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Designing less addictive opioids, through chemistry

While the COVID-19 pandemic raged on, the opioid epidemic got worse as drug overdose deaths soared. New research proposes a way to chemically modify opioids to reduce the risk of addiction.

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One potential way to make opioids less addictive is to make them target injured tissue rather than the healthy brain. PM Images/Photodisk via Getty Images

What if there was a way for pain patients to get all the pain-relieving power of opioids with none of the addicting side effects?

Opioids are one of the most powerful pain medications available, but millions of Americans have struggled with prescription opioid misuse after getting hooked on the feelings of calm and euphoria they also induce. But new research suggests there may be a way to chemically tailor opioids to reduce their addictive potential.

The first wave of the opioid epidemic in the United States began in the 1990s. By 2015, approximately 11.5 million Americans were struggling with prescription opioid misuse. The Centers for Disease Control and Prevention estimates that nearly 500,000 people died from opioid overdose from 1999 to 2019. Recent reports have shown that this ongoing health crisis has only intensified during the COVID-19 pandemic. The U.S. reached a record 93,000 overdose deaths in 2020, a 29% increase from the previous year.

Many people with opioid dependencies report using these drugs to relieve physical pain: Chronic pain treatment is a leading cause of opioid abuse. But there currently are no equivalent medications capable of the providing the same level of pain relief without the potential risk of addiction.

A less addictive opioid, however, could be an important tool to deal with the opioid epidemic. I’m a physical chemist interested in this problem, and my research group used computational chemistry to investigate how opioids like morphine can be redesigned to target specific pain regions without affecting the brain.

In the process of trying to develop a less addictive painkiller, researchers produced more forms of addictive opioids.

The biochemistry of opioids

There are many different classes of opioids that vary in chemical structure. However, all opioids contain the same type of chemical group that dictates their biochemical activity. Morphine, oxycodone and hydrocodone belong to the same major class of epoxymorphinan opioids and share nearly identical chemical structures.

Structures of epoxymorphinan structures
Morphine, oxycodone, and hydrocodone belong to the same class of opioids and have similar structures. Aaron Harrison, CC BY-ND

Fentanyl, on the other hand, belongs to the phenylpiperidine class of opioids and looks quite different.

Chemical structures of morphine and fentanyl
Morphine and fentanyl have different chemical structures but share a nitrogen group that undergo a similar chemical reaction in the bloodstream. Aaron Harrison, CC BY-ND

The chemical structures of these molecules will be a bit of mystery if you haven’t taken an organic chemistry class before. However, we can simplify the picture by focusing on what’s common between them. Both molecules contain a nitrogen that’s part of what’s called an amine group. This group can become positively charged via a chemical reaction that happens in water-based environments such as the bloodstream.

Morphine reaction with water to generate active opioid.
Neutrally-charged morphine undergoes a chemical reaction in water to become a positively-charged, biochemically active compound. Aaron Harrison, CC BY-ND

This positively charged structure is the biochemically active form of the opioid – it won’t have any effect on your body until it gains this positive charge. The positive charge on the nitrogen helps these drugs bind to the target site where the pain is originating and provide relief.

The typical acidity level of the average person’s body provides ideal conditions for morphine and fentanyl to become positively charged. This means that nearly all of the drug that’s consumed will be biochemically active throughout the body. Whether it’s in the brain or at the site of injury, cells all over the body will feel the effects of the drug.

Making opioids less addictive

Many of the addictive qualities of opioids are due to the feelings of calm and euphoria they induce in the brain. For conditions like arthritis and wound and postoperative pain, however, these drugs need to target only the diseased or injured areas of the body to provide pain relief. The question researchers face is whether it’s possible to limit the effect of opioids to specific areas of the body without affecting the brain.

One recently proposed solution focuses on the acidity difference between injured and healthy tissue. Injured tissue is more acidic than healthy tissue due to a process known as acidosis, where lactic acid and other acidic byproducts produced by damaged tissue collect. This means that an opioid could potentially be altered to be positively charged and active only in injured tissue, while staying neutral and inactive in normal tissue. The drug would be biochemically active only at a higher acidity level than found in healthy tissue.

