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What is an Opioid? Opiates as defined from MedcineNet: A medication

or an illegal drug that is derived from the opium poppy or that mimics the effect of an opiate (a synthetic opiate). Opiate drugs are narcotic sedatives that depress activity of the central nervous system, reduce pain, and induce sleep

Opiates work by interacting with the Opioid Receptors on the nerve cells in the brain and nervous system to produce pleasurable effects and ultimately relieve pain

Some additional Info

Narcotic -refers to opioids and opioid derivatives

Oxycodone versus Oxycontin- Oxycodone is the

actual substance(opioid) in Oxycontin, Oxycontin is

a 12 hr sustained release form of oxycodone

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Shocking Stats US Opioid Use

According to the National Survey on Drug Use and Health over 2 million Americans are

currently addicted to opioids

In 2012, 259 million prescriptions were written for opioids, which is more than enough to

give every American adult their own bottle of pills

61% of drug overdoses from 2014 were related to prescription drugs containing opioids

Direct correlation between increase in prescriptions and overdose rates

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Chasing the Pain- How the Epidemic Started

The opioid epidemic specifically the use of Oxycontin, the largest prescribed opioid, can be attributed to three main factors:

New trend in Pain Pharmacology starting in the early 1980’s

Strategic marketing campaign lead by Purdue Pharma, the maker of

Oxycontin

Change(liberalization)in physicians prescribing habits for opioids

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Change in Pain Pharmacology 1980’s

Historically opiates and narcotics had been prescribed primarily for cancer patients with

chronic pain

Starting in the early 1980’s shift in the usage of opiates starts to occur

Used for chronic non-cancer patients i.e.. dental pain, orthopedic pain

Two articles were posted in Medical journals in support of opioid use

New England Journal of Medicine “reported that less than one percent of patients at Boston

University Medical Center who received narcotics while hospitalized became addicted.”

Journal of Pain advocating for non-cancer patient use, “narcotics can be safely and effectively

prescribed to selected patients with relatively little risk of producing the maladaptive behaviors

which define opioid abuse.”

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Change in Pain Pharmacology 1980’s Cont’d

“While the number of cancer patients was not likely to increase drastically

from one year to the next, if a company could expand the indications for use

of a particular{narcotic} drug, then it could boost sales exponentially without

any real change in the country's health demography.”- Mike Mariani

This atmosphere created the perfect storm for Oxycontin to hit the market

1995 FDA approves Oxycontin

Additional strengths were released to market in 1996

In 2000 a 160mg tablet was released(no longer on the market)

High dosage forms contributed to the abuse of the drug, making it easy to

crush, sniff, snort and inject for a euphoric long lasting high. Now considered

a gateway drug to heroin

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Strategic Marketing Campaign led by Purdue Pharma

Lead by Arthur Slacker one of three owners of Purdue

Claim to fame was the Valium marketing campaign in which the drug hit $100 million in

revenue

Arthur launched a multifaceted marketing campaign of Oxycontin

From 1996-2001 Purdue Pharma held more than 40 national pain- management

conferences speaking to over 5K healthcare professionals

Creating sentiment "Forget fears about prescribing opioids to a more general pain

population. This isn’t heroin. This pill has a unique time release mechanism that means

it’s not very addictive at all.”

Collection of prescribing data for years

Purdue had collected data on physicians prescribing habits creating prescribing profiles

on individuals and physicians. Purdue used this data to target the higher prescribers .

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Strategic Marketing Campaign led by Purdue Pharma Cont’d

Patient Starter Coupon program- gave patients free prescription for a 7-30 day

supply

A total of 34,000 coupons had been redeemed nationally according to the

Washington, DC: General Accounting Office.

Why was Oxycontin the narcotic of choice for physicians? Other Narcotics

on the market ( i.e. Percocet, Vicodin, Fentanyl)

The crux of the entire marketing campaign was the drug’s “ incredibly

low risk of addiction” as a result of the time-release formulation

Even the FDA bought into this logic, a Medical Officer from the agency

stated “Delayed absorption, as provided by OxyContin tablets is believed

to reduce the abuse liability of a drug.”

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Examples of Purdue’s Advertisement Campaign

“Friend for life against the war on pain”

A campaign of deliberate deception?

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Change in Physicians’ Prescribing habits Based on the intense marketing campaign which included over 20k

pain- management related workshops and lectures espousing better pain management strategies coupled with the “incredibly low risk of addiction” doctors started to write scripts for Oxycontin more regularly and more liberally

By 2001 General Account Office confirmed Oxycontin became the most frequently prescribed brand-name opioid in the United States for treating moderate to severe pain

New pattern of thinking- Get ahead of the pain instead of behind the pain

Sentiment people want physicians to treat their pain adequately using opioids. Payment for doctors being based on patient surveys motivates physicians to write for opioids

“ We have created a culture where pain medication is not expected it is demanded by the patients” – Kevin Pho, M.D.

