Deaths-Related to Opioid Toxicity: Themes from a

Narrative Review

Parvaz Madadi, PhD

January 28th, 2014

Ontario Harm Reduction Distribution Program

Centre for Disease Control and Prevention, 2011

In 2008, there were ~ 14, 800 prescription opioid deaths in the United States.

Dhalla et al., CMAJ, 2009

Ontario data 1991 - 2004: Opioid analgesics and related mortality

Prescription practices & opioid-related deaths

Long-acting oxycodone introduction

Regions with high incidence of opioid-related deaths per capita have high opioid prescription utilization

Deaths appear to be concentrated amongst patients treated by physicians who prescribed opioids more frequently

High prescribed doses significantly associated with an increase risk of mortality

Dhalla et al. CMAJ, 2009

Gomes et al. Healthc Q, 2011

Dhalla et al. Can Fam Phys, 2011

Gomes et al. Arch Intern Med, 2011

Need for more individualized evidence and insight into why and how opioid-related deaths occur…

To identify patterns and characteristics amongst opioid-users whose cause of death was related to opioid toxicity in Ontario

Years: 2006 to 2008

Study Design: Retrospective, descriptive, population study in Ontarians

Objective:

Method Ontario: ~ 13 million individuals; diverse municipalities and regions Ontario Coroners Act: all sudden and unexpected deaths, and/or deaths thought to be from any cause other than disease must be reported to the Coroner’s Office from anywhere in the province of Ontario.

Death investigations involve classification of the cause of death as well as the manner of death

Coroner/medical, toxicology, pathology, police investigations reviewed

Opioid deaths isolated and studied

All drug related deaths in Ontario reviewed

Non-medical route of drug administration:

Coroner, police, autopsy Death scene investigations, puncture sites, patch debris

Indicators of diversion: Analysis of prescription

records, bottles, interviews (family , friends, healthcare

providers)

Method

More about the process…

Boxes of files, each file representing a

person who was no longer living…

Recurring themes, stories, and life trajectories….

SIX SELECTED THEMES FOR TODAY

Deaths which involve opioids tend to be

accidents

A range of potent opioids are involved in opioid-related deaths

Opioid misuse and diversion account for 30% of opioid-related

death

Opioid switching and dose adjustments are temporally associated

with opioid deaths

Substance abuse features are associated

with opioid-related accidental deaths

Opioid-related deaths are associated with

release from jail

Theme One: Deaths which involve opioids tend to be accidents

PLOS One, 2013

Demographic Characteristics Opioid-related deaths (n=1359)

Non-opioid drug-related deaths (n=971) p-value

Gender (male) 867 (64%) 572 (59%) 0.03

Age (yr); Median (IQR) Range

44 (25-51) [16-89]

46 (37-54) [14-94] <0.001

Coroner Death Classification

Accident 924 (68%) 437 (46%) <0.001

Undetermined 221 (16%) 163 (17%) 0.73

Suicide 214 (16%) 371 (38%) <0.001

Results

Mr. H was in his sixties, with a history of non-insulin dependent diabetes, sleep apnea, depression, cancer and migraines. He also suffered from chronic back pain and used regular doses of potent narcotic analgesics. He had been golfing over the few days prior to his death and had been using fentanyl patches as well as other narcotics to manage his pain. He was noted to be somewhat drowsy over the last few days. He was breathing forcefully during the night, which was not terribly unusual as he had sleep apnea. He was found unresponsive in the early morning. The cause of death was attributed to mixed drug intoxication involving fentanyl, morphine, oxycodone.

Theme One: Deaths which involve opioids tend to be accidents

Take Home Lessons

1. Toxicity from opioids may occur over a number of days

• Not entirely clear that a naloxone intervention was

needed

2. Underlying respiratory issues (sleep apnea, COPD,

smoking, bronchitis, flu) may predispose users to opioid-toxicity

• Mechanism of fatality is respiratory depression

Theme Two: A range of potent opioids are involved in opioid-related deaths

Distribution of opioids amongst single-opioid related deaths (n=1040) PLOS One, 2013

PLOS One, 2013

Of single opioid related deaths n = 1040

Manner of death per opioid type

Theme Three: Opioid misuse and diversion account for ~ 30% of opioid-related death

PLOS One, 2013

Indicators of diversion and misuse

Distribution of opioids amongst deaths related to “inappropriate route” of opioid administration (n=263)

Oxycodone34%

Morphine27%

Methadone

14%

Fentanyl9%

Hydromorphone8%

Codeine6%

Others2%

Unpublished

Using a deceased family member’s medication A woman was grieving the loss of her sister who had passed away recently from cancer. She did not show up to her sister’s funeral. The family found the woman motionless on her bed, with

dried vomitus on the pillow and sheets. The woman had her deceased sister’s

hydromorphone pills in her room which had been prescribed for cancer.