This theory was first explored using fentanyl. Researchers found that introducing a fluorine (F) atom near the nitrogen in the amine group can lower the acidity range in which fentanyl is active, making it less likely to be active at the normal acidity levels of the body.

Chemical structure of fluorinated fentanyl
Adding a fluorine atom to fentanyl can make it less likely to be biochemically active in healthy body tissues. Aaron Harrison

Adding fluorine to fentanyl showed increased opioid activity in the more acidic conditions of injured tissue compared to healthy tissue. This meant that the drug “turned on” only in parts of the body that needed pain relief. In addition, it showed a decrease in the severe side effects associated with opioids, like addictive potential and abnormally decreased breathing rates, while still providing pain relief.

My colleagues and I have recently extended this framework to morphine. We showed that similar fluorine substitutions can also adjust morphine’s active acidity range to specifically target injured tissue. Given that molecules in the same class of opioids as morphine share similar structures, we believe this approach would also work in other opioids like hydrocodone and oxycodone.

Chemical structure of fluorinated morphine
Adding a fluorine atom to morphine can make it less likely to be biochemically active in healthy body tissues. Aaron Harrison, CC BY-ND

Effectively treating pain without putting patients at risk for addiction remains a significant problem in health care. This approach has been tested only in lab settings and might not be in pharmacies for some time, if ever. But chemically altering existing opioids is a promising avenue towards developing drugs that alleviate pain without causing addiction.

[Understand new developments in science, health and technology, each week. Subscribe to The Conversation’s science newsletter.]

Aaron W. Harrison does not work for, consult, own shares in or receive funding from any company or organization that would benefit from this article, and has disclosed no relevant affiliations beyond their academic appointment.

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Young People Aren’t Nearly Angry Enough About Government Debt

Young People Aren’t Nearly Angry Enough About Government Debt

Authored by The American Institute for Economic Research,

Young people sometimes…

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Young People Aren't Nearly Angry Enough About Government Debt

Authored by The American Institute for Economic Research,

Young people sometimes seem to wake up in the morning in search of something to be outraged about. We are among the wealthiest and most educated humans in history. But we’re increasingly convinced that we’re worse off than our parents were, that the planet is in crisis, and that it’s probably not worth having kids.

I’ll generalize here about my own cohort (people born after 1981 but before 2010), commonly referred to as Millennials and Gen Z, as that shorthand corresponds to survey and demographic data. Millennials and Gen Z have valid economic complaints, and the conditions of our young adulthood perceptibly weakened traditional bridges to economic independence. We graduated with record amounts of student debt after President Obama nationalized that lending. Housing prices doubled during our household formation years due to zoning impediments and chronic underbuilding. Young Americans say economic issues are important to us, and candidates are courting our votes by promising student debt relief and cheaper housing (which they will never be able to deliver).

Young people, in our idealism and our rational ignorance of the actual appropriations process, typically support more government intervention, more spending programs, and more of every other burden that has landed us in such untenable economic circumstances to begin with. Perhaps not coincidentally, young people who’ve spent the most years in the increasingly partisan bubble of higher education are also the most likely to favor expanded government programs as a “solution” to those complaints.

It’s Your Debt, Boomer 

What most young people don’t yet understand is that we are sacrificing our young adulthood and our financial security to pay for debts run up by Baby Boomers. Part of every Millennial and Gen-Z paycheck is payable to people the same age as the members of Congress currently milking this system and miring us further in debt.

Our government spends more than it can extract from taxpayers. Social Security, which represents 20 percent of government spending, has run an annual deficit for 15 years. Last year Social Security alone overspent by $22.1 billion. To keep sending out checks to retirees, Social Security goes begging to the Treasury Department, and the Treasury borrows from the public by issuing bonds. Bonds allow investors (who are often also taxpayers) to pay for some retirees’ benefits now, and be paid back later. But investors only volunteer to lend Social Security the money it needs to cover its bills because the (younger) taxpayers will eventually repay the debt — with interest.

