5/29/2019

1

Iatrogenic Opioid Addiction

Can physicians increase the risk of opioid

addiction in their patients?

David M. Benjamin, Ph.D., Sc.D. (hon.)

Clinical Pharmacologist & Toxicologist

Affiliate Associate Professor

Dept. of Pharmaceutical Sciences

Northeastern University – Boston, MA Fellow, American Academy of Forensic Sciences (Toxicology)

Fellow, American Society for Healthcare Risk Management

Fellow, American College of Clinical Pharmacology

Fellow, American College of Legal Medicine

The Opium Poppy, Papaver Somniferans

E unum Pluribus

Terminology

Opium poppy – papaver somniferans synthesizes morphine-like

alkaloids and “non-narcotic” alkaloids: e.g.; papaverine (smooth

muscle relaxant) and noscapine, a cough suppressant.

Opiate – naturally occurring (morphine-like) alkaloid from the opium

poppy, e.g., morphine, codeine and thebaine (which is used to make

semi-synthetic opioids)

Opioid – morphine-like activity, but not naturally-occurring, e.g.,

heroin, oxycodone, hydromorphone and others.

Semi-Synthetic opioids – made in lab. from an opiate; not a naturally-

occurring alkaloid like codeine or thebaine, but made from one of them

or morphine, e.g., heroin, oxycodone, hydromorphone

Synthetic opioids – made in a chemistry. lab. e.g., methadone and

fentanyl.

5/29/2019

2

Addiction vs. Dependence

The term addiction is not found in the DSM IV.

The DSM IV defines Substance Dependence (in

pertinent part) as a maladaptive pattern of

substance use, leading to clinically significant

impairment or distress. This definition includes:

tolerance and withdrawal, and other

manifestations as: (1) being out of control, (2) use

causes problems, (3) continues use in spite of the

problems, (4) denies that a problem exists, and (5)

impairment of the quality of life. Blum and Benjamin, The Dependence-Addiction Paradigm: Good vs. Bad -

Treatment vs. Abuse, ACLM, ca, 2004.

The Opium “Family” – Natural,

Semi-Synthetic and Synthetic

Routes of Administration

Snorting

Injection, IV or “skin popped”

Smoked

Put where the sun doesn’t shine!

5/29/2019

3

How Bad is the Problem?

How Bad is the Problem?

“More people died of drug overdoses in

2014 in the U.S. than in any other year, and

60% of them were because of pain­killers.

Over the past 17 years, rates of opioid

overdose deaths have quadrupled, fueled by

over-prescription of painkillers and the

proliferation of cheaper forms of heroin and

synthetic opioids.”

Why We Need Drugs to Treat Opioid

Addiction, Alice Park, Time, Oct. 12, 2016

Cause of Opioid Deaths

1999-2016

Both over-prescribing of opioids and not prescribing

or “undertreatment” can lead to iatrogenic opioid

addiction and/or death from “street drugs.”

1. Over-prescribing of opioid painkillers OD

2. Physician stops prescribing for the patient,

and the patient buys a cheap form of heroin and/or

a synthetic opioid (fentanyl) on the street.

Fentanyl is 80 times as potent as morphine on a

ug-to-mg basis. (much is made in China) OD

5/29/2019

4

The Heroin Crisis

When the doc refuses to prescribe any more

opioids for the patient with chronic pain, they

just buy heroin on the street. It’s cheaper than a

prescription drug and easy to get.

Medication Use Process

T r a n s c r i p t i o n

Prescribing -> Dispensing -> Administering -> Monitoring

C o m m u n i c a t i o n

The physician prescribes an opioid. How do

you determine how many pills to prescribe?

The opioid crisis is a “supply side” problem!

Overprescribing: When the patient

doesn’t take all the prescribed meds, the

pills end up sold on the street.

5/29/2019

5

Heroin-related ED Visits

Heroin Epidemiology

Structure of Morphine

Morphine

5/29/2019

6

Structure of Heroin

(Diacetylmorphine)

6-Acetyl Group

6-MAM

3-Acetyl

Group

Metabolism of Heroin

T ½ = 6 mins

Heroin (Diacetyl Morphine) -----------

6-monoacetylmorphine

(aka, 6-MAM)

T ½ = 6-25 mins

6-monoacetylmorphine------------------> morphine

T½ = 2-3 hrs

Morphine --------------Morphine glucuronides

(more water soluble) and excreted with a

The Heroin Epidemic (Crisis)

Why do users risk death to abuse heroin?

Because the euphoria is so intense!

5/29/2019

7

Heroin Euphoria is so intense!

How do I know without having used any?

An ACLM MD, JD was in a clinical study of

heroin and told me. I’ve heard it before.

Structure of Fentanyl

N-phenyl-N-[1-(2-phenylethyl)piperidin-4-yl

propanamide (salt)

5/29/2019

8

Difference Between the structures

of Morphine and Fentanyl

Structure of Morphine

N-phenyl-N-[1-(2-

phenylethyl)piperidin-4-yl

Structure of Fentanyl

Oxycodone Metabolism

HYDROCODONE

HYDROMORPHONE OXYMORPHONE

MORPHINE OXYCODONE

Oxycodone Blood Levels

Single Oral Dose

Therap. BL Toxic BL

Oxycodone µg/ml 0.01 - 0.10 0.2 - 5.0

ng/ml 10-100 200-5,000

5/29/2019

9

Hint: When it Comes to Zeroes-

Always Lead and Never Follow!

