – Research Needs

• Minimal convincing data on safety and efficacy on pre-term infants• > 90% of opioids lack FDA approval for prescribed indication

• Tiny babies, tiny market

• Research needs:

• Randomized, masked, placebo-controlled trials

• Head-to-head efficacy trials

• Short and long-term neuro/developmental outcomes, with surveillance until at

least school age

Opioids and Pediatrics – Case Example

• FDA issued a Pediatric Written Request to manufacturer to study

Oxycodone/OxyContin in children; Reviewed by FDA Pediatric

Review Committee

• Safety and Pharmacokinetic studies performed in likely pediatric

patients led to some pediatric labeling

• Physicians received specific information to “safely manage pain in

this sub-group of patients”

• Negative publicity due to prescription opioid misuse has led to FDA

moratorium on new opioid labeling for children

Opioids and Pediatrics – Lack of Data

• Morphine, Methadone– Safety and efficacy in patients <18 years not established

• Hydromorphone– Pharmacokinetics not evaluated in children

• Fentanyl– Safety and efficacy of in children <2y not established

• Oxycodone, Hydrocodone– SOME pediatric dosing info

Opioids and Pediatrics

Opioids and Pediatrics – Life Challenges

• Few adolescents with an opioid use disorder receive treatment. For example, between 2001 and 2014 only 1 in 4 insured youth with an addiction received treatment

• Initial exposure in adolescents often occurs via prescription

• ~70% by MD’s, 30% via DMD’s

• Clinical need to seek alternative to opioids

• Talking to teens about pain treatment and life management

• Inherent difficulty in ED setting

• Still up to ED caregivers to recognize role in unwittingly initiating the process of addiction

Opioids and Pediatrics – Systemic Needs

• Safe, effective, non-addictive treatments to manage chronic pain. Simply reducing medical use poorly addresses untreated pain. Need new therapies.• “Biased agonists”: pain relief via mu-opioid receptor (less “reward”/respiratory depression) • Cannabinoids, sodium channel blockers, gene therapies, transcranial magnetic stimulation,

transcranial direct current stimulation, and electrical deep brain stimulation

• Addiction• Strategies to engage overdose patients in treatment• Need new meds to treat: Methadone, buprenorphine, and naltrexone medications generally

effective in compliant patients, but not all patients respond

• Novel molecular targets• kappa-opioid receptor/serotonin receptor modulators in early development• Vaccines may limit opioids from entering brain

Opioids and Pediatrics – Interdisciplinary Approaches• Illinois EMSC: Collaborative program between the Illinois Department of Public Health

and Loyola Medical Center to ensure appropriate emergency medical care is available for ill and injured children at every point along the continuum of care.

• The Children’s Hospitals and Clinics of Minnesota’s Palliative Care and Hospice Program: Seamless inpatient, home, and hospice care for children experiencing acute or chronic pain, or living with life-limiting medical conditions. Physician, family members, specialty-care providers, nurses, social workers, child life specialists, chaplains, and volunteers.

• CHLA, UCLA and others: Pediatric Pain Programs – interdisciplinary research, clinical service, and education. Evaluate and treat infants, children, adolescents, and young adults with complex chronic pain.