The prescription opioid epidemic in a nutshell

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"Not much I suppose..."

I would agree.

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i fail to understand your pessimism on pain experts.

would you want a panel of orthopedic surgeons make determinations on best quality care on blood pressure, diabetes management, cholesterol treatment? likewise, should internists and family practitioners who may have very limited exposure to the actual science of opioids be expert consultants?

and if you use the defense that these are experts based on their own individual resumes, then those individuals should be noted and not be covered globally by their supporting organizations.


of note, the Stakeholder Review Group does include some "pain experts", though its interesting that this includes AAPM and APS, along with PROP AS Addiction Medicine. But OB/GYN? Neurology? Hematology??
 
Dr. Coelho seems incapable of answering a simple, straightforward question. Perhaps because if he were to do so, he would confirm what we all already have concluded - he is a hypocrite.
 
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Pain specialists practicing on the front lines, especially in rural and low resourced areas, understand the dynamics of this issue better than academics, consultants, and others comfortably an arms-length away.
 
Double post
 
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Pain specialists practicing on the front lines, especially in rural and low resourced areas, understand the dynamics of this issue better than academics, consultants, and others comfortably an arms-length away.
Let's take a moment to remember who decided to throw away thousands of years of experience with opiates and declare them "safe," "effective" and with "addiction risk <1%" and whom set this whole catastrophe in motion. It wasn't everyday clinical doctors with their common sense and real world experience. It's was so called "experts" with padded resumes and fancy titles. They were dead wrong. Let's never forget this lesson, before we shelve our common sense, instincts and knowledge amassed from tens of thousands of patient encounters, and decide to blindly follow them and their often biased and incorrect "research" again.
 
Let's take a moment to remember who decided to throw away thousands of years of experience with opiates and declare them "safe," "effective" and with "addiction risk <1%" and whom set this whole catastrophe in motion. It wasn't everyday clinical doctors with their common sense and real world experience. It's was so called "experts" with padded resumes and fancy titles. They were dead wrong. Let's never forget this lesson, before we shelve our common sense, instincts and knowledge amassed from tens of thousands of patient encounters, and decide to blindly follow them and their often biased and incorrect "research" again.

That won't convince @101N. He doesn't think pain specialists, especially those in rural and under-resourced areas, need a seat at the table. Wisdom is not the same as book smart.
 
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Yet remarkably, he holds himself out to be a pain specialist who, I feel certain, would relish the a seat at the table to spew his disdain for those who disagree with his nihilistic view of the field.
 
That's nice, you are a doctor in rural Oregon. Have you published on opioid prescribing?
Do you have any special training in toxicology or opioids?
i fail to understand your pessimism on pain experts.

would you want a panel of orthopedic surgeons make determinations on best quality care on blood pressure, diabetes management, cholesterol treatment? likewise, should internists and family practitioners who may have very limited exposure to the actual science of opioids be expert consultants?

and if you use the defense that these are experts based on their own individual resumes, then those individuals should be noted and not be covered globally by their supporting organizations.


of note, the Stakeholder Review Group does include some "pain experts", though its interesting that this includes AAPM and APS, along with PROP AS Addiction Medicine. But OB/GYN? Neurology? Hematology??

IMO having done a pain fellowship and working in IPM
Does not make one an expert on opioid dosing for CNP or
Rational opioid policy. Within the specialty, and the various societies, opinions are still widely divergent. Moreover, most pain
Specialist still believe in double standard opioid dosing: high for
Specialists, low for primary care. Finally, many IPM specialists still implant for CNP.

The pain management community has, by and large, been too slow to recognize and respond to the opioid crisis to be considered credible experts. It was the epidemiologists - particularly Len Paulozzi & Mike Von Korff - and addiction folks - along with parents who lost their kids to OD's - who started the call to arms, not us.

Lastly, the highest risk group of patient for both addiction & ODD
are Medicaid pts and few amongst us see these because procedures typically aren't covered.
 
That's nice, you are a doctor in rural Oregon. Have you published on opioid prescribing?
Do you have any special training in toxicology or opioids?


IMO having done a pain fellowship and working in IPM
Does not make one an expert on opioid dosing for CNP or
Rational opioid policy. Within the specialty, and the various societies, opinions are still widely divergent. Moreover, most pain
Specialist still believe in double standard opioid dosing: high for
Specialists, low for primary care. Finally, many IPM specialists still implant for CNP.

