Let's Hope This is a Trend

By Rich Kozlovich 

This piece appeared in today, Court Overturns $465M Opioid Ruling Against Johnson & Johnson, saying:

It's the second blow to a case like this in the past month  The Oklahoma Supreme Court on Tuesday overturned a $465 million opioid ruling against drugmaker Johnson & Johnson, finding that a lower court wrongly interpreted the state's public nuisance law in the first case of its kind in the US to go to trial...........in a 5-1 decision that District Judge Thad Balkman in 2019 was wrong ..........“The court has allowed public nuisance claims to address discrete, localized problems, not policy problems,” ...........The ruling also said the company had no control over how patients then used the products.....The ruling comes a week after a California judge issued a tentative ruling that said local governments had not proven that Johnson & Johnson and other drugmakers used deceptive marketing to inflate prescriptions of their painkillers, leading to a public nuisance. (Click for more on what this could mean for thousands of similar lawsuits still pending.) 

 

The fact is these government actions are nothing more than legalized theft, and if this had been allowed to stand it wouldn't have stopped there.  It would have been the foundation for attacks against guns, cars and anything activists didn't like.   This public nuisance meme, while most likely good intentioned, is like so many good intentioned laws, they're being corrupted by greedy politicians, insane actives, and amoral attorneys.  

A Look At Long COVID

 May 3, 2021 By Michael D. Shaw @ HealthNewsDigest

The CDC describes “Long COVID” as: “[A] range of symptoms that can last weeks or months after first being infected with the virus that causes COVID-19 or can appear weeks after infection. Long COVID can happen to anyone who has had COVID-19, even if the illness was mild, or they had no symptoms.” Such patients may also refer to themselves as “long haulers.”

Different combinations of the following symptoms can be experienced:

• Fatigue
• Difficulty thinking or concentrating (aka “brain fog”)
• Headache
• Loss of smell or taste
• Dizziness on standing
• Fast-beating or pounding heart (aka heart palpitations)
• Chest pain
• Difficulty breathing or shortness of breath
• Cough
• Joint or muscle pain
• Depression or anxiety
• Fever
• Symptoms that get worse after physical or mental activities

Long COVID sufferers can have these symptoms for weeks or months, and they can disappear, and restart again. Overall, approximately 10% of people who’ve had COVID-19 develop long COVID. Interestingly, such a “long haul” effect had been observed in some SARS patients. And here.

The Economist recently posted an excellent article, entitled “Researchers are closing in on long covid.” Three proposed mechanisms are described. Long COVID could be a persistent viral infection; an autoimmune disorder; or a consequence of tissue damage caused by inflammation during the initial, acute infection.

The persistent infection scenario posits the hosting of an altered form of the virus which is not replicating, but is still producing waste that triggers an immune reaction. This type of thing has been seen with Measles, Dengue Fever, and Ebola–all caused by RNA viruses. According to Avindra Nath of the NIH, RNA viruses are prone to this phenomenon. This study indicates the presence of SARS-CoV-2 virus particles months after the acute infection.

As to autoimmunity, long COVID sufferers have shown abnormalities in one or more of their macrophages, B-cells, levels of interferons, and T-cells. In fact, T-cell exhaustion is observed in severe cases of COVID-19, and this can carry over into long COVID.

The inflammation hypothesis suggests that the immune response itself can cause irreparable collateral damage, a sort of limited cytokine storm, if you will. As suggested by Igor Koralnik, the SARS-CoV-2 virus could damage cells lining blood vessels, affecting blood flow to the brain, possibly explaining the brain fog.

Note that the three mechanisms are not mutually exclusive. Indeed, you could have a persistent infection because you have immune dysfunction, and inflammation can be part of this dysfunction.

A short time ago, we ran a guest article entitled “Are COVID 19, Chronic Fatigue Syndrome, And Autism Spectrum Disorder Linked?” It is worth highlighting some points from that piece…

1. Could it be that COVID-19 may not be acting strictly as a viral pneumonia? Instead, there is a large triggering of intense immune cascades (as in a series of sequential interactions), and that is the cause of death!
2. Failing to acknowledge the changing role of viruses has facilitated the explosion of serious diseases, including COVID-19.

The guest author of that piece, Michael J. Goldberg, MD told me, in another context:

“We were taught in medical school by Nobel level professors that there was a difference between “normal” viral titers (concentrations) and “elevated” viral titers, indicating the presence of an active virus. Then in the late 1980s and early 1990s very powerful medical leaders (CDC, NIH) inexplicably decided that elevated Herpes viral titers in children and adults were now meaningless. As a practicing pediatrician, to suddenly be required to ignore the role of herpesviruses was/is still beyond comprehension.”     

Then, there’s the matter of opioids. In a study to be published in Nature high rates of opioid use seem to occur with Long COVID patients. Certainly, these meds are prescribed for pain, and a goodly number of Long COVID patients have such complaints (bone and muscle pain).

However, there really are chronic pain patients that need these opioids, and thoughtless concerns over a new addiction menace will do more harm than good. Sadly, it is not uncommon for legit users of these meds to be put into dire situations based on the whims of clueless do-gooders. Just more Colonel Blimp pronouncements of medical orthodoxy.

The Great Opioid Shakedown of 2019 Will Be a Pyrrhic 'Victory'

By Josh Bloom — August 28, 2019 @ American Council on Science and Health.

(Editor's Note:  This is an issue that impacts a great many people, as a result this article generated a lot of comments.  I recommend reading them. Follow the link.  RK)

Oklahoma's August 26th verdict against Johnson & Johnson was never a question of "if," only "how much." Recently, it's been all the rage to assign blame for today's "opioid crisis," justified or not. And once the blaming starts so do the lawsuits.

There could not be a better time. Doctors, dentists, distributors, drug companies, Donald Trump, and maybe even Donald Duck have all assumed the role of villain in the ongoing decade-long debacle, while the real villains are no doubt smirking all the way to the bank (1).

But it's the drug companies that have all been squarely in the sights of lawyers and state officials; whether there was actual blame or not doesn't really matter. As the notorious Willie Sutton once answered when asked why he robbed banks, "that's where the money is." It's now the "perfect swarm" – lawyers, hatred for pharmaceutical companies, buckets of money, and a plausible but false narrative that overprescription of prescription pain meds led to opioid abuse and addiction.

On the surface, what just started happening to the pharmaceutical industry on Monday, thanks to Oklahoma's $572 million oh-so-predictable victory against Johnson & Johnson for causing the "opioid crisis," (2,3,4) may superficially resemble what happened to the tobacco industry in 1998, but that's where the similarities end.

The $246 billion that the tobacco industry agreed to pay in order to shield itself from state lawsuits, which began in 1994 when Mississippi attorney general sued Big Tobacco. Moore (rightfully) claimed that cigarette smoking caused diseases that the state had to pay to treat, so it wasn't unreasonable that the industry should cough up (sorry) some serious money to atone for its business practices.

"The state is obligated to pay for those for our citizens that are not covered in other ways, and we feel like they're caused by the tobacco products."
Mike Moore, 1994 in an NPR  interview

Whether or not you agree with the verdict, the amount of the settlement or whether the settlement would be used for its stated purpose – smoking cessation programs (it didn't) – it's at least reasonable that tobacco companies, which by definition, sell deadly products should assume some of the cost for the harm they cause. In the end, maybe a bunch of Philip Morris shareholders got stung (they didn't, see Figure 1) but even if the $246 billion didn't provide much help to the general public, at least it didn't hurt anyone, especially the shareholders.

Atria (formerly Philip Morris) stock price by year. Source: The Motley Fool

Not this time. There will be pain in the form of pain. Tobacco companies continued to sell cigarettes and did just fine. This is where the two examples diverge.

Once this mess is in the rearview mirror and Americans have moved on the next drug of choice (5) (and they always do) the results will be predictable:

• A bunch of rich lawyers
• States grabbing what they can and spending it on... who knows.
• Good luck trying to find a company insane enough to manufacture opioids.
• Good luck trying to find a doctor who is brave enough to write prescriptions for the opioids that won't be available.
• Wait until you see what the pills cost, assuming you can get them at all.