In other words, both Social Security and Medicare, along with various smaller federal entitlement programs, together comprising almost half of the federal budget, have been operating for a decade on the principle of “give us the money now, and stick the next generation with the check.” We saddle future generations with debt for present-day consumption.

The second largest item in the budget after Social Security is interest on the national debt — largely on Social Security and other entitlements that have already been spent. These mandatory benefits now consume three quarters of the federal budget: even Congress is not answerable for these programs. We never had the chance for our votes to impact that spending (not that older generations were much better represented) and it’s unclear if we ever will.

Young Americans probably don’t think much about the budget deficit (each year’s overspending) or the national debt (many years’ deficits put together, plus interest) much at all. And why should we? For our entire political memory, the federal government, as well as most of our state governments, have been steadily piling “public” debt upon our individual and collective heads. That’s just how it is. We are the frogs trying to make our way in the watery world as the temperature ticks imperceptibly higher. We have been swimming in debt forever, unaware that we’re being economically boiled alive.

Millennials have somewhat modest non-mortgage debt of around $27,000 (some self-reports say twice that much), including car notes, student loans, and credit cards. But we each owe more than $100,000 as a share of the national debt. And we don’t even know it.

When Millennials finally do have babies (and we are!) that infant born in 2024 will enter the world with a newly minted Social Security Number and $78,089 credit card bill for Granddad’s heart surgery and the interest on a benefit check that was mailed when her parents were in middle school. 

Headlines and comments sections love to sneer at “snowflakes” who’ve just hit the “real world,” and can’t figure out how to make ends meet, but the kids are onto something. A full 15 percent of our earnings are confiscated to pay into retirement and healthcare programs that will be insolvent by the time we’re old enough to enjoy them. The Federal Reserve and government debt are eating the economy. The same interest rates that are pushing mortgages out of reach are driving up the cost of interest to maintain the debt going forward. As we learn to save and invest, our dollars are slowly devalued. We’re right to feel trapped.  

Sure, if we’re alive and own a smartphone, we’re among the one percent of the wealthiest humans who’ve ever lived. Older generations could argue (persuasively!) that we have no idea what “poverty” is anymore. But with the state of government spending and debt…we are likely to find out. 

Despite being richer than Rockefeller, Millennials are right to say that the previous ways of building income security have been pushed out of reach. Our earning years are subsidizing not our own economic coming-of-age, but bank bailouts, wars abroad, and retirement and medical benefits for people who navigated a less-challenging wealth-building landscape. 

Redistribution goes both ways. Boomers are expected to pass on tens of trillions in unprecedented wealth to their children (if it isn’t eaten up by medical costs, despite heavy federal subsidies) and older generations’ financial support of the younger has had palpable lifting effects. Half of college costs are paid by families, and the trope of young people moving back home is only possible if mom and dad have the spare room and groceries to make that feasible.

Government “help” during COVID-19 resulted in the worst inflation in 40 years, as the federal government spent $42,000 per citizen on “stimulus” efforts, right around a Millennial’s average salary at that time. An absurd amount of fraud was perpetrated in the stimulus to save an economy from the lockdown that nearly ruined itTrillions in earmarked goodies were rubber stamped, carelessly added to young people’s growing bill. Government lenders deliberately removed fraud controls, fearing they couldn’t hand out $800 billion in young people’s future wages away fast enough. Important lessons were taught by those programs. The importance of self-sufficiency and the dignity of hard work weren’t top of the list.

Boomer Benefits are Stagnating Hiring, Wages, and Investment for Young People

Even if our workplace engagement suffered under government distortions, Millennials continue to work more hours than other generations and invest in side hustles and self employment at higher rates. Working hard and winning higher wages almost doesn’t matter, though, when our purchasing power is eaten from the other side. Buying power has dropped 20 percent in just five years. Life is $11,400/year more expensive than it was two years ago and deficit spending is the reason why

We’re having trouble getting hired for what we’re worth, because it costs employers 30 percent more than just our wages to employ us. The federal tax code both requires and incentivizes our employers to transfer a bunch of what we earned directly to insurance companies and those same Boomer-busted federal benefits, via tax-deductible benefits and payroll taxes. And the regulatory compliance costs of ravenous bureaucratic state. The price paid by each employer to keep each employee continues to rise — but Congress says your boss has to give most of the increase to someone other than you. 