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The Power of the Oxy Addiction The euphoric affects of Oxycontin contribute to addictive properties creating a physical

dependence that is very often unavoidable when a person is exposed to high doses of the drug for an extended period of time

The body adapts and develops a tolerance for Oxycontin making it almost impossible to stop taking them without some form of Oxycodone recovery treatment

“ He’d {the doctor} spent less than ten minutes with me. It had almost seemed too easy. I looked at the prescription, and

I noticed that my heart began to beat faster and I started to sweat. Just the mere sight of the prescription was enough to wake up the demon. I filled it on the way home. As I took the bottle out of the sack, I thought to myself “Welcome back, my friends. I’ve missed you.” It was the very beginning of the prescription so the bottle was full. I was confident that if I took two pills, I’d be able to make it up during the month. Just this once, I told myself. Then it’s back to the right dose. Yeah, sure. I spent the next couple of weeks trying desperately to keep my consumption under control. I did better on some days than others, but I was still using more than prescribed.”- Recovered Oxycontin addict

“ I needed Oxycontin to function like I needed air to breath”

“ The addiction was so strong before I knew it I was up to 80mg , running out of pills before my script, pleading desperately with my doctor for another script and making up excuses to Pharmacists for additional pills. I then resorted to the streets to get the drug”

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Consequences for the nation & Purdue Pharma

A nation addicted to oxycontin(opioids)- increased overdoses

People dependent on the drug lead to the destruction of communities

Now taking a reactionary stance to curb the epidemic

2003 FDA issued Warning Letter to Purdue Pharma for misleading advertising claims re:

addictive potential

2007 United States V. Purdue Pharma Largest Pharmaceutical settlement in US History

Lawsuit brought against Purdue Pharma, Inc and its top executives pled guilty that it

misrepresented and misbranded the risk of addiction

Purdue paid a fine of $634 million

Purdue’s estimated sales of Oxycontin were approx $35 billion as of Q32015

Investigations relating to the trial found that Purdue had encouraged doctors to over

prescribe Oxycontin for conditions that were not classified as severe pain and misbranded

the drug as low abuse potential

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Consequences for the nation & Purdue Pharma

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FDA & State Governments Involvement in curbing the epidemic

Black Box Warning on Extended Release Formulation in 2002 for abuse potential

2010 Purdue released a new formulation of Oxycontin designed to be abuse deterrent

Excipients were used to give it a thicker and gooey consistency

The original formulation stopped being shipped the same year

23Mar2016 FDA now requiring all Immediate Release Opioids to carry a black box warning

“The development of abuse-deterrent opioid analgesics is a public health priority for the FDA,” said Douglas

Throckmorton, M.D.

Directed to Wholesalers practices-DEA instituted Order Monitoring Plan (OMP) for wholesalers designed to monitor

wholesalers distribution of opioids. Focus on the choke point. Easier to monitor a handful of wholesalers as oppose to

thousands of pharmacies.

Directed towards Pharmacists practices-State level-Prescription Monitoring programs (PMPs) have been implemented

& state governors looking towards strengthening prescribing laws.

PMP requires pharmacist to check database to ensure script was not filled by another physician and at any

pharmacy recently. Pharmacists due diligence before filling opioid script

States are attempting to set forth general guidelines address best practices for prescribing painkillers

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New(OP) vs. Old Oxycontin(OC) formulation- Abuse deterrent technologies added

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Abuse deterrent polymers were used in the new formulation of Oxycontin (OP). Row #1-OP is thicker than the original (OC) formulation Row #2- Cannot be ground into a fine dust anymore Row #3- Sludgy substance not easy to inject

FDA & State Governments Involvement in curbing the epidemic

Directed towards Physicians: 16Mar2016 Center for Disease Control and Prevention released

revised guidelines for physicians(these are not binding)

"For the first time, the federal government is communicating clearly that the widespread

practice of treating common pain conditions with long-term opioids is inappropriate,"

Kolodny said. "The CDC is making it perfectly clear that medical practice needs to

change because we’re harming pain patients and fueling a public health crisis.“

New guidelines recommend physicians should prescribe for cancer-patients and or end

of life care – reverting back to original prescribing trends

Only when necessary outside of cancer patients and or end of life treatment

Give lowest amount for shortest amount of time

Do the benefits of opioids outweigh the risk for the patient ?