That's the harm that will inevitably come out of this disgraceful chapter in American history. Not only will millions of people have suffered and died unnecessarily but whatever has transpired in the last decade could be like Shangri-La compared to what's ahead.

Johnson & Johnson's worldwide sales in 2018 totaled $81.6 billion. I cannot find what portion of that amount came from opioid sales, but it is very likely to be insignificant. This can be inferred from a statement of Brad Beckworth, the lead attorney for Oklahoma:

“[J&J] made billions of dollars from it over a 20-year period."

 

Let's guess that that number is $10 billion. Since 2005, J&J's annual sales have averaged roughly $70 billion. Let's call it $60 billion to be conservative. This comes out to $1.2 trillion over this 20-year period. If the company earned $10 billion during this time then its opioid sales comprise 0.8% of the company's revenue during this period. Chump change. J&J would be out of its mind to continue to manufacture and sell opioids, given the 2,000 lawsuits it still faces, which will almost certainly add up to far more than whatever the company earned selling the drugs. Please believe that other companies that are facing this kind of exposure are thinking just this. So, who, if anyone, will bother to make these drugs? Maybe no one.

Or maybe these guys...

I wrote about Valeant (which doesn't even exist anymore) (6) back in 2016 when the company raised the price of dirt-cheap calcium EDTA, an antidote to lead poisoning, and not by a little:

After resolving manufacturing problems that caused shortages, Valeant pursued the hallmark strategy that made it infamous — taking sky-high price hikes. Before Valeant took control, the list price for a package of [calcium EDTA] vials had been stable at $950. But in January 2014, Valeant boosted the price to $7,116. By December 2014, several more increases took the price to $26,927, according to Truven Health Analytics.
Ed Silverman, Pharmalot (STAT). October, 2016.

If I've got this right, then in 10 years, assuming that the opioid crusade doesn't come crashing down, then your prescription pain meds, assuming you can get them at all, could easily run $1,000 for a few days worth of Vicodin, maybe more.

Then the US public (maybe even the clueless media) will see (and feel) the damage done by the CDC, PROP, predatory lawyers, and states that are so eager to join the scrum and scoop up every penny they can for money that will probably not even be used to do a damn thing to help current addicts –the few that will be alive, thanks to fentanyl, or prevent future addiction or death.

Then we're all looking at a world of pain. Nice country.

NOTES:

(1) Self-proclaimed (but thoroughly unqualified) expert Andrew Kolodny has been consulting for Oklahoma for a mere $725 per hour and is estimated to have earned $500,000 so far. Nice gig. Does this have anything to do his actions over the past decade regarding opioids? You tell me.
(2) Regardless of the facts of the case, J&J is most certainly guilty of having deep pockets.
(3) Before you accuse me of being a shill for J&J 1) read Johnson & Johnson's Shameless Exploitation Of The Opioid Crisis, 2) then shut up.
(4) J&J does not manufacture opioids, it just supplies the materials to other companies.
(5) This is already happening. Methamphetamine is roaring back onto the scene, once again thanks to government bumbling. See Why Sudafed Is Behind The Counter: A Meth Chemistry Lesson.
(6) Valeant changed its name to Bausch Health Companies in 2018. Tiger. Stripes.

Here's What Needs to Happen After the Johnson & Johnson Lawsuit

John R. Lott, Jr.  Aug 28, 2019

When General Motors and Ford sell more cars, they are involved in more accidents. They undoubtedly advertise more in those places where they sell more cars. Does that mean that the car companies are responsible for additional accidents in those places? That they are purposefully plotting to create more accidents?

Let’s hope not, but if Monday’s $570 million verdict by an Oklahoma judge against Johnson & Johnson for making opioids is any indication, those types of cases aren’t going to be far off.

Oklahoma had refused to settle out of court believing that they could receive a very large verdict. And the actual verdict is much larger than it might appear as it just represents the penalty for damages from a single year.

The state of Oklahoma claimed Johnson & Johnson and other pharmaceutical companies spent tens of millions of dollars annually in direct-to-physician marketing of opioids and that as opioid sales grew, so did addiction and overdoses............To Read More....

Opioids: Bad Science, Bad Policy, Bad Outcomes

Henry I. Miller and Josh Bloom 14 comments

 

There’s an old joke about the drunk who’s hunting for his lost keys under the lamppost, not because he thinks they’re there, but because the light is good. Well, that’s what the feds and state governments are doing to try to quell the epidemic of opioid addiction and overdoses.

 

The problem is quite real, but legislators and regulators are making incorrect assumptions and adopting flawed strategies. And then, there are some flawed clinical studies and statements by the U.S. surgeon general that conspire to create misunderstanding of the landscape. 

 

For a start, the problem isn’t currently prescribed opioids, such as fentanyl, morphine, oxycodone, and hydrocodone. A study published earlier this year in the New England Journal of Medicine found that from 2012 to 2017, a time when the overdose death rate was markedly accelerating, the rate of opioid prescriptions in patients who had not previously used opioids fell 54%, a decline driven by a decreasing number of prescribers...........To Read More....

 

 

 

Oh-Klahoma! 8 Questions J&J Should Ask Andrew Kolodny

 By Josh Bloom — June 18, 2019 @ American Council on Science and Health

Are These Guys Singing And Dancing  

In Anticipation Of A Big Payout?

Image udiscovermusic.com

 The state of Oklahoma is smelling blood in the water and it is going after blood money.   State Attorney General Mike Hunter has a very big "blood donor" in his sights: Johnson and Johnson, the maker and seller of opioid drugs, has been accused of deceptive marketing that contributed to the state's addiction problem. J&J has a whole lot of blood - a market cap of $372 billion - and Oklahoma a whopping transfusion. According to the Wall Street Journal, the state is talking about approximately $17 billion for "abatement."

“[The company] used a deceitful, multibillion-dollar brainwashing campaign’’
Oklahoma Attorney General Mike Hunter,  May 28, 2019 (Bloomberg News)

Not surprisingly, Andrew Kolodny, a tireless self-proclaimed expert on drugs and addiction, has been chosen to testify for the state. How could it be anyone else? If you take the news at face value Kolodny is not only the expert on opioids but perhaps the only person on earth even remotely qualified to speak about them -– which is, of course, a bunch of nonsense.

This is why I'm offering J&J's attorneys, eight questions that I would ask Kolodny if I had the chance.

No charge.

(Before you accuse me of being a J&J puppet or lackey, perhaps you ought to read this: "Johnson & Johnson's Shameless Exploitation Of The Opioid Crisis". I wrote it earlier this year.)

1. Opioids are used almost exclusively for control of pain. Do you have any formal training in pain management? Have you ever treated pain patients?

2. "When was last time you saw a patient? When was last time you prescribed a drug to a patient? What was the drug?"

3. "You and your organization PROP have recommended a 90 morphine milligram equivalents (MME) maximum dose per patient per day. Some states have enacted legislature based on MME limits. But critics have claimed that the concept of MME itself is flawed because of significant genetic variability in opioid metabolism from patient to patient. How do you answer those critics"? (1)

4. "All drugs have risks and benefits. Focusing on only the risks will necessarily give rise to an inaccurate portrayal of a given drug. What are the risks and benefits of alternative treatments for pain, such as NSAIDS, acetaminophen, systemic anti-inflammatory steroids, spinal injections, and gabapentanoids?"

5. "You have repeatedly referred to prescription analgesics as 'heroin pills.' Are you stating that Vicodin or Percocet are equivalent in analgesic potency, addiction potential, and overdose risk to heroin?"

6. "Chronic pain patients, even those who have been treated successfully for years, are being forcibly tapered off their medicines. Are you in favor of forced tapering? If so, why? You have also stated that 'the number of doctors who are inappropriately tapering pain patients is likely very small.' Do you have data to support this statement?

7. You have also stated that “'[pain patients are] being effectively manipulated to controversialize the CDC guidelines.” Do you have any proof or evidence to support this statement?"