The pain management community has, by and large, been too slow to recognize and respond to the opioid crisis to be considered credible experts. It was the epidemiologists - particularly Len Paulozzi & Mike Von Korff - and addiction folks - along with parents who lost their kids to OD's - who started the call to arms, not us.

Lastly, the highest risk group of patient for both addiction & ODD
are Medicaid pts and few amongst us see these because procedures typically aren't covered.

Well, Paul, since you asked: I am a MRO, CLIA-designated High Complexity Testing Clinical Consultant & Moderate Complexity Laboratory Director. I'm a co-author on an analytical method for urine toxicology of opioids and drugs of abuse. I teach PM&R residents and family practice residents who rotate at our Center opioid prescribing. I have a graduate degree in epidemiology. I have a graduate certificate in Health Policy. I completed an NIH training program in clinical research. I practice daily in a region of the country disproportionately affected by opioid misuse and abuse. I practice with a board-certified addiction medicine/pain medicine physiatrist, a drug/alcohol counselor, and a behavioralist doing integrative pain management every day. The ACGME would beg to differ with you that my training and experience (anesthesia-based pain fellowship) does not qualify me to hold myself out as a legitimate expert on opioid prescribing for CNP. And, others on this forum are even more qualified than me.

So, it's insulting (and tiresome) to assert that no one other a few (self-) selected experts have an important perspective. Still, you insist on doing that on this forum almost daily. You damage only your reputation and your credibility by speaking out of turn, not knowing your audience, and depending upon PERSONAL attacks against those who disagree with your PERSONAL opinions...

What qualifies YOU to
 
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Well, Paul, since you asked: I am a MRO, CLIA-designated High Complexity Testing Clinical Consultant & Moderate Complexity Laboratory Director. I'm a co-author on an analytical method for urine toxicology of opioids and drugs of abuse. I teach PM&R residents and family practice residents who rotate at our Center opioid prescribing. I have a graduate degree in epidemiology. I have a graduate certificate in Health Policy. I completed an NIH training program in clinical research. I practice daily in a region of the country disproportionately affected by opioid misuse and abuse. I practice with a board-certified addiction medicine/pain medicine physiatrist, a drug/alcohol counselor, and a behavioralist doing integrative pain management every day. The ACGME would beg to differ with you that my training and experience (anesthesia-based pain fellowship) does not qualify me to hold myself out as a legitimate expert on opioid prescribing for CNP. And, others on this forum are even more qualified than me.

So, it's insulting (and tiresome) to assert that no one other a few (self-) selected experts have an important perspective. Still, you insist on doing that on this forum almost daily. You damage only your reputation and your credibility by speaking out of turn, not knowing your audience, and depending upon PERSONAL attacks against those who disagree with your PERSONAL opinions...

What qualifies YOU to

Dave:

1. "I am a MRO, CLIA-designated High Complexity Testing Clinical Consultant & Moderate Complexity Laboratory Director." Great you've got an in-house tox screening lab.

2. "I have a graduate degree in epidemiology. I have a graduate certificate in Health Policy. I completed an NIH training program in clinical research." Good, but not relevant to the prescription opioid epidemic. ADF's are not what we are talking about. We are talking dosage now, you've been silent on that.

3. "I practice daily in a region of the country disproportionately affected by opioid misuse and abuse." Yes, OR has a lot of prescription misuse. Your counties are not in the top 10, but still. So, why don't you join the OPG group and do something about it? Jackson county has done more than any other to address the problem but you - and virtually no other IPM specialist in the state - attend their events.

4. "So, it's insulting (and tiresome) to assert that no one other a few (self-) selected experts have an important perspective." What is your perspective about the opioid crisis or the CDC's document? What's the solution? All I'm hearing is : "I'm an expert." "Meta-analyses are garbage." "Roger Chou doesn't know anything about pain because he's a family practioner." "CAM is mu-shu (pseudo-science nonsense)"
 
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As usual, Paul can't stick to a topic. When his "expert" issue is refuted, he now changes the discussion point to policy.
 
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The mere fact that PROP was included amongst the CDC's list of stakeholder review groups, as well as SIS's non-participation, speaks to this as a political document, not one based on science.