Always write: 1 mg not 1.0 mg

eg, Lanoxin 0.125 mg vs Xanax 1.0 mg hs

Correct Incorrect*

*Should be written: Xanax 1 mg hs

Blood Level-Time Profile

of 20 mg oxycodone (CR)

Tmax = ~3+ hrs

Cmax = ~> 15 ng/ml

From where do new Heroin Abusers

Come from?

Controlled Prescription Drugs (CPDs)

Those who switch from abusing CPDs

to abusing heroin do so because of:

Availability (e.g., lack of availability)

price differences,

and the reformulation of ER

oxycodone with naloxone precluding

crushing and snorting or injecting.

5/29/2019

10

Abusers Switching from Controlled

Prescription Drugs (CPDs) to Heroin

According to the Nat’l Survey on Drug Use &

Health, increased demand for and abuse of

heroin has been led by:

19 times higher among those who had previously

abused pain reliever CPDs. Four out of 5 recent

heroin initiates had previously abused pain

reliever CPDs.

While the number of CPD abusers switching to

heroin abuse is estimated at 3.6% of the total

number of CPD abusers, it represents a large

percentage of heroin initiates (79.5%).

Case Study

A patient with a legitimate chronic pain

problem had been treated with an ER

oxycodone product for many years with a good

result. One day, he received a letter in the mail

from his treating physician informing him that

the physician would no longer be able to

prescribe oxycodone or any other opioid for

him after 30 more days of therapy.

The patient became highly anxious and went

out and robbed a bank in order to obtain

money to buy opioids (heroin) on the street.

Case Study – 2nd part

He was arrested by federal agents for robbing

the bank and convicted of bank robbery in

federal court.

His defense attorney called me on the phone

and asked if I would write a letter to the judge

explaining the circumstances and asking the

judge for a lenient sentence for the defendant.

I wrote the judge and told him/her this was a

case of "iatrogenic addiction.”

5/29/2019

11

Too many prescriptions, at

too high a dose, for too

many days.

A supply side problem!

“The amount of opioids prescribed in the US is still too high, with too many opioid prescriptions for too

many days at too high a dosage,” stated Anne Schuchat, MD, acting director of the CDC.

“Healthcare providers have an important role in offering safer and more effective pain management

while reducing risks of opioid addiction and overdose.”

CDC Guidelines for Prescribing

Opioids for Chronic Pain - 2016

CDC Guideline for Prescribing

Opioids for Chronic Pain — US, 2016

The guideline addresses:

1) when to initiate or continue opioids

for chronic pain;

2) opioid selection, dosage, duration,

follow-up, and discontinuation; and

3) assessing risk and addressing harms of

opioid use.

5/29/2019

12

Robert Califf, MD, FDA’s Deputy

Commissioner for Medical Products

and Tobacco with other FDA leaders

Have called for a far-reaching

“Action Plan” to reassess the agency’s

approach to opioid medications

The Plan will:

focus on policies aimed at reversing

the epidemic

provide patients in pain access to

effective relief

(FDA will) re-examine the risk-benefit

paradigm for opioids and ensure that

the agency considers their wider

public health effects.

The Plan will:

Improve access to naloxone and

medication-assisted treatment

options for patients with opioid use

disorders

5/29/2019

13

Naloxone

Intranasal Formulation

of Naloxone

Naloxone for Injection

5/29/2019

14

The “Pill Mill”

US vs Freddy Williams, MD

445 F.3d 1302 (11th Cir. 2006)

Dr. Freddy Williams, an MD in Panama

City, FL, wrote over 21,000 prescriptions

for more than two million doses of

controlled substances. He was convicted

on 94 federal charges related to the

overprescribing of narcotics, most of which

were for oxycodone.

US vs Freddy Williams, MD

445 F.3d 1302 (11th Cir. 2006)

At the trial, an expert testified that Dr. Freddy

Williams failed to meet the usual standards of care,

and that the prescriptions were for “other than

legitimate medical purposes.”

Three patients overdosed, and two died.

Dr. Williams also had billed an insurance company

for some of the patient visits where he performed

no service other than writing prescriptions for

controlled substances.

US vs Freddy Williams, MD

445 F.3d 1302 (11th Cir. 2006)

“Evidence that a physician’s performance …

departed from accepted professional

standards supported the proposition that the

physician was not practicing medicine, but

was instead cloaking drug deals under the

guise of a professional medical practice.” (Id

at 1302)

Prison and restitution of $2+ million

See: Legal Med Perspectives July/August 2006 p.57 for a more

complete review (Am College of Legal Med, publisher)

5/29/2019

15

Forensic Cases

Wrongful Death (OD), Homicide

Death of a patient on opioids …

Who Could Be Held Responsible? Physician Prescriber

Pharmacist who Dispensed/Compounded Medication

Nurse who Administered Medication

Hospital Employing MD, Reg. Ph., or RN (this is a type of vicarious liability, ie, Respondeat Superior)

Pharmaceutical Manufacturer or Distributor (the drug was too concentrated or potent and unfit for its intended use)

© Richard S. Blum, 2000