8. "Will you, anyone in your family, friends or associates benefit financially from restrictions placed on prescription opioid drugs?"

Is Kolodny a believable witness, let alone an expert? I guess that depends upon how he answers questions like these. Assuming that Johnson and Johnson’s lawyers ask them.

Prediction: I have no idea what J&J did or did not do wrong, but the company is probably doomed no matter what. J&J has a big bull$eye on its back and Judge Thad Balkman, who will decide the case, is listening to a lot of bull.

But I could be wrong. After all, this is not an expert opinion.

NOTE: (1) See "Opioid Policies Based On Morphine Milligram Equivalents Are Automatically Flawed"

Please Help Fund Our Work Just like money, debunking junk science doesn't grow on trees. And we've done a lot of it recently in the media. But we are only able to do what we do because of the generous support of readers like you. So please donate

Dr. Aric Hausknecht Responds to SG Jerome Adams' Tylenol Recommendation

By Josh Bloom — July 12, 2019 @ American Council on Science and Health

#Special to ACSH.

ACSH friend Dr. Aric Hausknecht, a New York neurologist and pain management physician, has taken issue with the July 4th advice tweeted by Surgeon General Jerome Adams, M.D., which recommended the use of IV Tylenol for post-op pain.

Dr. Hausknecht gave us exclusive permission to print his response to Dr. Adams.

I am writing in response to recent comments made by the U.S. Surgeon General, Jerome Adams, regarding the use of intravenous acetaminophen for anesthesia and post-operative pain relief. The Surgeon General implies that acetaminophen (Tylenol) is equally efficacious to intravenous (IV) opioids for pain relief. Apparently, his comments are based upon, Comparison of the Analgesic Effect of Intravenous Acetaminophen and Morphine Sulfate in Rib Fracture; a Randomized Double-Blind Clinical Trial,  Emerg (Tehran). 2015 Summer; 3(3): 99–102. The authors of this paper concluded, "The findings of the present study showed that IV acetaminophen and morphine have the same therapeutic value in relieving the pain of rib fracture."

However, this study was carried out on a limited population group, 54 patients in total, and the statistical analysis is of questionable validity. At best, this study establishes a need for further inquiry, but in no way does this study provide adequate evidence to use IV acetaminophen as a substitute for IV opioids.

In another related paper, Intravenous versus Oral Acetaminophen for Pain: Systematic Review of Current Evidence to Support Clinical Decision-Making, Can J Hosp Pharm. 2015 May-Jun; 68(3): 238–247, the authors performed a literature review from 1948-2014 and "summarized and evaluated the available published literature describing efficacy, safety, and pharmacokinetic outcomes of randomized studies assessing oral versus IV dosage forms of acetaminophen." The authors concluded, "For patients who can take an oral dosage form, no clear indication exists for preferential prescribing of IV acetaminophen." On the basis of this comprehensive review, the authors concluded, "Therefore, on the basis of current evidence, if a patient has a functioning gastrointestinal tract and is able to take oral formulations, IV formulations (of acetaminophen) are not indicated."

Additionally, IV acetaminophen is FDA approved for use in the management of mild-to-moderate pain and moderate-to-severe pain with adjunctive opioid analgesics. It is not clear why a physician who is in a position to shape public policy would recommend  standards of care that suggest that IV acetaminophen is equally efficacious to IV opioids when: 1) that premise is unproven, 2) there is strong evidence that oral acetaminophen is equally efficacious to IV acetaminophen,  3) IV acetaminophen should probably not be administered to a patient that can tolerate oral administration, 4) IV acetaminophen is not FDA approved as a stand-alone analgesic agent for mild-to-moderate pain and moderate-to-severe pain, and, 5) it is contrary to good and accepted medical practice that has established that opioids are more efficacious than acetaminophen for postoperative pain and for moderate-severe pain.
I remain,

Aric Hausknecht, MD
Diplomate American Board of Psychiatry and Neurology
 

Tags: 

Tylenol

post-operative care

post-operative pain

opioid denial

 

And then to follow up

US Surgeon Gen. Backpedals on Flawed Tylenol Study. Cause of ACSH.
Dr. Jerome Adams celebrated Independence Day by trumpeting a study which concluded that Tylenol worked as well as morphine for controlling the pain from a broken rib. But the study was complete nonsense. ACSH caught the Surgeon General and now he's backpedaling like the woman in the bicycle scene from The Wizard of Oz (played backward of course)..............To Read More.....

Please Help Fund Our Work - If you follow our work, you know that we here at ACSH go after the fraudsters, the hucksters and the snake-oil peddlers. And when we're not debunking their misleading or dangerous junk science, we're always aiming to give you the most accurate and dependable health news. But we can only continue to do that with support from our readers and friends who value what we do. So if you can ... Please Donate. Thank you.

Opioid Deaths Are Not Solely a Medical Issue

By Chuck Dinerstein — July 9, 2019

Pop quiz! What is the cause of our opioid epidemic?

A. Doctors prescribe too many opioids.
B. The government insisted doctors control pain better
C. Big Pharma created addictive drugs and lied to us
D. Free trade policy

Pencils down, time is up. While variations in the first three responses all may have some culpability, how many of you put down that last choice? A new study in Population Health suggests that our free trade policy did play a role.

Let’s first address how opioid overdoses and free trade may be related. Free trade shifts the manufacture of goods to the cheapest supplier, the Dollar Store, Walmart, and Amazon are built upon that economic principle. But for the country that cannot compete on price, and that would be us in many instances, trade-related job loss closes factories, eliminates middle-class jobs, and as it turns out disproportionately impacts those regions on the US most burdened by opioids’ disruption. The displaced workers, often less-educated, have only short term unemployment benefits for what has become a long term problem. There is also evidence that one way to make ends meet, is to apply for disability benefits; benefits that require a medical examination and are associated with a greater likelihood of being prescribed opioids...........To Read More...

Need General Surgery? Ignore The Surgeon General

By Josh Bloom — July 8, 2019 @ American Council on Science and Health

Just what we don't need. Another anti-opioid (pro-pain) zealot spreading the false gospel. But we have one anyhow - US Surgeon General Jerome Adams, M.D.

On July 3rd Dr. Adams Tweeted the following:

Isn't that swell? Being obsessed over whether post-op patients do or don't need a few doses of opiate pain medication instead of focusing on the patient's individual needs? Since when did recovery from surgery become a contest?

"My patients can survive a knee replacement with only ibuprofen. They may scream a little, but eventually, they stop. Usually."

"Oh yeah? My patients don't even need general anesthesia for spinal fusion! We just strap 'em down, stick a couple of acupuncture needles at their ear and... voila! A titanium rod across four cervical vertebrae."

Sort of an analgesic version of "Name The Tune."

Adams' Tweet the next day was worse...

Wow! Tylenol works better than morphine. That must be one hell of a study.

It is - one hell of a terrible study. Here's why.

Adams was referring to a 54-person randomized clinical trial of pain control following rib fractures, which are notoriously painful. The trial, which was conducted in an emergency department Iran, compared IV Tylenol (1000 mg) and morphine (0.1 mg per kilo of body weight) (1). The result? Tylenol worked as well as IV morphine for relief of pain from rib fractures, that is until you bother to read the paper, which was published in the journal Emergency (Tehran). On the slight chance that you're not a subscriber, here's a summary.

• Thirty minutes post-administration of drug the mean pain score on a scale of 1-11 was 5.5 for the morphine-treated patients and 4.9 for the Tylenol-treated patients. These two numbers make up the "evidence" behind Dr. Adams' claims of equivalence of Tylenol and morphine. Except the data aren't even close to statistically significant - P = 0.23. No, Tylenol is not equivalent to morphine; there is no way to tell from this study. Its numbers are meaningless.

Even the authors seem to acknowledge this fact, assuming you can figure out what they're talking about:

The success rate reported for this drug in this study was 80% that although [sic] did not have significant difference with morphine (58.6%), it had more improvement rate, clinically. 