Additionally, the reduction of the maximum MED from 120 to 90 without any scientific justification, and the lack of any mention of abuse-deterrent formulations, speaks to this being an agenda-driven, partisan, advocacy viewpoint, not at all the balanced, well-reasoned perspective one would have hoped for.
 
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Well, Paul, since you asked: I am a MRO, CLIA-designated High Complexity Testing Clinical Consultant & Moderate Complexity Laboratory Director. I'm a co-author on an analytical method for urine toxicology of opioids and drugs of abuse. I teach PM&R residents and family practice residents who rotate at our Center opioid prescribing. I have a graduate degree in epidemiology. I have a graduate certificate in Health Policy. I completed an NIH training program in clinical research. I practice daily in a region of the country disproportionately affected by opioid misuse and abuse. I practice with a board-certified addiction medicine/pain medicine physiatrist, a drug/alcohol counselor, and a behavioralist doing integrative pain management every day. The ACGME would beg to differ with you that my training and experience (anesthesia-based pain fellowship) does not qualify me to hold myself out as a legitimate expert on opioid prescribing for CNP. And, others on this forum are even more qualified than me.

So, it's insulting (and tiresome) to assert that no one other a few (self-) selected experts have an important perspective. Still, you insist on doing that on this forum almost daily. You damage only your reputation and your credibility by speaking out of turn, not knowing your audience, and depending upon PERSONAL attacks against those who disagree with your PERSONAL opinions...

What qualifies YOU to
Standing ovation:

 
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You guys are too funny! I feel like I'm back in kindergarten on the playground during recess. ROFL

I'll just add this for the fun of it. The leading cause of preventable death in the United States is preventable medical errors in hospitals. It is the 3rd leading cause of death (preventable & unpreventable both), beat only by heart disease and cancer - killing an estimated 210,000 - 440,000 patients annually. Where's Chicken Little when you need him? As several of you are fond of saying, follow the money. There's no money to be made in chasing that rabbit.

In the meantime, try to behave yourselves like the professionals I trust you are.

http://www.npr.org/sections/health-...ny-die-from-medical-mistakes-in-u-s-hospitals
https://www.documentcloud.org/docum...ce-based-estimate-of.html#document/p1/a117333
http://www.forbes.com/sites/leahbinder/2013/09/23/stunning-news-on-preventable-deaths-in-hospitals/
 
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What's the solution? All I'm hearing is : "I'm an expert." "Meta-analyses are garbage." "Roger Chou doesn't know anything about pain because he's a family practioner." "CAM is mu-shu (pseudo-science nonsense)"

Yes! Finally, we agree about something!

Why won't CDC disclose the Core Expert Group that they consulted for development of their guidelines? Why does the stakeholder group include PROP which is not a physician-governed organization? It's a special interest group.

You persist in inferring things about others experience and qualifications without any first hand knowledge.

PROP was rebuffed by FDA not for political reasons like they've claimed, but because they failed to do their homework, failed to build a working coalition, and failed to align stakeholder in a way necessary to execute their objectives. Did they really think that FDA would say, "You're right. We were wrong about drug safety. Mea Culpa. I wonder what else we were wrong about?" Then, PROP turns around and try to fire its Commissioner. That's going to be effective. Now, they've turned to CDC--historically a more politicized Federal agency--hoping they can squeeze out the regulatory juice needed to further their agenda.

My opinion is that PROP perseverates on past politics: Blame and finger pointing directed toward Pharma for igniting an opioid misuse and abuse epidemic. Pharma lied and killed the Bonica-model of pain rehabilitation by selling the false hope that chronic pain could be pharmacologically managed more cheaply with pills than anything else. You know who else was complicit? Health plans, HMO's, policymakers, and doctors. Everyone wanted to "believe." But, that is the past--as sad and terrible as it may be--and does NOTHING to advance an agenda for building infrastructure required to comprehensively manage persistent pain. Why is PROP not funding prospective opioid outcome registries, brokering new models of integrated treatment for pain and addiction, and being a positive agent for change?

There is no safe dose for opioids just as there is no safe dose for Lasix. Everyone knows that adverse patient selection drives opioid deaths. Dose is *ONE* dimension of the problem, but by relentlessly focusing on dose, deeper structural aspects of the issue are ignored. Dose is convenient because it can be measured. But, not everything that measures counts and what counts can't always be measured. What are the structural and equity issues that result in the highest risk patients being treated with opioids and, in turn, achieving the worst outcomes? I asked Roger this once at a conference in Canada and he just stared at me blankly: I guess the effect size for common sense asymptotically approaches infinity for some questions...