Healthcare professional diversion An Ontario nurse came home from work, went

into the bathroom, and did not emerge for half an hour. Her husband went into the bathroom, found his wife unconscious, and called the

ambulance. The ambulance crew observed an empty IV bag, tubing, and a butterfly IV in the

bathroom. The IV bag had a label indicating that it contained fentanyl .

Using friend’s medication A man was visiting his friend who had methadone

in his possession. The man was not feeling well and drank his friend’s methadone, ate some soup and had ointment rubbed on his back. The friend

went to work in the morning and left the man sleeping. On returning home from work the

friend found the man still in the same position in the bed lying on this left side. Post-mortem exam

confirmed acute methadone intoxication.

Using friend’s medication A woman was discovered unresponsive in the

basement of a friend’s house. She was pronounced dead at the scene. The day before she had been

complaining of abdominal pain. She used someone else’s hydromorphone to try to deal with the pain. An autopsy did not reveal an anatomical cause for the death but did show evidence of gastritis and possible pancreatitis. Toxicology revealed a high

dose of hydromorphone.

Case Narratives of Opioid Misuse and Diversion

Theme Four: Opioid switching and dose adjustments are temporally associated with opioid deaths

Ms. P was a 43 year old female who was recovering from crack cocaine and prescription medication abuse. In addition, she suffered from smoker’s bronchitis. She was receiving benzodiazepines, oxycodone and had started on the methadone program two weeks before her death. Her dose had just been increased to 40 mg from 25 mg prior to death. One day before her death she complained of feeling woozy. The cause of death was attributed to combined CNS effects of the drugs (mixed drug intoxication).

Theme Four: Opioid switching

Opioid Switching Prior to Death: 3.6% of cohort

1. Methadone --- n = 15

2. Oxycodone ---- n = 10

3. Fentanyl -------- n = 10

4. Hydromorphone n = 4

5. Morphine --------- n = 3

Take Home Lessons 1. Switching to a more potent opioid, adding an opioid

to someone taking methadone, or adjusting a methadone dosage, are practices that can be potentially lethal if not done with great caution.

2. The mix of ‘downers’ (benzodiazpeines + opioids + alcohol) is often associated with multidrug intoxications

3. Patients and healthcare providers should recognize what the early signs of opioid overdose may be (woozy, drowsy, tired)

Theme Five: Substance abuse features are associated with opioid-related accidental deaths

PLOS One, 2013

Substance abuse-related Features

Accidents (n=921)

Suicides (n=215) OR 95% CI P-value

History of alcohol abuse 221 (24%) 25 (12%) 2.3 [1.5-3.6] 0.0001

Cirrhosis 70 (8%) 5 (2%) 0.003

History of illicit drug abuse 486 (53%) 17 (8.1%) 8.3 [5.2-12.8] <0.0001

Cocaine/metabolite detected 308 (34%) 22 (11%) 4.32 [2.7-6.9] <0.0001

Depression 167 (18%) 112 (54%) 5.2 [3.8-7.1] <0.0001

Hepatitis 123 (13%) 3 (1%) <0.0001

Theme Six: Opioid-related deaths are temporally associated with release from jail

PLOS One, 2013

4% of deaths temporally related to incarceration (n=46)

Take Home Lessons 1. A high rate of acute drug-related mortality amongst

prison populations in the immediate post-release period has been described in other settings

2. Decreased tolerance during incarceration - upon release may utilize previous doses

3. Coordinated effort between prison and public health systems are needed to provide education to inmates on these issues.

Summary

• Deaths which have resulted from the use, abuse, and misuse of opioids have touched every community in Ontario. – Opioid-related deaths span across age, geographical,

and demographic specifications.

• This data assists in quantifying the contribution of opioid abuse and illicit opioid diversion to mortality • 1 in 5 opioid deaths: injection, inhalation, or chewing • Diversion: at least 7.4% of deaths

Summary

• Support targeted prevention, harm reduction, and educational strategies based on sub-populations of users • Both accidental and intentional opioid-related deaths

• Engagement of diverse stakeholders

• Assist in identifying and providing resources for vulnerable individuals

• Examples within Ontario data set: Prior to release from

incarceration, mental health support

Collaborators

• Dr. Gideon Koren (Clinical Pharmacology and Toxicology at SickKids)

• Dr. Bert Lauwers (formerly from the Office of the Chief Coroner of Ontairo)

• Ms. Doris Hildebrandt (Office of the Chief Coroner of Ontario)

• Funding Support: Postdoctoral Fellowship from the Canadian Institutes for Health Research

Death Classifications

• Accidental: due to an occurrence, incident, or event that happens without foresight or expectation

• Suicide: an intentional act of omission or commission in a person knowing the probable consequence of what he/she is about to do

• Undetermined: (a) there is no evidence for any specific classification; (b) there is equal evidence, or a significant contest, among two or more classifications, or (c) a death is a suicide that does not meet a high degree of probability.