Huh?

ACSH advisor, biostatistician Dr. Stan Young had this to say.

The rage these days is to say OTC pain med is as good as morphine etc. Here the authors claim victory if there is no difference. "Proving equal" is a different game. You just have to worry about statistical power. Just run a small, underpowered study and you can easily get no difference (victory).

It gets worse...

• There was no control group, so we don't know if either group got relief from the medicine or the reduction in pain score was due to a placebo effect. 

The initial pain score of both groups was "the same" but with P = 0.19 this may or may not be true. The group that received the Tylenol could have come in with more pain, less pain, or no difference. We cannot tell from the data.

• The success rate (defined as a 3 point reduction in pain score) was 80% for Tylenol and 59% for morphine. That isn't significant either. P = 0.09. Even the authors acknowledge this:

"The success rate reported for this drug in this study was 80% that although did not have [sic] significant difference with morphine (58.6%), it had more improvement rate, clinically." 
Mehrdad Esmailian, et. al., Emerg (Tehran). 2015 Summer; 3(3): 99–102.

• When there was a treatment failure after 30 minutes (inadequate pain relief), morphine was given as a rescue therapy. This automatically skews the results. It's like saying "Tylenol works as well as morphine except when it doesn't." Nor do the authors tell us how often this happened. 

Finally, we have this:

"Presentation of side effects was similar in both groups."

Are they kidding? All we've been hearing for a decade is how dangerous opiate analgesics are and there was no difference in side effects between the Tylenol and morphine groups? Was there any morphine in the morphine, because I can't think of any other explanation for this.

This is what our Surgeon General used to "inform" us that IV Tylenol works as well as morphine - a 2015 paper in a journal with maybe two readers, which is filled with a whole lot of information, none of it valid.

What a joke.

NOTE

(1) A dose of 0.1 mg per kilo of body weight (7 mg for a 70 kg patient) is within guidelines for an initial dose of morphine.

Please Help Fund Our Work - If you follow our work, you know that we here at ACSH go after the fraudsters, the hucksters and the snake-oil peddlers. And when we're not debunking their misleading or dangerous junk science, we're always aiming to give you the most accurate and dependable health news. But we can only continue to do that with support from our readers and friends who value what we do. So if you can ... Please Donate. Thank you.

Advil As A Substitute For Opioids? NY Times' Gina Kolata 'Busts' One Myth With Another

By Josh Bloom — July 2, 2019 @ American Council on Science and Health

The New York Times' coverage of the so-called "opioid crisis" (1) has been generally dreadful, but I was still surprised with a new article by Gina Kolata - the paper's science reporter - entitled "10 Medical Myths We Should Stop Believing. Doctors, Too."

Ms. Kolata usually gets it right, so I was a bit surprised when I ran into #5:

To treat emergency room patients in acute pain, a single dose of oral opioids is no better than drugs like aspirin and ibuprofen.

Kolata cites a 2017 JAMA Network paper which makes this claim; it didn't sound any better two years ago than it does now. That's because "Effect of a Single Dose of Oral Opioid and Nonopioid Analgesics on Acute Extremity Pain in the Emergency Department - A Randomized Clinical Trial" is a giant mess, no doubt driven by opioid hysteria, which hasn't let up, despite its "factual" skeleton being gradually picked to bits.

With only a passing glance it might be tempting to believe Andrew K. Chang, MD and colleagues' conclusion that is cited by Ms. Kolata, but it takes only a little more than a glance to see serious flaws in the JAMA Network paper. Here are some of them.

The study included four groups of people in pain (416 total) who were seen at either of two emergency departments at the Montefiore Medical Center in the Bronx between 2015-16. The four groups that were compared:

• Group 1 received 400 mg of ibuprofen plus 1000 mg of acetaminophen.
• Group 2 received 5 mg of hydrocodone and 300 mg of acetaminophen. 
• Group 3 received 5 mg of oxycodone plus 325 mg of acetaminophen. 
• Group 4 received 30 mg of codeine and 325 mg of acetaminophen.

Problem #1 - Dose

If the four groups were chosen to make a point then the authors did a splendid job. There is a sleight of hand here and it's fairly obvious:

• The maximum therapeutic single dose of Advil (ibuprofen) is 400 mg. Doses higher than 400 mg have not been shown to be more effective.
• The maximum recommended single dose of acetaminophen (Tylenol) is 1,000 mg. Higher doses can cause irreversible liver damage. 
• The usual adult dose of hydrocodone is 5-10 mg.
• The usual adult dose of oxycodone is 5-15 mg. (2)
• The usual adult dose of codeine is 15-60 mg.

What's going on here should be "painfully" obvious. The study was designed to compare the analgesic power of the highest permitted dose of Advil and Tylenol with the lowest effective doses of hydrocodone and oxycodone. That's not playing fair. Here are some "real life" analogies:

Peter Dinklage weighs more than Andre the Giant (Because Andre the Giant is dead)....or...The Boston Red Sox are better than the New York Yankees (But only if the Yankees are playing with blindfolds on).

If the group ran this same trial with a realistic, not absolute minimum, opioid dose I'm betting we'd see very different results.

Problem #2 - The elephant in the kidney.

The study group was limited to patients with acute extremity pain - "pain originating distal to and including the shoulder joint in the upper extremities and distal to and including the hip joint in the lower extremities."

Two words: Kidney. Stones. Throw those bad boys in there and let's see how well Advil and Tylenol work. And you wouldn't even need to use a subjective pain scale. A decibel meter would provide measurable evidence. So would an obscenity meter.

Problem #3 - Opioids to the rescue - for some. 

Approximately 18% of the patients received "rescue analgesia." In other words, when some poor soul was lying there screaming his or her head off they were given oxycodone or morphine. So, 73 patients didn't get adequate relief from either Advil/Tylenol or low-dose opioids. Is it rude to ask why they were given insufficient pain medicine in the first place?

And doesn't this sort of prove that opioids are superior for pain relief? The 73 did not get "rescue Tylenol" because a) some of them had already been given the maximum dose, and b) in most cases Tylenol is worthless as a pain killer. Does this 18% skew the numbers? Don't bet on "no."

Problem #4 - If you have pain don't go to Montefiore.

An obvious question - why would anyone want to go to an ER with "moderate to severe acute extremity pain" when 75% of the patients in this study weren't even given an opioid? Perhaps I'm being overly picky but human experimentation in the ER doesn't sound like such a swell idea. Neither is making people suffer for no reason.

Another obvious question - why??? Has the medical world gone so bats### crazy that we are now worried that a single dose of 10-15 mg of oxycodone is going to addict anyone? No, it's not. The Chang paper was about ideology, not medicine. Just like the rest of the "opioid crisis."
NOTES:

(1) As I have written many times in the past, we are not having an "opioid crisis." We are having a fentanyl crisis.
(2) Oxycodone is 1.5-2-times stronger than hydrocodone, so these recommended doses don't make a lot of sense. I have no idea why there is an apparent discrepancy in dose.
(3) I have written about the Montefiore study in more detail. (See Advil Works As Well As Opioids For Acute Pain? Not So Fast.)

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Opioids an amazing necessity in our healing society

Glenn A. Marsch, guest columnist Jun 20, 2019

We are in a blessed time now that the medical profession is more likely to heal us than to kill us by its ministrations. In the ancient world, to go to a physician was a gamble, often subjecting patients to such hair-raising horrors as bloodletting. And snake oil remedies were common. The ancients did the best they could, and we moderns don’t give them the credit they deserve. The general attitude toward physicians was summed up by the Roman poet Martial: “Until recently, Diaulus was a doctor; now he is an undertaker. He is still doing as an undertaker what he used to do as a doctor.”