I've interacted with Jim Shames and others doing policy work on this issue multiple times. Maybe my region is outside the top 10 in our state for overdose and death because almost 10 years ago my partner and I personally paid for Gary Franklin to come visit, hosted him, and arranged for talks at every hospital Grand Rounds in our catchment area. I said then what I say now, "The crux of this issue comes down to mitigating the risk of dangerous pills versus dangerous people." I've done much work on local and regional levels and try to put my energy where I feel my impact matters the most.

And, you know what, I've done it all without insulting people--calling them sell-outs, hypocrites, or stupid. Your anonymous actions matter more than anything you do when others are watching. For that, you should be ashamed of yourself.
 
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Yes! Finally, we agree about something!

Why won't CDC disclose the Core Expert Group that they consulted for development of their guidelines? Why does the stakeholder group include PROP which is not a physician-governed organization? It's a special interest group.

You persist in inferring things about others experience and qualifications without any first hand knowledge.

PROP was rebuffed by FDA not for political reasons like they've claimed, but because they failed to do their homework, failed to build a working coalition, and failed to align stakeholder in a way necessary to execute their objectives. Did they really think that FDA would say, "You're right. We were wrong about drug safety. Mea Culpa. I wonder what else we were wrong about?" Then, PROP turns around and try to fire its Commissioner. That's going to be effective. Now, they've turned to CDC--historically a more politicized Federal agency--hoping they can squeeze out the regulatory juice needed to further their agenda.

My opinion is that PROP perseverates on past politics: Blame and finger pointing directed toward Pharma for igniting an opioid misuse and abuse epidemic. Pharma lied and killed the Bonica-model of pain rehabilitation by selling the false hope that chronic pain could be pharmacologically managed more cheaply with pills than anything else. You know who else was complicit? Health plans, HMO's, policymakers, and doctors. Everyone wanted to "believe." But, that is the past--as sad and terrible as it may be--and does NOTHING to advance an agenda for building infrastructure required to comprehensively manage persistent pain. Why is PROP not funding prospective opioid outcome registries, brokering new models of integrated treatment for pain and addiction, and being a positive agent for change?

There is no safe dose for opioids just as there is no safe dose for Lasix. Everyone knows that adverse patient selection drives opioid deaths. Dose is *ONE* dimension of the problem, but by relentlessly focusing on dose, deeper structural aspects of the issue are ignored. Dose is convenient because it can be measured. But, not everything that measures counts and what counts can't always be measured. What are the structural and equity issues that result in the highest risk patients being treated with opioids and, in turn, achieving the worst outcomes? I asked Roger this once at a conference in Canada and he just stared at me blankly: I guess the effect size for common sense asymptotically approaches infinity for some questions...

I've interacted with Jim Shames and others doing policy work on this issue multiple times. Maybe my region is outside the top 10 in our state for overdose and death because almost 10 years ago my partner and I personally paid for Gary Franklin to come visit, hosted him, and arranged for talks at every hospital Grand Rounds in our catchment area. I said then what I say now, "The crux of this issue comes down to mitigating the risk of dangerous pills versus dangerous people." I've done much work on local and regional levels and try to put my energy where I feel my impact matters the most.

And, you know what, I've done it all without insulting people--calling them sell-outs, hypocrites, or stupid. Your anonymous actions matter more than anything you do when others are watching. For that, you should be ashamed of yourself.
It's getting pretty close to trolling at this point.
 
It's getting pretty close to trolling at this point.
Well, also, calling out other people by name is violating the TOS. You can self-identify (and, also, use your name as your username, although that is discouraged), but others can't ID you without violating rules.

All you guys know each other, but, for interested onlookers such as myself, y'all are still relatively anonymous (until you aren't). God's honest truth, I would hate to see anyone get banned (and there is VERY little that I "hate" in this world).
 