Federal spending programs that many people consider good government, including Social Security, Medicare, Medicaid, and health insurance for children (CHIP) aren’t a small amount of the federal budget. Government spends on these programs because people support and demand them, and because cutting those benefits would be a re-election death sentence. That’s why they call cutting Social Security the “third rail of politics.” If you touch those benefits, you die. Congress is held hostage by Baby Boomers who are running up the bill with no sign of slowing down. 

Young people generally support Social Security and the public health insurance programs, even though a 2021 poll by Nationwide Financial found 47 percent of Millennials agree with the statement “I will not get a dime of the Social Security benefits I have earned.”

In the same survey, Millennials were the most likely of any generation to believe that Social Security benefits should be enough to live on as a sole income, and guessed the retirement age was 52 (it’s 67 for anyone born after 1959 — and that’s likely to rise). Young people are the most likely to see government guarantees as a valid way to live — even though we seem to understand that those promises aren’t guarantees at all.

Healthcare costs tied to an aging population and wonderful-but-expensive growth in medical technologies and medications will balloon over the next few years, and so will the deficits in Boomer benefit programs. Newly developed obesity drugs alone are expected to add $13.6 billion to Medicare spending. By 2030, every single Baby Boomer will be 65, eligible for publicly funded healthcare.

The first Millennial will be eligible to claim Medicare (assuming the program exists and the qualifying age is still 65, both of which are improbable) in 2046. As it happens, that’s also the year that the Boomer benefits programs (which will then be bloated with Gen Xers) and the interest payments we’re incurring to provide those benefits now, are projected to consume 100 percent of federal tax revenue.

Government spending is being transferred to bureaucrats and then to the beneficiaries of government spending who are, in some sense, your diabetic grandma who needs a Medicare-paid dialysis treatment, but in a much more immediate sense, are the insurance companiespharma giants, and hospital corporations who wrote the healthcare legislation. Some percentage of every college graduate’s paycheck buys bullets that get fired at nothing and inflating the private investment portfolios of government contractors, with dubious, wasteful outcomes from the prison-industrial complex to the perpetual war machine.

No bank or nation in the world can lend the kind of money the American government needs to borrow to fulfill its obligations to citizens. Someone will have to bite the bullet. Even some of the co-authors of the current disaster are wrestling with the truth. 

Forget avocado toast and streaming subscriptions. We’re already sensing it, but we haven’t yet seen it. Young people are not well-informed, and often actively misled, about what’s rotten in this economic system. But we are seeing the consequences on store shelves and mortgage contracts and we can sense disaster is coming. We’re about to get stuck with the bill.

Tyler Durden Tue, 03/19/2024 - 20:20

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Student loan borrowers may finally get answers to loan forgiveness issues

A major student loan service company has been invited to face Congress over its alleged servicing failures.

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U.S. Sen. Elizabeth Warren (D-MA) wants answers from one of the top student loan service companies in the country for allegedly botching its student loan forgiveness process involving the federal Public Service Loan Forgiveness program, leaving borrowers confused and without answers.

The senator sent a letter to Mohela CEO Scott Giles on March 18 inviting him to testify before Congress at a hearing on April 10 titled “MOHELA’s Performance as a Student Loan Servicer.” During the hearing, Giles will have to answer for why his company allegedly failed to send billing statements to student loan borrowers in a timely manner and miscalculated monthly payments for borrowers when it was time for them to repay their loans in September last year.

Related: Here's who qualifies for Biden's student loan debt relief starting next month

Also, in the letter, Warren highlighted a report that claimed that Mohela failed to perform basic servicing functions for borrowers eligible for PSLF, which led to over 800,000 public service workers facing delays in receiving student debt relief. The report also accuses the company of using a “‘call deflection’ scheme” to keep customers away from speaking to a customer service representative and instead redirecting them to parts of their website.

“Your company has contributed to student loan borrowers’ difficulties by mishandling borrowers’ return to repayment following the COVID-19 pandemic-related pause on payments, interest, and collections and by impeding public servants’ access to PSLF relief,” wrote Warren in the letter.