Arguably, not till the 20th century were we more likely to be healed than hurt by our doctors..........In reality, the opioid crisis is not one crisis but several. According to an article on the American Council on Science and Health website, opioid prescriptions in the United States doubled from 2003-2013, but this increase does not appear to be responsible for the majority of deaths due to addiction and drug overdosing. For example, in recent years the number of deaths per capita due to opioid overdose does not appear to be correlated with the number of opioid prescriptions written by physicians per capita..................If sufferers cannot obtain these drugs from their physicians with whom they have legitimate healing relationships, they will obtain them from illicit sources. It is an act of desperation. This is the real driver for the opioid epidemic — illicit drug use...........To Read More....

Can Xanax Kill You?

By Josh Bloom — April 24, 2019

From  Then They Came For My Xanax - Opioid Madness Metastasizes (August 9, 2018):

"Self-righteous busybodies, apparently not content with the carnage caused by their magnificently inept mishandling of the fake opioid crisis have taken up a new cause - one that will make many of you anxious. They are now concerned about an increase in the number of prescriptions written for another class of drugs - benzodiazepines, such as Xanax and Valium, which are used to treat anxiety."

The busybodies, even though they've taken some pretty good hits lately, courtesy of the FDA and even the CDC, aren't going to go away. As long as there are lives to interfere with there will be busybodies to interfere with them.

 

Xanax attracts the most attention of the benzodiazepines - it is the most prescribed drug in the class - so I thought it might be interesting to see how dangerous the drug really is (by itself). It is virtually impossible to kill yourself with a Valium overdose. (See Can Valium Kill You?). Does the same hold true for Xanax? Pretty much. 

 

In rats, the LD₅₀ - the single dose that will kill 50% of test animals - ranges from 331-1271 mg of drug per kilo of body weight, the equivalent of 76-292 mg, hundreds of 0.5 mg pills. If you could mathematically predict a lethal dose in humans based on the rat LD₅₀ data (you can't), the number of pills needed to kill a person would be in the tens of thousands. Nonetheless, these values are qualitatively useful; they can distinguish between drugs that are highly toxic and those that are not.

 

Based on rodent data Xanax (alprazolam) would not be expected to be especially deadly to humans. 

In the real world, this appears to be the case. But there are no human toxicity studies, so we can only look to the literature for case studies about the toxicity of Xanax in people. There isn't much there. 

• Wolf, et.al., (2005) examined alprazolam-related deaths in Palm Beach County. Of the 178 cases, only two were attributed to alprazolam alone. The majority of deaths were due to combined drug toxicity, mostly from cocaine, methadone, and heroin. (1).
• Jenkins, et. al., (1997) of the Office of the Chief Medical Examiner in Baltimore, reported the suicide of a 44-year old woman with ongoing psychiatric problems. The deceased woman's current medications were alprazolam, fluoxetine (Prozac), phenytoin, lorazepam (Ativan), and venlafaxine (Effexor). The medical examiner ruled that the cause of death was alprazolam intoxication. Analysis of the blood revealed a concentration of 2.1 mg of alprazolam per liter - the highest ever reported in the literature (2). There is no way to estimate from a single blood concentration how much Xanax she consumed, but that is a seriously high blood concentration for any drug; it must have been quite a bit.
• In a retrospective study (2004), Isbister and colleagues examined 2063 single benzodiazepine overdose admissions (3). Of these, 131 admissions were due to alprazolam overdoses and 823 due to diazepam (Valium). The remaining were due to other benzodiazepines. But people who overdosed with alprazolam were 22% more likely to be admitted to the ICU and also to be comatose. No deaths were reported. The authors concluded that "alprazolam was significantly more toxic than other benzodiazepines." 
• Kakkar and Kumar, writing in the Journal of Indian Academic Forensic Medicine (4), described the attempted suicide of a woman who was undergoing treatment for severe depression. She consumed 60 mg of Xanax - 120-times the "normal" (5) dose. When she was brought into the ER she was comatose and needed to be intubated. Ten hours after intubation she was able to breaths on her own. After 24 hours she regained consciousness and was released one day later with no neurological complications. After 48 hours she walked out of the hospital.

There are some take-home lessons from these few reports:

Although the safety profile of Xanax is inferior to that of Valium, it is surprisingly safe (6), especially when compared to other common drugs. The lethal dose of Xanax is approximately 10-1,000-times that of its maximum recommended dose. Let's pick 100-times. By contrast, this ratio of toxic dose/maximum recommended dose is much lower for the following common drugs (lower numbers indicate a greater risk of a fatal overdose from ingesting large amounts of the drug) (7):

• Tylenol 2-7X
• Aspirin 9X
• Benadryl 4-25X
• Ritalin ~3X

Keeping in mind that these are very rough estimates, yet there are a whole lot of common drugs out there that have a much higher fatal overdose potential than Xanax. The drug is very useful for anxiety and panic attacks but can cause addiction and dependency, and becomes far more dangerous in combination with other drugs. Much like any other drug Xanax has risks and benefits. It should not be handed out like candy but it is not the molecular miscreant that the addiction "experts" claim it is.

You are more likely to die from a bottle of Tylenol (8). Or busybodies.

NOTES:

(1) B. Wolf, et. al., The American Journal of Forensic Medicine and Pathology: March 2005 - Volume 26 - Issue 1 - pp 24-27
(2) Journal of Analytical Toxicology, Vol. 21, May/June 1997
(3) Isbister et.al., Br J Clin Pharmacol. 2004 Jul;58(1):88-95. Review.
(4 Kakkar and Kumar, J Indian Acad Forensic Med. October-December 2014, Vol. 36, No. 4
(5) It is difficult to determine a "normal" dose of Xanax. For anxiety, it is 0.25-0.50 mg three times per day. For panic disorders, doses as high as 10 mg/day are used. This is why all comparisons to other drugs are crude approximations.
(6) I am discussing only acute toxicity of Xanax alone - the risk of death from a single dose - not addiction potential, withdrawal, or the risk of death when other drugs, especially alcohol, are used. These are very different issues.
(7) These multiples are very rough estimates of the relative risk of overdose deaths of Xanax compared to four other common drugs. Data were from multiple sources, some of which differed significantly from each other. The numbers are qualitative, not quantitative. It can be reasonably concluded that the risk of a fatal overdose of Xanax from swallowing a bottle of pills is significantly less than for Tylenol, etc.
(8) No, I’m not kidding. Neurologist and pain management physician Dr. Aric Hauskenect calls Tylenol “by far the most dangerous drug in the world.” See Pain In The Time Of Opioid Denial: An Interview With Aric Hausknecht, M.D." 

Heroin Activates Negative Emotional Learning Brain Circuits

By Alex Berezow — April 5, 2019 @ American Council on Science and Health

Addiction is a complex phenomenon. Genetic, physiological, cultural, and socioeconomic factors all appear to play a role.

The ongoing opioid crisis is particularly troublesome due to its high death toll. In 2017, more than 70,000 Americans died from drug overdoses, the lion's share of which were due to opioids like heroin and fentanyl. People who break out of the addiction describe opioids in almost romantic terms:

"I loved it. It was my everything. I loved it more than my family, more than my job, more than my friends, more than my girlfriend at the time."

What is it about opioids that makes them so powerfully addictive? According to new research, one reason appears to be that they engage brain circuits associated with negative emotional learning, which in turn creates persistent unpleasant emotions that a user suppresses with yet more opioids.
Reporting in the Journal of Clinical Investigation, a team of researchers subjected rats to a behavioral experiment. The rats were first trained to self-administer heroin. (Yes, they really can be taught to do that.) One group of rats was allowed only brief (1-hour) access to heroin, while the other group was allowed long (12-hour) access. As expected, the rats in the long-access group became addicted, using more and more heroin over time. (See graph.)

Then, while the rats were getting blitzed on heroin, the researchers gave them injections of either saline (which does nothing) or naloxone (which blocks the effect of heroin and triggers withdrawal symptoms). Simultaneously, they provided the rats with an olfactory cue, such as lemon- or vanilla-scented bedding. The rats that were getting naloxone quickly learned to associate withdrawal symptoms with the smell of lemon or vanilla. As a result, simply smelling lemon or vanilla made the addicted rats seek out more heroin.