My name is Peter Zimmerman, in case anyone was curious. So now anyone who wants to should feel free to identify me without fear of violating TOS. I practice in South Louisiana (New Orleans, Baton Rouge, and Lafayette). ampaphb represents the first initials of my family members (alan, marcia, peter, andrea, paula, hannah, ben)
 
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My name is Peter Zimmerman, in case anyone was curious. So now anyone who wants to should feel free to identify me without fear of violating TOS. I practice in South Louisiana (New Orleans, Baton Rouge, and Lafayette). ampaphb represents the first initials of my family members (alan, marcia, peter, andrea, paula, hannah, ben)

Well I am definitely not letting any of you cretins know my name. And I got rid of the BMW yesterday. (FZ-09 comes in Tuesday).
 
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Well, also, calling out other people by name is violating the TOS. You can self-identify (and, also, use your name as your username, although that is discouraged), but others can't ID you without violating rules.

All you guys know each other, but, for interested onlookers such as myself, y'all are still relatively anonymous (until you aren't). God's honest truth, I would hate to see anyone get banned (and there is VERY little that I "hate" in this world).

Are you kidding? Anonymity on the Internet is so 1990's. Everyone lurks on Pain Rounds: Patients, claims adjusters, hospital peer review folk, recruiters, device & drug reps, and hospital admins...that's why it's wise to own what you say.
 
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Are you kidding? Anonymity on the Internet is so 1990's. Everyone lurks on Pain Rounds: Patients, claims adjusters, hospital peer review folk, recruiters, device & drug reps, and hospital admins...that's why it's wise to own what you say.
Well, I can't remember the last time I deleted something - I am of the same mind: stand by what you say. There's one guy who has the lion's share of his posts as "nvm" - I wish the guy (?) would have the courage of his convictions and just nut up and have the guts to stand up for what he said.

As for anonymity, there was barely any internet in the 90s (comparatively). There are so many people on SDN I don't know, because I am too lazy to search them out. Whatever!
 
Maybe got my dates off by a few years...http://www.medscape.com/viewarticle/837417

2006 was the big year with 1000s of deaths from this.

But I recall hearing about this before I became a doctor growing up in the Phila suburbs. And I am correct so.

SO ducttape: Nana booboo, stick your head in dodo, I am better than you dude.

http://www.nytimes.com/1991/02/04/nyregion/toxic-heroin-has-killed-12-officials-say.html

http://articles.baltimoresun.com/1992-03-12/news/1992072009_1_fentanyl-heroin-synthetic-drugs


http://www.foxnews.com/health/2015/...erdose-on-laced-heroin-in-3-day-span-chicago/
 
Can we ethically just let these people die instead of saving them with high dose narcan?? It sure would save us lots of healthcare dollars
I thought the decision reduce the amount of Tylenol in percocet and hydrocodone was solely made so that addicts would die at home from an opiate overdose rather than in ICU from hepatic failure. And this was done as a cost savings measure.
 
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Latest review for 2 people who are not getting opiates from me: Both were on opiates from elsewhere.

I wish I had found this site before I wasted time and money on appointments for my daughter (age 21 normal imaging) and I (400+ pound woman in scooter). This man is the most arrogant person I have ever met. He made up mind that there was no help for me based on my physical appearance. He was dismissive, rude, and had no regard for anything I have done in the past or the opinions of any of my previous doctors. He made light of the severe pain my daughter is in and was more interested in making comments about her pleasant physical appearance. I would NEVER recommend this man to anyone. I want to leave a doctors office feeling comforted and hopeful, not useless and discouraged. Not only was the whole experience uncomfortable and inappropriate, they kept my daughter and I in our separate rooms for 40 minutes AFTER the appointment, I have no idea what took so long. By the end, the only thing on our minds was to escape and never return.
 
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Give me what I want or I will slander you to everyone I can.
 
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http://www.asam.org/for-the-public/definition-of-addiction

Iatrogenic addiction is a misnomer. It is almost always an underlying condition brought into the open by the refusing to maintain that underlying addiction. The iatrogenic part for us is when there is secondary gain on the part of the provider. It is not the drug, it is the person who takes it.
 
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http://www.cnn.com/2015/10/31/us/california-overdose-doctor-murder/index.html
Jury convicts California doctor of murder in overdose deaths


Doctor convicted of murder in overdose deaths

Doctor convicted of murder in overdose deaths
Source: kcal

Doctor convicted of murder in overdose deaths 02:09
Story highlights
  • Hsiu-Ying "Lisa" Tseng was convicted for the deaths of three patients, all in their 20s
  • Their deaths occurred between March and December 2009
(CNN)A California doctor has been convicted of murder in connection with three prescription drug overdose deaths.