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FDA & State Governments Involvement in curbing the epidemic Cont’d

Directed to Sponsors: Agency has held several forums to better understand the extent of the opioid abuse and public health concerns

2015 FDA Guidance Document published to develop abuse- deterrent technologies

Science of abuse deterrent technologies is relatively new, FDA maintain “flexible , adaptive approach in evaluating abuse deterrent technologies”

Guidance outlines FDA’s recommendation on including abuse-deterrent technologies are part of opioid drug formulation –helpful for opioid innovators

Examining the drugs abuse potential in in vitro studies, understanding the drugs potential to be manipulated and abused. These results will impact what other preclinical and clinical testing is required

In Vivo- Examine the PK and PD profiles if the drug is taken in true form vs. manipulated form

Clinical Abuse Deterrent study- How attractive is the formulation for abuses and how will it be abused?

PostMarket studies- Evaluate how effective are drugs with abuse- deterrent technologies in reducing abuse

Examples of Opioids Deterrent formulations

Use of chemical barriers- making the pill hard to crush, chewing or grinding, change properties of the drug if abuse is attempted ie product turns into a paste

Antagonistic combinations- If the drug is not taken as directed ( crushed, chewed, injected) antagonistic affects will be come active reducing the euphoric feeling

Aversion – Substances can be combined to produce an unpleasant effect if the dosage form is manipulated prior to ingestion or a higher dosage than directed is used

FDA Opioid Action Plan – February 2016

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1. Expand use of advisory committees-Expert advisory committee will be required to meet anytime a

opioid with non- abuse deterrent technologies is up for approval

2 . Develop warnings and safety information for immediate-release (IR) opioid labeling-

Additional warnings to be added to the label, provide more info so doctors can prescribe

appropriately

3. Strengthen postmarket requirements- Better understanding of the long-term impact of opioid use

and insight into misuses

4. Update Risk Evaluation and Mitigation Strategy (REMS) Program-Increase training for prescribes

on pain management

5. Expand access to abuse-deterrent formulations (ADFs) to discourage abuse- Further explore

abuse –deterrent formulations

6. Support better treatment- More access to overdose treatment medications i.e. Naxolone OTC

7. Reassess the risk-benefit approval framework for opioid use-Upcoming Adcom to discuss opioid

impact on public health

FDA & State Governments Involvement in curbing the epidemic

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Additional Affects from Opioid Epidemic

The opioid epidemic has spawned the development of new categories of drugs to treat the addiction and side effects of the opioid narcotics:

Suboxone (buprenorphine/naloxone) an opioid drug that has a "ceiling effect" that binds to opiate receptors in a way that mitigates withdrawal symptoms without producing the high risk of overdose has become a mainstay in treating opiate addiction

Evivo (naloxone) injections are now being used to treat and reverse acute overdose symptoms. In many cases they are prescribed for patients taking high doses of opiates just to have available for a caretaker to administer in the event of an inadvertent overdose

Movantik(naloxegol) has been developed to combat a common side effect with opiates referred to as opioid induced constipation or OIC

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Moral Dilemma Measuring a subjective symptom- Pain is not a vital sign or a

diagnosed diseased

Prescribing for people truly in pain without supporting addiction – Regulate abuse without while assessing legitimate uses

Look to other solutions to manage the pain, i.e. physical therapy

Managing Physicians’ autonomy to prescribe- New York Time’s article “The American Medical Association says the decision to prescribe drugs should “stay in the hands of physicians. Of course, doctors should have discretion to make medical decisions, including what drugs to use, but state governments also have a duty to protect people by placing sensible limits on the use of risky substances.”

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References Prescription Drugs: OxyContin Abuse and Diversion and Efforts to Address the

Problem. Washington, DC: General Accounting Office; December 2003. Publication GAO-04-110

The Promotion and Marketing of OxyContin: Commercial Triumph, Public Health Tragedy

Centers for Disease Control and Prevention. (2014). Opioid Painkiller Prescribing, Where You Live Makes a Difference. Atlanta, GA: Centers for Disease Control and Prevention.

National Institute on Drug Abuse. (2015). Drugs of Abuse: Opioids. Bethesda, MD: National Institute on Drug Abuse

How the American opiate epidemic was started by one pharmaceutical company Author Mike Mariani

Who Is Responsible for the Pain-Pill Epidemic? Author Celine Gounder

MedicneNet

American Society of Addiction Medicine- Opioid Addiction 2016 Facts & Figures

FDA Guidance Document- Abuse-Deterrent Opioids Evaluation and Labeling

Governors Unite in the War Against Opioids- New York Times Author Editorial Board

USA Today- Doctors Told to stop prescribing opiates for chronic pain 22

Questions?

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