In other words, the researchers demonstrated that the rats had undergone conditioned negative reinforcement, which is the reinforcing of one behavior (i.e., self-administering heroin) under a particular condition (i.e., smelling lemon or vanilla) to avoid something negative (i.e., withdrawal symptoms).

Finally, the authors exposed the rats to the scents and examined what happened in their brains.

Regions of the amygdala (associated with fear) and the hypothalamus (associated with emotion) lit up in the addicted rats, demonstrating a link between these brain circuits and the rats' heroin-seeking behavior.

What does this mean for humans? It could mean that opioid addicts learn to associate unpleasant withdrawal symptoms with other stimuli in the environment, such as smells or visual cues. The presence of these otherwise neutral environmental cues could cause the addict to constantly anticipate withdrawal, encouraging him to use more opioids.

Obviously, a better understanding of this phenomenon could help shed light on relapsing and overdosing. To solve the opioid crisis, we need all the information we can get.

Source: Stephanie A. Carmack et al. "Heroin addiction engages negative emotional learning brain circuits in rats." Journal of Clinical Investigation. Published online: 26-March-2019. DOI: 10.1172/JCI125534

Cuomo's Out of Control Craving for an Opioid Slush Fund

by Jeff Stier RealClear Policy March 21, 2019

Sometimes a bad idea is a bad idea, no matter how you package it. New York Governor Andrew Cuomo is trying again, after his $600 million opioid tax was slapped down in December by an Obama appointed federal judge.  Proponents of the earlier tax scheme pointed to a key provision which forbade manufacturers from passing along the cost to patients. This was an essential element of the plan, who in their right mind would want to punish patients whose doctors legitimately prescribe opioids for acute pain?.............As a result of the ruling, Governor Cuomo was in a bind. He could have simply abandoned the cash grab, or he could have tweaked the law to make it constitutional by permitting the tax to be passed along to pain patients. Unfortunately, he went with the latter. Like an addict, he went for the fix, regardless of the harmful consequences........To Read More..........

An Opioid Study So Bad That It Disproves Itself?

By Josh Bloom — January 23, 2019 @ American Council on Science and Health

Here's a first. A study that might actually disprove itself. I've never seen anything like it.

A paper in JAMA Open Network tries to hop on the anti-opioid bandwagon but fails so badly that I had to stare at the screen in disbelief for a while. Did I really just see this? Does it mean what I think it does? Did the authors fail to realize what their own data say?

Here's the title:

The intent of the study is obvious - to let us know that more pharmaceutical money leads to more opioid prescriptions being written, which results in more OD deaths. While this may be "intuitively obvious," this does not make it correct. Here's why.

The authors, mainly from Boston Medical Center, gathered prescription data from 67,507 US physicians in 2,208 counties between August 1, 2013, and December 31, 2015. They used these data to assert (Cue to "Same Old Song," Four Tops, 1966) that the more that drug companies push opioid pills to doctors the more people died over a 2+ year period. But they may have given us cause to reach an entirely different conclusion.

Let's start with their Table 2, which examines the association between pharma money and OD death using three different models, each of them representing a different way of measuring "money."

Table 2 (partial): Source: JAMA Network

There are three ways that the scientists used to measure pharma money: marketing dollars (A), the number of physician payments (B), and the number of physicians who received payments (C). In each model, there is an associated relative risk (RR) of increased deaths in those counties ranging from 1.09-1.18, which means a 9-18% increase.

ACSH advisor and expert biostatistician Dr. Stan Young is uncharacteristically understated:

"An odds ratio, OR, of 1.000 is even odds, no effect. If an OR is close to 1.000, then any small bias could have produced the effect. An OR of 1.1 is not impressive."
Dr. Stan Young, private communication, 1/23/19

In other words, when the increased relative risk is so low the presence of any kind of bias, for example, age, race, socioeconomic status, or the presence of other drugs, could turn the very low observed increase could turn into a zero increase. Even if we assume a perfect selection process, we are looking at an increase in deaths of about 15% at best. In other words, not much.

Now let's look at Table 3, which shows that more pharma money results in doctors writing more prescriptions - something that can't be a huge surprise.

Table 3 (partial): Source: JAMA Network

But now we see that pharma money results in a large increase in the number of prescriptions written by doctors. With a higher relative risk (1.8-13.6-fold, 80-1260 % increase) the chance of bias affecting the results is quite low.

So, let's put these two conclusions together:

A. More pharma money leads to a very small (perhaps, zero) increase in overdose deaths.
B. More pharma money leads to a significant increase in written prescriptions.
So, it is reasonable to conclude that:
C. Despite a whole lot more written prescriptions, the rise in OD deaths is minimal, if any.
So, it's also reasonable to conclude that:
D. Prescribed opioids aren't causing many (or any) deaths, something that patient advocates have been screaming forever.

There are other limitations of the study that are disclosed in the paper as required. It would be rather easy to debunk the study based on these alone. But let's not. Instead, let's ask a question: Did the authors start out trying make a point only to end up making the opposite point instead? If so, do they realize this? Or are they just hoping that we don't?

I have no idea. Perhaps someone can explain? Crazy.

Feds battle opioid abuse with a circular firing squad

Henry I. Miller and Josh Bloom March 11, 2019

The ongoing battle to control opioid addiction has not gone well. Many of the government’s efforts have been medically and scientifically flawed and unproductive. Some have even been counterproductive. Public policy is in disarray.

A Feb. 1 article  in the Journal of the American Medical Association concluded, “Under current conditions, the opioid overdose crisis is expected to worsen — with the annual number of opioid overdose deaths projected to reach nearly 82,000 by 2025, resulting in approximately 700,000 deaths from 2016 to 2025.” But here’s the rub: In their system dynamics model, preventing prescription opioid misuse alone would have only a modest effect — a few percent — on lowering opioid overdose deaths in the near future.

In spite of abundant commentary that suggests otherwise, the crux of the problem is not physician-prescribed opioids, but illegal supplies smuggled from abroad. Nevertheless, the federal and state governments are focusing on prescriptions. It reminds us of the old joke about the drunk who’s hunting for his lost keys under the lamppost, not because he thinks they’re there, but because that's where the light is good.

It should come as no surprise that with bureaucrats and politicians making policy on the basis of flawed assumptions, the outcomes are poor. And patients are paying the price.

Bureaucrats are now dictating not only acceptable prescribing practices of opioid painkillers, but also how much can be manufactured. This power grab is both unprecedented and disturbing, and patients who need these pain medications, which are unrivaled for efficacy, are suffering.

One example of wrong-headed policy was President Trump’s asking then-Attorney General Jeff Sessions to sue opioid manufacturers, and another was a rule issued last July that gives the Drug Enforcement Administration unprecedented authority to set annual opioid production limits: “If DEA believes that a particular opioid or a particular company’s opioids are being diverted for misuse, this allows DEA to reduce the amount that can be produced in a given year.” In August, the feds did, in fact, propose cutting manufacturing 2019 quotas for six commonly abused prescription opioids by an average of 10 percent.

Enter the law of unintended consequences. Opioids, including fentanyl, morphine, and hydromorphone, some of our most important and potent analgesics, which are commonly used in patients with advanced cancer and for pain control after surgery, are now in shortage, according to the Food and Drug Administration. All of these drugs had their manufacturing quotas reduced by the feds.

Thus, the feds’ actions have succeeded not in ameliorating the scourge of opioid abuse and overdoses, which results from drugs made in China and elsewhere abroad smuggled across our borders, but in unnecessarily causing several other problems. These include a shortage of critical drugs produced by legitimate manufacturers and expanding the market and boosting the street price for illegal, dangerous imports.

Common misconceptions about the nature, extent, and causes of opioid addiction have led to this wrong-headed government interference. For example, President Trump has said, “People go to the hospital for a period of a week and they come out and they’re drug addicts,” but that is a myth.

True addiction in pain patients is rare. Many scholarly reviews have concluded that the addiction rate is less than one percent even in patients who have required long-term opioid medication for severe pain due to injury or illness. The current death toll from opioid use is largely the result of abuse, not medical use, of these drugs. And yet, as of last October, 33 states had instituted laws that restrict opioid prescribing in some way.