The move from Warren comes after the U.S. Department of Education withheld $7.2 million in payments to its servicer Mohela in October as punishment because it failed to issue timely billing statements to 2.5 million borrowers which resulted in 800,000 borrowers becoming delinquent on their loans. The department ordered Mohela to put those affected by the issues into forbearance until the mess was resolved.

U.S. President Joe Biden is joined by Education Secretary Miguel Cardona (L) as he announces new actions to protect borrowers after the Supreme Court struck down his student loan forgiveness plan in the Roosevelt Room at the White House on June 30, 2023 in Washington, DC. 

Chip Somodevilla/Getty Images

Mohela is also currently facing two class-action lawsuits, one filed in December last year and another in January this year, for its alleged “failure to timely process and render decisions for student loan borrowers enrolled in the Public Service Loan Forgiveness program.”

In response to recent criticism surrounding its alleged issues and failures regarding the PSLF program, Mohela claimed in a statement to the Missouri Independent that it “does not have authority to process loan forgiveness until authorization is provided by FSA, which can take months to occur.”

The company also claimed that there are “false accusations” inside of the bombshell report, which was released in February, that details the company’s servicing failures.

“It is unfortunate and irresponsible that information is being spun to create a false narrative in an attempt to mislead the public. False accusations are being disingenuously branded as an investigative report,” said Mohela. 

Related: Amazon just made a major announcement that will bring you big savings — and we have all the details

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International

Bolsonaro Indicted By Brazilian Police For Falsifying Covid-19 Vaccine Records

Bolsonaro Indicted By Brazilian Police For Falsifying Covid-19 Vaccine Records

Federal police in Brazil have indicted former President Jair…

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Bolsonaro Indicted By Brazilian Police For Falsifying Covid-19 Vaccine Records

Federal police in Brazil have indicted former President Jair Bolsonaro for falsifying his Covid-19 vaccine card in order to travel to the United States and elsewhere during the pandemic.

Federal prosecutors will review the indictment and decide whether to pursue the case - which would be the first time the former president has faced criminal charges.

According to the indictment, Bolsonaro ordered a top deputy to obtain falsified Covid-19 vaccine records of himself and his 13-year-old daughter in late 2022, right before he flew to Florida for a three-month stay following his election loss.

Brazilian police are also waiting to hear back from the US DOJ on whether Bolsonaro used said cards to enter the United States, which would open him up to further criminal charges, the NY Times reports.

Bolsonaro has repeatedly claimed not to have received the Covid-19 vaccine, but denies any involvement in a plan to falsify his vaccination records. A previous investigation by Brazil's comptroller general concluded that Bolsonaro's vaccination records were false.

The records show that Bolsonaro, a COVID-19 skeptic who publicly opposed the vaccine, received a dose of the immunizer in a public healthcare center in Sao Paulo in July 2021. [ZH: hilarious, Reuters calling the vaccine an 'immunizer.']

The investigation concluded, however, that the former president had left the city the previous day and didn't leave Brasilia until three days later, according to a statement.

The nurse listed in the records as having applied the vaccine on Bolsonaro denied doing so and was no longer working at the center. The listed vaccine lot was also not available on that date, the comptroller general's office said. -Reuters

"It's a selective investigation. I'm calm, I don't owe anything," Bolsonaro told Reuters. "The world knows that I didn't take the vaccine."

During the pandemic, Bolsonaro panned the vaccine - and instead insisted on alternative treatments such as Ivermectin, which has antiviral properties against Covid-19. For this, he was investigated by Brazil's congress, which recommended that the former president be charged with "crimes against humanity," among other things, for his actions during the pandemic.

In May, Brazilian police raided Bolsonaro's home, confiscating his cell phone and arresting one of his closest aides and two of his security cards in connection to the vaccine record investigation.

Brazil's electoral court ruled that Bolsonaro can't run for public office until 2030 after he suggested that the country's voting system was rigged. For that, he has to sit out the 2026 election.

Tyler Durden Tue, 03/19/2024 - 11:00

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