Prosecutors said this is the first time in the United States that a doctor has been convicted of murder for over-prescribing drugs.

Hsiu-Ying "Lisa" Tseng, 45, was found guilty of 23 counts, including 19 counts of unlawful controlled substance prescription and one count of obtaining a controlled substance by fraud.

Tseng was convicted on Friday of second-degree murder for the deaths of Vu Nguyen, 28, of Lake Forest; Steven Ogle, 24, of Palm Desert; and Joseph Rovero, 21, an Arizona State University student from San Ramon. All were in their 20s when they died between March and December 2009.

"This verdict sends a strong message to individuals in the medical community who put patients at risk for their own financial gain," District Attorney Jackie Lacey said. "In this case, the doctor stole the lives of three young people in her misguided effort to get rich quick."

Tseng's attorney, Tracy Green, said the case doesn't bode well for doctors who prescribe controlled substances.

"While we disagree with the jury's decision, we appreciate their conscientiousness," Green said. "I think the jury did the best job they could and ultimately the plan will be to appeal the decision."

Tseng was arrested three years ago after undercover agents posed as patients with pain problems.

CNN's Dottie Evans contributed to this report
 
She deserves it. She is a drug dealer posing as a doctor.

Agreed but this sets a very dangerous precedent for the rest of us legitimate docs.

Looking for ampaphb to weigh in.
 
Agreed but this sets a very dangerous precedent for the rest of us legitimate docs.

Looking for ampaphb to weigh in.
Its not a precedent It's happened many times before. The behavior is usually way, WAY beyond what any rational, ethic person would do. That can't through all opiate prescribers in jail. Just the ones so outrageously dangerous and negligent that everyone around them is shocked it never happened sooner. Everyone one of these I've read in detail about have so many red flags and egregious actions, I'm ready to pull out my own pitchfork before finishing reading the evidence. Like this case. Called by authorities of 9 deaths in 3 years. Kids in their 20s. Multiple talks/sanctions from the board. My God, how stupid can you be?
 
Its not a precedent It's happened many times before. The behavior is usually way, WAY beyond what any rational, ethic person would do. That can't through all opiate prescribers in jail. Just the ones so outrageously dangerous and negligent that everyone around them is shocked it never happened sooner. Everyone one of these I've read in detail about have so many red flags and egregious actions, I'm ready to pull out my own pitchfork before finishing reading the evidence. Like this case. Called by authorities of 9 deaths in 3 years. Kids in their 20s. Multiple talks/sanctions from the board. My God, how stupid can you be?

She opened her latest clinic with 5 million in cash from profits for prior "work".
 
We are creating a nation of addicts
http://www.cnn.com/2015/11/02/opinions/beckel-nation-of-addicts/index.html

"Ostensibly, the doctors prescribing these drugs are well-intentioned; they don't mean to create addicts. They simply don't have the education to know better. During their four years of medical school, doctors receive no more than an average of eight hours' training in addiction, according to a survey in the Journal of Studies on Alcohol and Drugs. The bitter irony here is that not only are these meds fiercely addictive, they also aren't an especially effective solution to the problem they're used to treat."

:rolleyes:
 
We are creating a nation of addicts
http://www.cnn.com/2015/11/02/opinions/beckel-nation-of-addicts/index.html

"Ostensibly, the doctors prescribing these drugs are well-intentioned; they don't mean to create addicts. They simply don't have the education to know better. During their four years of medical school, doctors receive no more than an average of eight hours' training in addiction, according to a survey in the Journal of Studies on Alcohol and Drugs. The bitter irony here is that not only are these meds fiercely addictive, they also aren't an especially effective solution to the problem they're used to treat."

:rolleyes:
Doesn't take medical training to know whether or not you are a drug dealer
 
Sad and scary at once...

Rising morbidity and mortality in midlife among white non-Hispanic Americans in the 21st century.
Anne Case1 and Angus Deaton1 Woodrow Wilson School of Public and International Affairs and Department of Economics, Princeton University, Princeton, NJ 08544 Contributed by Angus Deaton, September 17, 2015 (sent for review August 22, 2015; reviewed by David Cutler, Jon Skinner, and David Weir)

http://www.pnas.org/content/early/2015/10/29/1518393112.full.pdf
 
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