For example, Florida has a three-day limit on prescribed opioids, with the possibility of a seven-day supply if strict conditions are met. Massachusetts limits first-time patients to a seven-day supply and forbids a second prescription until the first expires. And nationwide, millions of pain patients, even those who were functioning well with long-term opioid therapy, are being forcibly tapered or having their medicines stopped outright, regardless of their wishes or those of their physicians.

This is bad public policy and bad medicine. After surgery, for example, we know that post-operative pain varies widely from patient to patient, so a standardized, one-size-fits-all dose of an analgesic is inappropriate and will also fail those afflicted with other kinds of pain, both acute and chronic. The principles of pharmacology tell us why.

The effect of a drug on an individual is directly related to body weight, and also to the efficiency of drug metabolism. The rate of metabolism of opioids can vary as much as 30-fold from one individual to the next because of genetic differences in the enzymes found in the liver and in bacteria in the gut that are responsible for the degradation of the drugs. This means a given dose of an opioid could be dangerously high for one person while too low to be effective for another.

If the science is bad, the legal precedents are worse. In the mad rush to address a complex problem with simplistic thinking, there has been an insidious but largely ignored trend toward state governments and federal agencies, in effect, writing prescriptions. In a country so respectful of individuals’ rights, how could we surrender the sanctity of the patient-physician relationship without a whimper.

The decadeslong war on drugs, which has never succeeded in controlling abuse or addiction, has now mistakenly declared American drug companies and doctors to be the enemy. In the name of addressing a crisis, we are focusing on the wrong targets and sacrificing freedoms in a new, dangerous way. That’s a prescription for disaster.

Henry I. Miller, a physician and molecular biologist, is a senior fellow at the Pacific Research Institute. Josh Bloom holds a Ph.D. in organic chemistry and is the director of Chemical and Pharmaceutical Sciences at the American Council on Science and Health.

Sen. Ron Wyden Smears Opioid Task Force. Why?

By Josh Bloom — December 28, 2018

It is now indisputable that the CDC Guideline for Prescribing Opioids for Chronic Pain, United States, 2016 was a catastrophe by any measure. Not only have the "guidelines," predictably, metastasized into laws, but they are also scientifically without any merit. (See Opioid Policies Based On Morphine Milligram Equivalents Are Automatically Flawed). One size fits none.

The past two years have been a bloodbath for both users and abusers of opioids. Since 2016, chronic pain patients, even those who had been treated successfully for decades with opioid analgesic drugs, have been forcibly tapered from their medications or denied them entirely. These patients, many of whom have become disabled without the drugs they need, exist in a state of constant terror. What happens when their meds run out? Increasingly, the only alternative is suicide. Most of the pain patients I have spoken to or corresponded with -- hundreds of them -- have a suicide plan in place; indeed, stories of suicides of undertreated patients are becoming all too common.

Addicts, who were supposedly going to be protected by these laws, have fared even worse. Within the past five years, the number of opioid prescriptions has decreased by 25%. The result? The number of deaths from these drugs has remained constant, while during the same time, the number of overdose deaths from fentanyl and heroin -- the real killers -- has increased by five-fold. The conclusion is inescapable: as prescription opioid analgesics become more difficult to obtain, those who are dependent upon them, both addicts and patients, increasingly turn to the streets where a fatal dose of illicit fentanyl can be waiting in any bag or vial.

Fortunately, there is now an ongoing effort to undo some of the damage. Two years ago, the Pain Management Best Practices Inter-Agency Task Force was formed by the U.S. Department of Health and Human Services (HHS), to reexamine the original guidelines. It's about time. right? Maybe not. Some policymakers apparently don't want anything reexamined.

The task force's draft report was issued today, but that didn't stop certain people and/or groups, who apparently are opposed to any changes, from starting a smear campaign against the task force and some of its members earlier this month. The smear was appallingly unoriginal, claiming that they were "bought off" by pharmaceutical industry money.

Is there any merit to these trite charges, or are they just baseless smears? Who is behind the smear campaign and why? You don't have to look far, just West. Specifically, 405 E 8th Ave. # 2020 in Eugene -- the Oregon office of Senator Ron Wyden (D-Ore.) (1).

Sen. Ron Wyden's (D-Ore.) December 18th letter to Alex Azar, the head of HHS, objected to the composition of the Task Force, claiming that some people in the 29-member committee should not serve because they have been bought off by money from the pharmaceutical industry. In other words, corruption.

That's a serious allegation and should be backed up with serious evidence. Is there any? That's an easy one. No.

The entire 29-person task force was vetted for conflicts of interest. And they all passed. The vetting process was no different from that of all other panels and groups. Wyden certainly knows this, yet that didn't prevent him from writing the following about one of the members:



Dr. Cheng addresses these charges:

I was on a scientific review committee that reviewed investigator-initiated research proposals on non-opioid alternative treatment for chronic pain. All the research proposals were submitted by investigators from academic institutions in the US. None of the proposals were submitted by Purdue Pharma employees or affiliates as specifically defined by the request for applications (RFA).  In this role, my sole involvement was to review and critique the scientific merit of the research proposals, nothing else. I was not involved in any way or shape in any Purdue Pharma’s promotion of its products. In the end of 2016, I was elected president-elect of American Academy of Pain Medicine. So I divested from industry involvement as required. At that time and still to this date, I have no financial relations to industry... there has been no conflict of interest between my work in HHS and industry. Jianguo Cheng, MD, Private Communication, 12/27/2018

 Cheng was not alone. Dr. Rollin Gallagher, who has a long and distinguished record in pain management, also got slimed:

But Dr. Gallager tells quite a different story:

My salary as Editor in Chief of Pain Medicine has by contract always been paid by AAPM through a stipend for editorial services from the publishers of Pain Medicine; it is not paid by industry funds as Senator Wyden suggests. This arrangement assures independence of the editorial peer-review process from sponsoring societies. Furthermore, I voluntarily stopped all relationships with industry, consulting or advisory, more than 10 years ago, to assure the editorial independence of Pain Medicine. Finally, authors are required to disclose any industry involvement in their research when submitting their papers for peer-review. I have held leadership roles in Federal Medicine for more than a decade, including National Director for Pain Management for the VA. Industry relationships are not permitted.  Rollin Gallagher, M.D. Private communication, 12/28/2018

Given the strict vetting process and the response from both physicians, it is not a stretch to conclude that Wyden knowingly put out false or misleading information to throw a wrench into the work of the Task Force. But why? Could it possibly be due to this?

Table 1. Ron Wyden's top contributors by industry for the 2015-16 election cycle. Source: OpenSecrets.org

Table 1 is rather revealing. Three (red) of the 10 top contributors (by industry) to Wyden's campaign would financially benefit by restricted use of opioid drugs. Three others (yellow) may or may not; there is no data to prove or disprove this, although OpenSecrets.org says that lawyers and lobbyists may act to pass through money from industries to campaigns. Perhaps most interestingly, Wyden, who equates the pharmaceutical industry (green) with the devil himself, gets a substantial amount of money from it.

And then there's this:

 

Sen. Wyden was a top recipient of contributions from three health-related industries between 2013-2016. (Source: OpenSecrets.org)

 

It would seem that Sen. Wyden received substantial support from companies and industries that stand to gain financially by restriction of opioid drugs. Of course, none of this was in his letter to Secretary Azar.

Who is more believable? A Senator who smears a thoroughly vetted Task Force while himself taking substantial sums of money from industries that stand to benefit from his discrediting of the group? Or the Task Force itself, which, as pointed out by Drs. Cheng and Gallagher has no conflict of interest whatsoever?

You decide.

NOTES:

(1) It is probably not a coincidence that Wyden is an Oregonian. Oregon is arguably the worst of all states for pain patients, especially if they are poor (See Shades Of Tuskegee - Oregon's Monstrous Experiments On Poor Pain Patients). The state is so anti-opioid that a proposal by Oregon's Health Evidence Review Commission (HERC) would have ended Medicaid payments for long-term pain relief starting January 1, 2019, had they not backtracked, but not by much.

 

 

Organic Chemistry Can Defeat Any Fentanyl Agreement

By Josh Bloom — December 5, 2018 @ American Council on Science and Health

It's not news that President Trump is having discussions with China's President Xi about getting a handle on fentanyl and "fentanyl-related substances." What is not widely known is that while an agreement between the two countries may be of some help in curbing the surge of opioid overdose deaths that we read about daily (1) there is a power that neither superpower can match - organic synthesis.

Organic synthesis is the science (and also art) of converting one molecule to another by using specific chemical reactions to bring about the desired transformation. Fentanyl itself is the product of organic synthesis; it was first made by chemist Paul Jannsen in 1960. Jannsen would become famous for forming Jannsen Pharmaceuticals, which is now part of Johnson and Johnson. Fentanyl would become famous for very different reasons.

Just as organic synthesis was responsible for the discovery of fentanyl it is also responsible for the "fentanyl-related substances," some of which are far more powerful than fentanyl itself, that are increasingly appearing in the US and being seized by the DEA. And while it may be possible to gain some control over fentanyl by legal means, "fentanyl-related substances" present a different (and worse) set of problems. And it's all because of organic chemistry.

The problem with the working plans is the term "fentanyl-related substances," which is another way of saying fentanyl analogs (2). There is no way to objectively define what this term means. Does it mean drugs that are structurally similar to fentanyl? Or does it mean drugs with the properties of fentanyl that can be put on a list and declared to be illegal? The first definition is subjective and will inevitably give wrong answers. The second is impossible. To make sense of any of this we need to take a look at the structure of fentanyl.

Two different chemists can look at the structure of just about any molecule and subdivide it into regions that he/she believes represents a "map" of the molecule; this is quite subjective. In Figure 1 I've shown two of an infinite number of possible "maps." Both structures are the fentanyl molecule and each contains four structural elements (again, arbitrary), but the structural elements are clearly different. Let's stick with the one on the left. It's simpler.

Figure 1. Two (of an infinite number) of different ways to look at the chemical structure of fentanyl, both arbitrary. The four colors represent "sections" of the fentanyl molecule. Note that the only difference is the placement of the circle, which determines the "section."

CATEGORIZING FENTANYL-LIKE SUBSTANCES BY STRUCTURAL SIMILARITY

Everything that it takes to poke a hole in this plan can be found in Figure 2. Whether you're a chemist or not it's pretty clear that despropionylfentanyl aka 4-ANPP (3) (Right) looks a whole lot like fentanyl (Left). Let's say that the "eyeball chemical similarity" is ~90%. So, it is reasonable to assume that these two chemicals would both be on the same list. But in order for it to be correct, that list would have to be entitled "Chemicals that look alike but behave completely differently." Little is known about the pharmacology of despropionylfentanyl but it sure isn't fentanyl; 4-ANPP is listed as an "irritant" on the safety data sheet of Matix Scientific, a supplier of the chemical. It is not an opioid even though it may "look" like one.

Figure 2. Fentanyl (Left) and despropionylfentanyl , aka 4-ANPP, (Right) look very similar but despropionylfentanyl has none of the properties of fentanyl. They differ only by the propionyl group (blue circle), but this makes all the difference in the world.

 

MAKING A LIST AND CHECKING IT A BILLION TIMES

There is no conceivable way of anticipating and listing all possible fentanyl analogs; the number is infinite. The DEA says that there are about 12 known fentanyl analogs that are now being circulated in the US. This does not even begin to scratch the surface of what could be synthesized. The vast majority of fentanyl analogs that we will see in the future don't even exist yet, except perhaps in the mind of a chemist. Or maybe he/she hasn't even thought of it yet.
A way to demonstrate the magnitude of the numbers is to look at one of several synthetic steps used to put fentanyl together. It is called acylation - the formation of an amide bond. Without this bond, the molecule will have no opioid properties.

 

Figure 3. The reaction of 4-ANPP plus a carboxylic acid to form a fentanyl analog. The red hatch line indicates the critical amide bond. There are a huge number of possibilities for X, each yielding a different analog.

Here's one of many reasons why a list is not possible. If search the database of Sigma-Aldrich, the largest supplier of research chemicals, using "carboxylic acid" as the search term you'll see this:

The company sells 8,313 different carboxylic acids, so one could theoretically make 8,313 possible fentanyl analogs just from 4-ANPP (4). But it doesn't stop here. Not even close. Because fentanyl analogs don't need the exact 4-ANPP portion (also called the skeleton) of the molecule to be opioids. There are plenty of known fentanyl analogs that do not. Some look very much like fentanyl...

Figure 4. Close analogs of fentanyl. The red arrow shows a single change in the molecule. The analog at the top, 3-methylfentanyl is about 50-times more potent than fentanyl itself. Source: Jannetto, P. J. et. al., (2018). The Fentanyl Epidemic and Evolution of Fentanyl Analogs in the United States and the European Union. Clinical Chemistry, clinchem.2017.281626. doi:10.1373/clinchem.2017.281626

and some do not...

Figure 5. Analogs of fentanyl that are structurally dissimilar to fentanyl. 

The take-home message here is that there are millions of fentanyl analogs that can be made from commercially available chemicals. It is all but certain that many of them will have fentanyl-like properties and that some of these will make even the most powerful analogs today, such as carfentanil and sufentanil, seem like cotton candy. The term used to describe the use of synthetic organic chemistry to maximize potency (and other properties) of potential drugs is "structure-activity relationships. (SAR)" It is the cornerstone of new drug discovery, both legal and otherwise. Conceptually it's very simple; SAR makes better analogs.

One tool that has been used by law-enforcement to ban new drugs that aren't specifically illegal is the 1986 Federal Analogue Act, which expands the definition of a controlled substance (5). The same language could be applied to an international agreement. Here is part of it:

"...the chemical structure of which is substantially similar to the chemical structure of a controlled substance..."

Here we go again. What is "substantially similar?" That depends on who you ask. It's just about impossible to come up with any kind of list or law that cannot be beaten by the power of organic synthesis, Figures 4 and 5 show us this.

And to make matters worse, where do you put this?

U-47700 is a potent opioid analgesic which is about seven-times stronger than morphine (6). It bears no resemblance to fentanyl but acts somewhat like it.

Good luck trying to fit U-47700 (and other analogs like it) onto a list of "fentanyl-related substances." Because it doesn't belong there, even though it's way more potent than morphine.

It should now be obvious that it is very far from simple to ban fentanyl and "fentanyl-related substances." Agreement with China or not, this mess isn't going away anytime soon. Chemists will see to that.

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NOTES:

(1) As I've written many times before, it is illicit fentanyl and its analogs that now are killing thousands of Americans every year, not Vicodin.

(2) Analogs are chemical cousins of a drug (or another chemical). They usually have a similar chemical structure and elicit a similar biological response, but both can also be quite different. The term is sometimes subjective.

(3) Despropionylfentanyl, 4-Aminophenyl-1-phenethylpiperidine, and 4-ANPP are all names for the same molecule. It takes about 2 seconds to convert it to fentanyl, so it is highly controlled, so you'll never be able to buy it. But a competent organic chemist can just make it from any number of smaller, common chemicals. It just takes a bit more work. See how easy this is?

(4) No one is right or wrong mind would ever try to make all of these. Most of the "fentanyl derivatives" made from complex or large carboxylic acids wouldn't work. But there are probably a couple of hundred that would. Organic chemists just know this stuff.

(5) The act makes it possible to declare drugs illegal, even though they are not even known yet. Unless you get a good lawyer who can convince the court that whatever you're caught with isn't "similar enough."

(6) Reference: Cheney BV, Szmuszkovicz J, Lahti RA, Zichi DA (December 1985). "Factors affecting binding of trans-N-[2-(methylamino)cyclohexyl]benzamides at the primary morphine receptor". Journal of Medicinal Chemistry. 28 (12): 1853–64.